Scientific Integrity - Text and Cases in Responsible Conduct of Research-Francis L. Macrina

Scientific
Integrity
This page intentionally left blank
Scientific
Integrity
FOURTH EDITION
Text and Cases in Responsible Conduct of Research
Francis L. Macrina
Edward Myers Professor of Dentistry and
Vice President for Research
VCU Philips Institute for Oral Health Research
Virginia Commonwealth University
Richmond, Virginia
Washington, DC
Publisher’s Note: Scientific Integrity: Text and Cases in Responsible Conduct of Research (Fourth Edition) is
intended to serve as a text for courses and workshops on responsible conduct in scientific research. The
text is not meant in any way to serve as a set of guidelines, rules, or statements officially endorsed by the
American Society for Microbiology or any other scientific organization or institution.
The case studies used throughout this text are hypothetical and are not intended to describe any actual
organization or actual person, living or dead. The opinions in the text, express or implied, are those of
the authors and do not represent official policies of the American Society for Microbiology.
Cover Image: Taken in 2009 by a camera onboard the National Aeronautics and Space Administration
(NASA) Hubble Space Telescope, the image is that of a celestial body designated NGC 6302, a
“planetary nebula.” It is more commonly known as the Butterfly Nebula because of its distinct butterfly
shape. Originally, the term planetary nebula had been used to describe objects, viewable with binoculars
or a small telescope, that have a roundish appearance similar to a planet. However, as revealed by larger
telescopes, planetary nebulas are really stars that have ejected much of their mass during a destructive
phase of their evolution that will lead to their demise. The star in NGC 6302 occurs at the juncture
of the two butterfly “wings” and cannot be seen in the photograph because it is shrouded in dust. The
ejected gases and ultraviolet radiation emanating from the dying star create glowing material that defines
the butterfly shape. More information may be found at: http://www.nasa.gov/mission_pages/hubble
/multimedia/ero/erongc6302.html.
The cover image was downloaded from the NASA web site. It is not copyrighted and is considered in
the public domain by that agency. NASA is hereby gratefully acknowledged for its use. NASA’s image use
policy may be found at: http://www.nasa.gov/audience/formedia/features/MP_Photo_Guidelines.html
#.Uzx7svldWCl
Copyright © 2014 American Society for Microbiology. ASM Press is a registered trademark of the
American Society for Microbiology. All rights reserved. No part of this publication may be reproduced
or transmitted in whole or in part or reutilized in any form or by any means, electronic or mechanical,
including photocopying and recording, or by any information storage and retrieval system, without
permission in writing from the publisher.
Disclaimer: To the best of the publisher’s knowledge, this publication provides information concerning
the subject matter covered that is accurate as of the date of publication. The publisher is not providing
legal, medical, or other professional services. Any reference herein to any specific commercial products,
procedures, or services by trade name, trademark, manufacturer, or otherwise does not constitute or
imply endorsement, recommendation, or favored status by the American Society for Microbiology
(ASM). The views and opinions of the author(s) expressed in this publication do not necessarily state or
reflect those of ASM, and they shall not be used to advertise or endorse any product.
Library of Congress Cataloging-in-Publication Data
Macrina, Francis L., author.
Scientific integrity : text and cases in responsible conduct of research / by Francis L. Macrina, Edward
Myers Professor of Dentistry and Vice President for Research, VCU Philips Institute for Oral Health
Research, Virginia Commonwealth University, Richmond, Virginia. —Fourth edition.
pages cm
ISBN 978-1-55581-661-2 (print) —ISBN 978-1-55581-848-7 (electronic) 1. Research—Moral and
ethical aspects. 2. Medical sciences—Research—Moral and ethical aspects. 3. Integrity. I. Title.
Q180.55.M67M33 2014
174.95—dc23
2014017024
doi:10.1128/9781555818487
Printed in the United States of America

10 9 8 7 6 5 4 3 2 1
Address editorial correspondence to: ASM Press, 1752 N St., N.W., Washington, DC 20036-2904, USA.
Send orders to: ASM Press, P.O. Box 605, Herndon, VA 20172, USA.
Phone: 800-546-2416; 703-661-1593. Fax: 703-661-1501.
E-mail: books@asmusa.org
Online: http://www.asmscience.org
For Mary
and
Laurel, Mike, Dylan, and Megan

Frank, Neeley, Lauren, and Nicholas
In memory of
My mentors
John J. Quinn 1931-2009
Elias Balbinder 1926-2011
and
My colleague, and pioneer in research ethics education

Karen M. T. Muskavitch 1953-2009
Contents
Contributors xiii
Foreword xv
Michael J. Zigmond and Beth A. Fischer
Preface xxv
Acknowledgments xxviii
Note to Students and Instructors xxix
A Website Companion for Scientific Integrity: Text and Cases in Responsible Conduct
of Research, Fourth Edition xxxii
chapter 1 Methods, Manners, and the Responsible

Conduct of Research 1
Francis L. Macrina
Overview • Scientific Misconduct • Responsible Conduct of Research •
Conclusion • Discussion Questions • Resources
chapter 2 Ethics and the Scientist 25

Bruce A. Fuchs and Francis L. Macrina
Overview • Ethics and the Scientist • Science as a Profession • Underlying
Philosophical Issues • Utilitarianism • Deontology • Values of the Scientific
Community • Critical Thinking and the Case Study Approach • Moral
Reasoning in the Conduct of Science • Conclusion • Discussion Questions • Case
Studies • Principles and Responsibilities of Research Conduct • Resources
chapter 3 Mentoring 53
Francis L. Macrina
Overview • Characteristics of the Mentor-Trainee Relationship • Choosing a
Mentor • Foundations of Mentoring • Diversity, Research, and Research
Training • Learning Mentoring Skills • Conclusion • Discussion Questions •
Case Studies • Resources
ix
x Contents
chapter 4 Authorship and Peer Review 83

Francis L. Macrina
Scientific Publication and Authorship • The Need for Authorship
Criteria • Instructions for Authors • Authorship: Definitions, Duties, and
Responsibilities • Peer Review • Publication’s Changing Landscape • Conclusion
• Discussion Questions • Case Studies • Resources
chapter 5 Use of Humans in Biomedical Experimentation 135

Paul S. Swerdlow and Francis L. Macrina
Overview • Are You Conducting Human Subjects Research? •The Issue of
Informed Consent • IRBs • The IRB and the Informed Consent Issue •
Research Exempt from the Federal Regulations • The IRB and Expedited
Review • Human Experimentation Involving Special Populations • The Health
Insurance Portability and Accountability Act (HIPAA) • Fetal Tissue and
Embryonic Stem Cell Research • Conclusion • Discussion Questions • Case
Studies • The Declaration of Helsinki • Resources
chapter 6 Use of Animals in Biomedical Experimentation 173

Introduction • Ethical Challenges to the Use of Animals in Research • Practical
Matters: Constraints on the Behavior of Scientists • A Continuum of Realities •
Conclusion • Discussion Questions • Case Studies • Resources
chapter 7 Competing Interests in Research 209

S. Gaylen Bradley
Introduction • Conflict of Effort • Conflict of Conscience • Conflict of Interest •
Managing Competing Interests • Conclusion • Discussion Questions • Case
Studies • Resources
chapter 8 Collaborative Research 243

L. Michelle Bennett and Francis L. Macrina
Overview • Drivers of Collaborative Research • A Case in Point • Challenges
of Collaborative Research • The Nature of Collaboration • Collaborative
Agreements and Institutional Commitment • Fundamentals for Successful
Team and Collaboration Dynamics • Mentoring in the Era of Team Science •
Diversity • Authorship • Data Sharing, Custody, and Ownership • Managing
Conflict and Promoting Disagreement • Collaborations with Industry •
Collaboration with International Partners • Conflict of Interest • Miscellanies •
Conclusion • Discussion Questions • Case Studies • Resources
Contents xi
chapter 9 Research Data and Intellectual Property 287

Thomas D. Mays and Francis L. Macrina
Introduction • Research Data • Rights in Tangible Personal Property • Trade
Secrets • Trademarks • Copyrights • Patents • Patent Law in the Age of
Biotechnology • Seeking a Patent • Conclusion • Discussion Questions • Case
Studies • Authors’ Note • Resources • Glossary
chapter 10 Scientific Record Keeping 329

Francis L. Macrina
Introduction • Why Do We Keep Records? • Defining Data • Data Ownership
• Data Storage and Retention • Tools of the Trade • Laboratory Record-Keeping
Policies • Record-Keeping Practices • Electronic Record Keeping • Conclusion •
Discussion Questions • Case Studies • Resources
chapter 11 Science, Technology, and Society 361

Cindy L. Munro and Francis L. Macrina
Responsibilities of Scientists to Society • rDNA Technology • Genetic
Technology • DURC • Conclusion • Discussion Questions • Resources
appendix I Surveys as a Tool for Training in Scientific Integrity 387

Michael W. Kalichman
appendix II Student Exercises 413
appendix III Standards of Conduct 429
appendix IV Sample Protocols for Human and Animal

Experimentation 445
appendix V Example of a U.S. Patent Specification 489
appendix VI Laboratory Notebook Instructions 503
appendix VII Safe Laboratory Practices Resources 509
Index 517
Contributors
L. Michelle Bennett, Ph.D. Thomas D. Mays, Ph.D., J.D.

Deputy Scientific Director, Division of Intramural Counsel for Intellectual Property
Research Bureau of Competition
National Heart, Lung, and Blood Institute Federal Trade Commission
National Institutes of Health Washington, District of Columbia
Bethesda, Maryland
Cindy L. Munro, Ph.D., R.N., ANP-BC,
S. Gaylen Bradley, Ph.D. FAAN, FAANP, FAAAS
Dean Emeritus, Basic Health Sciences Associate Dean of Research and Innovation,
Virginia Commonwealth University Professor
Richmond, Virginia University of South Florida College of Nursing
Tampa, Florida
Bruce A. Fuchs, Ph.D.
National Institutes of Health Paul S. Swerdlow, M.D.
Bethesda, Maryland Professor of Medicine, Oncology (Hematology/
Oncology) and Pediatrics
Michael W. Kalichman, Ph.D. Wayne State University School of Medicine
Director, Research Ethics Program Detroit, Michigan
& Professor of Pathology
University of California, San Diego
xiii
Foreword
Teaching Responsible Conduct

Responsibly
L ike Frank Macrina, the author of this outstanding textbook, we have

been teaching students, postdoctoral fellows, faculty, and staff about
the responsible conduct of research (RCR) for many years, and we w elcome
the opportunity to share some of what we have learned during that time.
Neither this short essay nor the book itself is a manual on the responsible
conduct of research. You can find such manuals—many professional soci-
eties have them, and federal agencies do, too. And, yes, Dr. Macrina will
introduce you to some rules and regulations, generally agreed-upon stan-
dards, and even some laws. But mostly you will be given the opportunity to
think—to think about what it means to act responsibly.
There are several reasons for focusing on thinking rather than simply
memorizing rules. First, active engagement is critical to promoting real
understanding. Second, acceptable standards often differ with the research
culture and thus can vary with geography, discipline, and department and
even among individual laboratories. Third, important issues are always
evolving. Ask yourself, which issues of significance to research today were
not even considerations a generation ago? Consider, for example, that the
use of Photoshop® to “enhance” a figure, or the cutting and pasting of text
found on the Internet, could not have become issues until those tools be-
came available in the early 1990s. Which other issues have recently
emerged? And what do you imagine will be the issues that will confront
you a decade from now? Will it be the automatic genetic profiling of each
individual at birth? The ability of one person to monitor the thought pro-
cesses of another?
Before you go any further, we invite you to take a moment to make a list
of what you think are the central issues in RCR and then see how we and
Dr. Macrina do. Did we miss some issues you think are important? If so,
xv
xvi Foreword
raise the issues among your colleagues. And write to the author—you may
play an important part in the development of the next edition!
In this brief Foreword we deal with two issues. We begin by consider-
ing how instruction might best be provided. We then analyze some of the
federal and institutional guidelines that have played an important role in
promoting the introduction of RCR training into academic programs,
suggesting that they are an important driving force for ethics education
but also that they in part have led to some of its most serious—and
contentious—problems.
Teaching RCR: how, who, and when?
We all learned at an early age to pay more attention to what people do

than what they say. One of our favorite cartoons is by Edward Argo. It
portrays a young child standing in the corner facing the wall and saying to
his stuffed animal friend, “The same people who told me the stork brought
me are making me stand here for lying.” You can substitute your own
favorite example of the discrepancy between words and actions in lecture
halls and the workplace. This is why the “how” of RCR instruction is so
much more important than the precise details of what is included in the
curriculum.
How to teach? The most common approach for teaching most things, in-
cluding RCR, is by lecturing. And certainly that can be a useful method for
delivering large amounts of material to sizeable groups of individuals. But
all too often lectures quickly devolve into an exercise in dictation, providing
little opportunity for engagement with the material and real learning.
Should this be pointed out to an instructor, the response is often “I can’t
take time for discussion, there is just too much to teach!” We, too, have been
guilty of this mindset, forgetting the extensive research indicating that little
of the material delivered in a purely lecture format is retained.
There are many other problems with that approach, as well: the instruc-
tor may not be sufficiently knowledgeable in the subject matter or skilled
in the art of teaching; the composition of the class may be highly heteroge-
neous and thus not amenable to a “one size fits all” approach; the material
may be presented out of context and, thus, its significance may be difficult
to grasp or even undermined. Lecturing is not an effective way of teaching
anything, let alone research ethics. We describe an alternative approach
below.
Who should teach? The topic of ethics immediately brings philosophers
to mind, and indeed philosophers can play a valuable role in promoting
research ethics. They can help both teachers and trainees to understand
ways of thinking about ethical problems. But we do not believe that philos-
ophers are effective as the primary instructors of courses on this critical
Foreword xvii
subject. For this, one needs people with experience in the practice of re-
search, or at least individuals working in a partnership with active research-
ers. And these RCR instructors must treat their task as they would a
research project: by thinking deeply about the subject matter, reading the
literature, seeking advice from others, developing and testing hypotheses
about what will be effective, and finally getting feedback on their own per-
formance as well as the impact they are having on their trainees.
Instruction that does not involve active researchers is unacceptable for
at least two reasons. First, the message provided by courses that do not
involve investigators is that such individuals either do not know enough
about RCR to teach it, or that they do not feel it is worth their time to do
so. Second, non-scientists can be dangerously out of touch with the every-
day reality of practitioners. For example, we have heard instructors say that
all authors of any research paper must have reviewed all of the data and be
able to explain all of the methods used. In theory this sounds entirely rea-
sonable. But a moment’s thought will make clear that such a rule is incon-
sistent with the complex, collaborative, and interdisciplinary nature of
most of today’s research.
In addition to those who direct formal courses in RCR, research group
directors are another critical component of the instruction. Whatever their
intention when they accepted jobs at educational institutions, all too often
these individuals come to view the members of their teams largely as re-
search assistants. Thus, anything that takes their lab members out of the lab
is a distraction from the task at hand, and RCR training often tops the list of
those “distractions.” We understand this; advancement in academia is typi-
cally based on research productivity, not on mentoring. Yet, it goes without
saying (though we will say it), that irresponsible research can never be good re-
search. Research that involves cutting corners or using erroneous statistical
tests, not to mention intentionally manipulating data, may be at the heart of
many failures to replicate published studies that have recently been a focus
of much discussion in both the professional and the lay literature (see, for
example, references 1 and 2). Moreover, whereas courses on RCR—when
they are offered—may involve less than a dozen hours of instruction, often
at the outset of a training program, research advisors influence members of
their groups for thousands of hours over many years. And as we have already
implied, it is the example set by research directors and others in the aca-
demic environment that really counts. Moreover, it is not only the trainees
that they influence, it is all members of their research group.
This brings us to the overriding issue of “climate.” As one would expect,
a corollary of the importance of setting a good example is that the climate
in which research is done has a significant impact. Some 20 years ago, Me-
lissa Anderson, Karen Louis, and Judith Swazey set out to study this topic
as part of the Acadia Institute’s Project on Professional Values and Ethical
xviii Foreword
Issues in the Graduate Education of Scientists and Engineers. They found

that graduate students who were socialized in departments in which the
culture was more “caring” (e.g., one that promoted collaboration versus
competition among individuals in a laboratory and was made up largely of
faculty who showed an active interest in the career development of their
students) reported witnessing fewer incidents of misconduct than did stu-
dents in less caring environments (3). Studies conducted since then con-
tinue to echo those findings (e.g., references 4 and 5).
When should instruction occur? As we have noted, instruction in RCR is
typically provided as brief, required workshops or courses taken at the very
beginning of a training program. The participants in such courses are usu-
ally limited to graduate students, though sometimes postdocs are expected
to attend as well. And the impact of the course on participants is typically
either not evaluated or is done so through a short essay. There is nothing
good about this approach; indeed, it is destructive. The message is obvious:
“This is something we unfortunately must require you to do, so let’s get it
over with as quickly as we can, and then we can move on to the important
things.” Consider a very different model:
1. Upon arrival at an institution, all individuals— be they students,
postdocs, faculty, staff, or administrators—are introduced to the im-
portance of RCR, their own role in ensuring that it occurs, and some
of the major issues. (Time: 1 to 2 hours.)
2. Next, all individuals involved in the research enterprise engage in a
weekly seminar in which some of the key topics are explored during
discussions that are facilitated primarily by active researchers and are
usually focused on specific cases. (Time: 1 hour  8 to 12 sessions.)
3. At the same time, RCR appears in the core curriculum. When an
instructor discusses an issue of basic science, he or she might raise
issues of fabrication or falsification of data, perhaps by discussing a
real case in which that occurred. Likewise, when describing a clinical
condition, the class might discuss the role of informed consent or
genetic counseling. (Time: 15 minutes every couple of weeks in every
course, totaling 12 hours in a curriculum involving 6 courses.)
4. Finally, we move into our workspaces, be they a lab, faculty, or admin-
istrative meeting. The role of instructor now gradually shifts to the
trainee, staff member, faculty member, or administrator. Ethics cases
of direct relevance to the tasks at hand continue to be discussed, with
the cases constructed and/or led by different members of the group.
(Time: 1 hour  2 to 3 sessions per year for the duration of an indi-
vidual’s involvement in that unit, say a total of 10 hours over 5 years.)
Now, add it up: It comes to at least 30 hours over 5 years. “Are you kid-
ding?” we hear the faculty saying. “I only get 2 hours to teach my students
Foreword xix
about RNA editing or the Nernst equation or [fill in the blank], and you
want me to spend 30 hours talking about ethics?!” But teaching about a
specific topic in biology, math, or virtually any other discipline is not the
right analogy. In fact, no one content area provides the right comparison,
for what we must ultimately achieve through RCR education is the devel-
opment of a complex skill: that of being able to reason through an ethical
issue, one that often does not even have a “right” answer.
A far better exercise is to compare approaches for teaching RCR with the
way in which we teach our trainees how to critically evaluate the scientific
literature in their area of research. This is not accomplished in a 1-hour or
even an 8-hour block. We begin by introducing the trainees to some of the
basic concepts of the field. Next we have them participate in “journal
clubs”—in-depth, small group discussions of an individual paper, simple pa-
pers at first, and then increasingly complex ones. The papers are presented,
and the discussions led, by the trainees themselves. From there we move on
to discussions of papers within the research group or even in one-on-one
discussions between the lab director and a specific trainee. And these train-
ees soon begin to write their own papers, for which they must read and
evaluate the literature. Finally, in the case of graduate students, we challenge
them in preliminary exams, comprehensive exams, seminar proposal meet-
ings, and the dissertation defense—all the time probing their understanding
of the literature and their ability to justify their conclusions. As for postdocs,
staff, and faculty, they get challenged, too. It happens each time they make a
presentation. Yes, this process does involve learning some content—the
proper organization of a paper, how to select the right statistical test, the
importance of citing conflicts of interest. But mostly it involves the ability to
critically analyze and then defend a position. Total time? Incalculable. Is do-
ing research responsibly really not as important as being able to critically
evaluate the literature and then defend your position?
The Role of Federal and Institutional

Guidelines
The U.S. Federal guidelines on RCR training have played a critical part in
the establishment of RCR programs. Before the National Institutes of
Health (NIH) issued such guidelines, few training programs included ex-
plicit instruction in research ethics. Thus, the NIH guidelines have had a
very positive impact by promoting RCR instruction for researchers. Yet,
those same guidelines also have had the unintended effect of undermining
the perceived importance of RCR, by turning what should—and can—be a
valuable learning experience into one viewed as an exercise simply de-
signed to ensure that a limited population meets a bureaucratic require-
ment delivered in isolation from the research enterprise.
xx Foreword
Federal guidelines
Federal guidelines vary by agency, though it is not clear why this should
be. Why, for example, does the U.S. National Science Foundation (NSF)
insist that any institution that receives NSF funding have an institution
wide program of RCR training, whereas the NIH requires RCR training
only for individuals supported by training and career awards? Other agen-
cies have their own idiosyncrasies.
The NIH guidelines relating to RCR instruction appeared in 1989, and
most training programs quickly learned that they were required to provide
instruction in research ethics to at least a subset of their trainees. Since
those initial guidelines, the NIH description of an acceptable RCR pro-
gram has gradually evolved. Their most recent recommendations on how
to fulfill their requirement for providing instruction in RCR (6) include an
excellent set of “Basic Principles” that deserve to be read carefully as they
include many of the key characteristics that we believe are critical to devel-
oping a good program.
The guidelines require that active researchers be involved in providing
the instruction, and they specify a minimum number of hours of face-to-
face instruction. But otherwise, they are not overly prescriptive. For ex-
ample, the method of instruction is left open (except that online training
does not count toward the required number of hours of face-to-face in-
struction). Moreover, NIH does not dictate the topics that must be ad-
dressed, but instead suggests nine content areas that “have been incorporated
into most acceptable plans for such instruction.” Theirs is a fine list, though
vague in regard to the scope of some topics. In particular, “research mis-
conduct” is listed but never defined within the guidelines. But its major
failing is in its definition of who must receive instruction: “individuals sup-
ported by any NIH training, research, education, fellowship, or career
award” (6). This, of course, overlooks the great majority of graduate stu-
dents and postdocs, both because the number of such NIH-supported po-
sitions is limited and because a great many trainees are not even eligible
for those positions by virtue of their citizenship. It also omits staff, faculty,
and administrators involved in the research endeavor.
In their 2009 guidelines, the NSF provided much less direction on the
content of RCR training. They also indicated that “training plans are not
required to be included in proposals submitted to NSF,” although they
added “institutions are advised that they [the plans] are subject to review,
upon request.” And most relevant to us, NSF specifies that the “institution
must have a plan in place to provide appropriate training and oversight in
the responsible and ethical conduct of research to undergraduates, graduate
students, and postdoctoral researchers who will be supported by NSF to con-
duct research” (italics added) (7). Staff, faculty, and administrators are not
Foreword xxi
mentioned. Nor does NSF indicate the acceptability of exclusively relying

on online instruction to meet their requirements.
Clearly, what is needed is a federal requirement—better yet, the readi-
ness of institutions to establish programs without such a requirement—that
merges these two statements and goes even further, implementing meaning-
ful RCR training for everyone connected to the research enterprise. This
was, in fact, recommended by the Commission on Research Integrity (CRI)
established by then U.S. Secretary of Health and Human Services Donna
Shalala in 1993 at the request of the U.S. Congress. The Commission was
chaired by Kenneth Ryan and it issued its report, “Integrity and Misconduct
in Research,” in 1995 (8). The 105-page document (including appendices
and references) is worth reading even almost 20 years later. One recommen-
dation deserves particular attention. Under the heading “Providing Educa-
tion in the Responsible Conduct of Research” the report states:
“The Commission believes that, on balance, [required education in research
integrity] should be more broadly implemented to ensure that, through such
training, all individuals who perform research in institutional settings are sensi-
tized to the ethical issues inherent in research. At present, the training is required
only of recipients of institutional training grants, and does not reach all
graduate, professional, and postdoctoral students or more senior researchers
and other members of research groups, such as technicians. The Commis-
sion strongly believes that all of these individuals would benefit from partic-
ipation. Providing such training is an important step toward creating a
positive research environment that stresses the achievement of research in-
tegrity more than the avoidance of research misconduct.” (Italics added.) (8)
The role of professional societies and research institutions

Soon after the release of the Ryan report, the Federation of American Soci-
eties of Experimental Biology (FASEB) held a meeting attended by repre-
sentatives from a large number of scientific societies to discuss the
recommendations, which one of us attended (M.J.Z.). A major focus was the
definition of misconduct and the topic of who should be trained. Our mem-
ory of the event is somewhat clouded by the passage of time, but the tenor
of that discussion remains clear: the group was unambiguous in their criti-
cism of the suggestion by Dr. Ryan (who was in attendance) and his Com-
mission that such an “unfunded mandate” be put in place. A few years later,
in a letter sent to the director of the Office of Research Integrity in 2000,
Mary Hendrix, then the president of FASEB, wrote: “Students and trainees
must have instruction in the responsible conduct of research. . . But the ex-
tension of this requirement to ‘all staff,’ including subcontractors and con-
sultants, will result in an enormous involvement of time and resources.” (9)
The issue of “unfunded mandates” has recurred in other discussions of
the Ryan report’s recommendation about RCR training. For example, in a
xxii Foreword
2009 letter to NSF, Richard Marchase, then the president of FASEB, wrote
in regard to NSF’s new guidelines: “Even with access to educational mate-
rials, the implementation and administration of new training programs is
not without cost. NSF should explore ways to fund these efforts so that
additional training requirements do not burden institutions with new, un-
funded mandates” (10). And, now 20 years after the Ryan Commission re-
port was issued, the recommendation of universal training in RCR—which
we wholeheartedly endorse—has not been made part of federal policy.
We recognize the many obligations shouldered by research institutions
as well as professional societies. However, we also believe that providing
training in RCR to everyone involved in the research enterprise is at the
very core of ensuring that all research is done responsibly. That should not
require any federal mandate, funded or not. Yes, institutions are burdened
with an enormous number of requirements. They must ensure the value of
the degrees they award by overseeing the curriculum and the process of
certification. They must ensure fiscal responsibility. They are responsible
for fulfilling the requirements for human and laboratory animal research
and for laboratory safety. And that is just the beginning of the list. Thus, it
is not surprising that many institutions view training in RCR as yet an-
other requirement they need to check off, and that they often do only as
much as they deem necessary to fulfill the requirement. However, research
institutions should never define themselves in terms of the minimum
needed to get by. Fulfilling the mandate to provide training in RCR cannot
not be viewed as an end but as a means—a means to ensure the highest
level of scholarship.
A Final Thought: How the Behavior

of an Individual Can Ripple Across
the Scientific Enterprise
There are many reasons to do everything that can be done to promote re-
sponsible research. Here we focus on one: the essential nature of trust and
the cost of failing to meet that trust. The advancement of science requires
trust—trust in the literature, in our collaborators, in the data we are
handed, and most of all in ourselves. Each of us must know when to ignore
an observation we make, when to repeat it, how to determine its signifi-
cance, and when to publish. Observations in science sometimes come from
an individual working on his or her own with little knowledge of what
came before. But observations do not become advancements until others
learn about them and are able to take them seriously, at least seriously
enough to try to replicate them or to examine a corollary.
How much does a story in the media about research misconduct cost?
Nothing? Wrong. It costs millions, maybe billions, of dollars. It leads indi-
viduals to stop contributing to foundations that support research. It leads
Foreword xxiii
voters to write their government representatives to tell them not to fund

NSF or NIH. And it leads legislators to decide on their own that funding
for research should be curtailed. Misconduct in science creates a breach of
trust that threatens the viability of the research enterprise. It puts financial
resources at risk and undermines the public’s trust in research findings.
Perhaps worst of all, it can lead to students deciding that research is not for
them.
The textbook you are about to enter is a tool—an extraordinarily valu-
able tool—to be used to foster responsible behavior. But, like any tool, it
must be used in an educated manner in combination with other resources,
including you. That is, it must be used responsibly. We wish you well.
Michael J. Zigmond and Beth A. Fischer
Pittsburgh, Pennsylvania
References
1. Moonesinghe R, Khoury MJ, Janssens AC. 2007. Most published

research findings are false—but a little replication goes a long way.
PLoS Med 4(2):e28.
2. Anonymous. 2013. The trouble with scientific research; how sci-
ence goes wrong. The Economist October 19, 2013.
3. Anderson MS, Louis KS, Earle J. 1994. Disciplinary and depart-
mental effects on observations of faculty and graduate student mis-
conduct. Special Issue: Perspectives on Research Misconduct
(May–Jun 1994). J Higher Ed 65(No. 3):331–350.
4. Martinson BC, Anderson MS, Crain AL, de Vries R. 2006. Scien-
tists’ perceptions of organizational justice and self-reported mis
behaviors. J Empir Res Hum Res Ethics 1:51–66.
5. Crain AL, Martinson BC, Thrush CR. 2013. Development and
validation of the Survey of Organizational Research Climate
(SORC). Sci Engineering Ethics 19:813–834.
6. National Institutes of Health. 2009. Update on the requirement for
instruction in the responsible conduct of research. grants.nih.gov/grants
/guide/notice-files/NOT-OD-10-019.html
7. National Science Foundation. 2010. Award and administration guide-
lines. www.nsf.gov/pubs/policydocs/pappguide/nsf10_1/aag_4.jsp.
8. Ryan KA; committee members. 1995. Integrity and Misconduct in
Research; Report of the Commission on Research Integrity. 1996-746-425.
U.S. Government Printing Office, Washington, DC.
9. FASEB. 2000. FASEB supports goal of ORI training guidelines but
strongly criticizes its approach. FASEB News, August 11, 2000.
10. Marchase RB. 2009. Untitled letter to Ms. Jean Feldman, April 7,
2009. Available through www.faseb.org.
Preface
T he first edition of Scientific Integrity: Text and Cases in Responsible Con-

duct of Research was published in 1995. The second and third edi-
tions each grew in length by approximately 20%, reflecting expansion in
both scope and content. The Fourth Edition continues in this pattern. It
is almost 30% larger than the Third Edition, and the addition of new and
revised content arguably exceeds that of the second and third editions
combined. The growth of the Fourth Edition has been driven by signifi-
cant changes in the field of responsible research conduct. These changes
have been evident in mandates, policies, laws, and other developments
that continue to change the research landscape. Being aware of and un-
derstanding such change are critical elements needed to conduct research
responsibly. Accountability and compliance as components of research
conduct are essential to earning the trust of the public who, directly or
indirectly, provide the resources for doing research that takes place in
universities, research institutes, and other institutions in the not-for-
profit sector.
Updated or new content may be found throughout this edition of the
text, as noted in the following selected examples. Institutions, scientific so-
cieties, academies, and international organizations have published values
that are expected to be held by researchers. And, the global research com-
munity has begun to articulate the values that undergird responsible re-
search. Scientific organizations, societies, and institutions continue to
develop guidance, recommendations, and tools that aim to increase the
effectiveness of the mentor-trainee relationship. Authorship, peer review,
and publication practices comprise a dynamic arena influenced by the
open access movement, public access to federal grant-supported publica-
tions, postpublication review, and refined guidelines that speak to the
xxv
xxvi Preface
responsibility and accountability of authorship. A significant revision of

the federal policies and practices that are required for the use of animals in
research has been published and enacted. A new federal conflict of interest
policy for researchers has been implemented, and new developments in
the assignment of intellectual property have been defined by a ruling of
the U.S. Supreme Court. Data sharing has been more specifically ad-
dressed by federal funding agencies, and the scientific record-keeping field
continues to evolve in response to electronic technologies.
All of the Fourth Edition chapters have been updated and revised, and
two in particular have undergone major rewrites. “Collaborative Research”
(chapter 8) now reflects new developments and practices found in a grow-
ing body of literature that provides guidance on collaboration, interdisci-
plinary research, and team science. I was pleased to work with Michelle
Bennett who coauthored this chapter with me. The last chapter in the text,
now titled “Science, Technology, and Society,” replaces a chapter that ap-
peared in the first three editions titled “Genetic Technology and Scientific
Integrity.” My coauthor, Cindy Munro, and I used the Third Edition chap-
ter as a basis to create the “Science, Technology and Society” chapter in
this volume. Using both historical perspective and contemporary issues,
we aimed to stimulate thinking on scientific research and the ways it con-
nects with and impacts on society. In doing so, we hope to encourage sci-
entists to think deeply about the societal responsibilities of their research
and its applications.
As with previous editions, the content of the book is augmented by the
inclusion of interactive exercises like short case studies, survey tools, and a
play-acting scenario that explores authorship credit. Approximately 35%
of the end-of-chapter cases are new or significantly revised. Appendixes III
(standards of conduct) and IV (subjects protections protocols) contain new,
updated documents, and Appendix VII is new to the book. This appendix
presents resources relevant to safe laboratory practices.
Although the Fourth Edition of Scientific Integrity: Text and Cases in Re-
sponsible Conduct of Research covers a variety of topics related to the conduct
of scientific investigation, it is not a rulebook for the researcher or trainee.
Guidelines and policies, standards, and codes are presented and discussed
so that readers will be aware that many of the relevant issues are influenced
by both written policies and normative standards. Yet, the values of the
individual take on major importance in doing scientific research. Scientists
continually make judgments and decisions about their research. Whether
the issue is the timely release of experimental materials to a colleague or
decisions about authorship on a manuscript, personal and professional
standards and values come into play. Thus, definitive, unambiguous advice
on dealing with these and other issues cannot be taught in textbooks. To be
sure, this book provides relevant content material on responsible research
Preface xxvii
conduct. But equally important, it provides tools to apply that knowledge.

This book will challenge you to solve ethical research dilemmas in a vari-
ety of ways, most notably with case scenarios. Contemplation and informed
analysis become the platform for learning in this setting. To echo the
words of Michael Zigmond and Beth Fischer in the foreword, the ultimate
aim of this book is to provide the opportunity to think: “to think about
what it means to act responsibly.” The tools in this text provide material
for such use in many of the venues and contexts found in the educational
model that Zigmond and Fischer propose. In its case dilemmas, discussion
questions, and other exercises, the book provides tools for challenging stu-
dents at various points in their training programs. I have used such mate-
rial in developing questions for both written and oral comprehensive
exams and for dissertation defenses. Integrating the concepts of respon-
sible conduct of research into our training infrastructure sends the mes-
sage that learning RCR subject matter and mastering its use in solving
problems is a critical part of continuing professional development.
The Fourth Edition of Scientific Integrity: Text and Cases in Responsible
Conduct of Research aims to plant the seeds of awareness of existing, chang-
ing, and emerging standards in scientific conduct. Likewise, it provides the
tools to promote critical thinking in the use of that information. My hope
is that the book will set the stage for lifelong learning in responsible re-
search conduct.
Francis L. Macrina
Richmond, Virginia
Acknowledgments
A ssistance in preparing this updated edition came in many forms and

from many people. An inventory of help included providing case
studies or ideas for case studies, consultation and insightful conversations,
manuscript review and editing, content ideas, provision of assorted in-
structional materials, and various and sundry assistance with manuscript
production. For such contributions I thank: Wayne Barbee, Mark Bates,
Lisa Ballance, John Blake, Alan Boehm, Al Chakrabarty, Amy Chuang,
John Clore, Ponjola Coney, Daniel Conrad, Linda Costanzo, Richard
Costanzo, Wu Deng, Janie Drinkard, Paul Fawcett, David Fenstermacher,
Patty Gerber, Mary Jo Grap, Phil Hylemon, J. David Jentsch, Lindsay
Kondo, Kenneth Kendler, Susan Kimbrough, Todd Kitten, Jane Lalich,
Crystal Lantz, Joel Levine, Marston Linehan, Sahar Lotfi-Emran, Monika
Markowitz, Charles McCarthy, Melissa McGinn, Ivelina Metcheva, Cindy
Munro, Peter Nguyen, Ann Nichols-Casebolt, Susan Robb, Chet Scerra,
Jessica Venable, Enid Virago, Stacy Voils, and James Ward. Special ac-
knowledgement and thanks go to Michelle Stickler and Allen Morris who
provided critical reviews and updating ideas for some of the chapters. I
thank my colleague Andrekia Branch who, as usual, provided essential as-
sistance in the production of the manuscript and the book’s companion
website. Finally, I thankfully acknowledge Christine Charlip, Director,
ASM Press, for her patience, guidance, and encouragement throughout
this project. I am especially pleased to thank Ellie Tupper, Senior Produc-
tion Editor at ASM Press, and to celebrate her expert contributions in the
production of all four editions of Scientific Integrity.
xxviii
Note to Students
and Instructors
T his text contains multiple means to facilitate learning by applying

knowledge to solve problems or ethical challenges in the field of re-
sponsible conduct of research (RCR).
Each chapter contains discussion questions at the end of the textual ma-
terial. These are designed for in-class discussion, or they may be used as
the basis for writing assignments. Each question is open-ended and seeks
to provoke thought based on what has been discussed in the body of the
chapter.
Many of the topics covered in teaching scientific integrity lend them-
selves to the case study approach. Except for chapters 1 and 11, at the end
of each chapter you will find 10 short cases designed for classroom discus-
sion. These cases allow students to solve realistic problems encountered in
scientific research, using their knowledge of responsible conduct issues
coupled with their critical thinking skills.
Appendix I comprises a collection of brief surveys that probe attitudes
and knowledge about core areas of RCR. These surveys may be used as
instructional tools by having students in RCR courses complete them, fol-
lowed by the presentation of the compiled results in class. This can be or-
chestrated by the instructor or the students. Presentation of such results,
especially response patterns that show a difference of opinion on an issue,
serves as a catalyst to promote classroom discussion with an eye toward
exploring knowledge and attitudes about topic areas in research conduct.
Appendix II contains complex case-type scenarios that may be discussed
in class or written about. Their complexity often demands some research
to formulate solutions or answers to questions posed.
Appendix II also contains a dramatic script that provides an opportunity
for students to role- play a scenario about authorship in science. It is
xxix
xxx Note to Students and Instructors
designed for use with anywhere from a few to 11 students. Students are
given scripted lines to recite and then must use ad lib presentation to make
their case for (or against) authorship on a proposed manuscript.
How To Use End-of-Chapter Case Studies
The end-of-chapter short cases are designed for classroom use. These
short scenarios are 200 to 400 words and can be read aloud in a few min-
utes. Most of the cases in this book have been used in our courses. Students
are assigned two to three cases from which they select one to present for
discussion to a small group of classmates.
Assigning a case set in advance of the class provides students with the
opportunity to think about their arguments and to have time to do re-
search or to seek consultation on the topic. For example, a student might
want to consult relevant guideline or policy documents. Although many
cases do not require research, they may not work as well if the student has
not been at least indirectly exposed to the research environment. In the
student evaluations of our courses, we have asked what factors were im-
portant in the selection of cases for discussion. Student responses indicate
that two of the most important features are (i) the belief that the case
would promote lively classroom discussion and (ii) the fact that the case
had some personal appeal. That is, students frequently picked cases about
which they had some background knowledge or personal experience.
A student leading the discussion of the case begins by reading it aloud in
class. He or she then acts as the moderator for the rest of the discussion of
the particular case. Discussion of cases is aided by a seating arrangement
that allows everyone in the classroom to see one another (e.g., seating
around a conference table or arranging chairs into a circle or semicircle).
Typical classroom seating arrangements with students facing the front of
the room make it difficult for everyone to see who’s talking, and this incon-
venience can dampen group participation. Case discussions work optimally
in small classrooms, with no more than 10 to 12 students. A typical case
discussion will take 15 to 20 minutes.
Student participation is very important in the process. The instructor—
who is present during the discussion—should serve only as a facilitator,
contributing when clarification is needed, when discussion bogs down, or
when closure on a case is needed. After reading the case, the student pres-
ents his or her impressions, identifying the issues and suggesting a possible
solution. The classroom is then open to discussion, and the students air
their views on the topic without more than one person talking at once.
The instructor or student moderator may have to act as a peacekeeper.
Sometimes disputes arise and discussions can become animated, even
Note to Students and Instructors xxxi
intense. However, dialogue should never be allowed to become insulting

or inappropriate or to include ad hominem comments.
Short cases are designed to encourage the discussants to think critically
as they analyze and solve the problem at hand. For many cases, this will
mean dissecting the facts of the case and separating the relevant issues
from the non-relevant ones. Cases will evoke uncertainties and ambigu-
ities. Sometimes the discussion will begin by students asking questions
about the case. If something needs clarification or explanation, it should be
provided by the student discussant or by the instructor, when needed. It is
appropriate for the case leader to make assumptions about the scenario in
order to keep discussion moving towards closure.
One of the principal features of the cases is that they allow discussants
to apply their knowledge and personal standards to problems encountered
in doing scientific research. Discussion should lead to one or more accept-
able solutions to the problem. This is important to remember in bringing
cases to closure. Much of the time a consensus answer will not emerge.
There may be several acceptable solutions. In proposing solutions, discus-
sants should always be able to arrive at a position that can be defended. A
solution is valid as long as it is legal and does not violate what the discus-
sants view as acceptable norms and standards, written or otherwise.
The case reader should evaluate the quality and quantity of the class
discussion and bring the case to closure at the appropriate time. Summa-
rizing the discussion helps to do this. Any opposing points of view should
be adequately represented in the summary. Occasionally, there may be stu-
dents who are uncomfortable with the outcomes reached. If this happens,
the instructor should encourage continued discussion outside of the class-
room with him or her, or with the student’s mentor.
In summary, case discussion should foster critical thinking as the discus-
sants examine and apply their personal and professional values. The pro-
cess is one of self-discovery as students formulate answers based on their
values and knowledge of professional standards and practices.
We b s i t e
A Website Companion for Scientific

Integrity: Text and Cases in Responsible
Conduct of Research, Fourth Edition
This website, created and maintained by the author, may be accessed at:
www.scientificintegrity.net
The site is arranged into sections that correspond to the textbook chap-
ters. It features:
• All of the URLs cited in the text, allowing easy user access to online
resources;
• URLs to supplemental materials in all of the chapter topic areas
• Updates on policies and regulations pertaining to research conduct
and RCR education
• PDF files of each of the surveys contained in Appendix I, which can
be printed for classroom use by students and instructors
• Short case discussions providing exemplars that will inform future
case discussants about the scope and depth of the analysis of selected
scenarios.
The website does not require user registration and is not password
protected.
xxxii
chapter 1
Methods, Manners, and the

Responsible Conduct of Research
Overview • Scientific Misconduct • Responsible Conduct of Research
• Conclusion • Discussion Questions • Resources
Overview
W hat do we mean by “integrity in science”? The word “integrity”

raises images of wholeness and soundness, even perfection. Science
is a process we use to gain new knowledge about and understanding of the
world around us. Dictionaries often refer to this process as systematic and
exact, but the workings of science frequently defy that description. As we’ll
discuss below, the well-taught scientific method is not always recognizable
in reality. If not held as the ideal by scientists, certainly the perception of
the public is that science is systematic and exact: data are collected objec-
tively and tested empirically. Science as a process is iterative. Over time,
new facts, ideas, and interpretations resulting from continuing investiga-
tion augment our knowledge and understanding. On the other hand,
sometimes they lead us to reinterpret or even discard as invalid our under-
standing of what we are studying. Either way, who would argue with the
notion that for science to provide an understanding of nature and the
physical world, the utmost integrity must be woven into both its experi-
mentation and its interpretations?
Today, “integrity in science,” “integrity in research,” and similar phrase-
ology have made their way into the lexicons of scientists, politicians, news
reporters, and others. Integrity is expected, because science is built upon a
foundation of trust and honesty. Long before federal agencies published
definitions of scientific misconduct, it was obvious that lying, cheating, and
stealing in the conduct of research were wrong. We are astonished and
Scientific Integrity: Text and Cases in Responsible Conduct of Research, 4th ed.
by Francis L. Macrina
© 2014 ASM Press, Washington, DC
doi:10.1128/9781555818487.ch1
1
2 Chapter 1
incredulous when a scientist admits to falsifying or fabricating research

results. Data must be repeatable. Important findings will be checked, and
cheating will inevitably be uncovered. Performing experiments, collecting
data, and interpreting their meaning constitute a system of auditing often
described as the self-correcting nature of science. Fabricated or falsified
results cannot escape this process unnoticed.
In recent times, stories about scientific misconduct allegations, investi-
gations, and convictions have appeared with disconcerting frequency in
the news sections of interdisciplinary journals like Science and Nature. The
same holds true for the general print and electronic news media. Books on
scientific misconduct appear regularly, addressing specific cases or collec-
tions of cases. The cases are not limited to any one scientific discipline, and
their incidence has been reported worldwide.
Are increasing numbers of scientists acting unethically and dishonestly?
Can it be profitable to fabricate or falsify results? Has the competitive na-
ture of scientific research placed pressures on scientists that lead to mis-
conduct? Before addressing the issues prompted by such questions, let’s
talk some about doing research and about researchers.
Perceptions of scientists and science

Understanding, as best we can, how scientists do research is critical to ap-
preciating the differences between acceptable scientific conduct and scien-
tific misconduct. Science, after all, is the work of humans, and humans are
fallible, impressionable, impulsive, and subjective. They can fall prey to
self-deception, rationalizing their actions in ways that mislead themselves
and others. The term “sloppy science” is frequently used to describe some
behaviors, but the distinction between sloppy science and scientific mis-
conduct can be nebulous. Those seeking clear-cut answers commonly in-
voke the idea of deliberate deception as the defining element in misconduct.
But proving that someone made a conscious decision to falsify or fabricate
data or to steal another’s ideas can be extremely difficult, if not impossible.
Nevertheless, each year we find government publications and websites re-
porting annual summaries of closed research misconduct cases where guilt
was established from the evidence or admitted to by the accused.
In these times, both scientists and the public have a heightened aware-
ness of the accountability that goes with doing research. Scientists, admin-
istrators, funding agencies, and advocacy groups regularly speak of earning
and keeping the public trust when it comes to publicly supported research.
News coverage of allegations of or convictions for misconduct in science
or related transgressions erodes the confidence that the public has in re-
search as an activity that benefits society. This undercuts the public’s re-
gard for science as the definitive vehicle for uncovering truth. The public
often becomes confused when scientists disagree with one another. They
Methods, Manners, and the Responsible Conduct of Research 3
cannot understand how scientific facts can be disputed. Yet definitions of

scientific misconduct frequently affirm that scientists will have “honest dif-
ferences in interpretations or judgments of data” and that “honest error” in
science does occur. In advertising, for example, there seems to be no
greater virtue than the claim that a product was “scientifically tested” or,
better yet, “scientifically proven to achieve results.” The public finds the
idea of “scientific truth” an attractive one. After all, when we consider the
research that occurs in universities, research institutes, government labs,
and other places, the public is paying the bills with its tax and philanthropic
dollars. And the people want their money’s worth! The public has difficulty
understanding that the scientific method can generate erroneous results
and propagate incorrect interpretations. An even tougher sell is the notion
that these very things are built into how science works. Sometimes making
mistakes and learning from them can catalyze and accelerate discovery.
When new facts prompt scientists to change their previous interpreta-
tions and conclusions, the effect on the public is disquieting. The public
may fail to appreciate that the basis of sound scientific decision making is
often linked to hypothesis nullification in using the scientific method. This
usually unfolds as part of the iterative nature of the investigative process
and may involve further work by the scientist who initially proposed the
hypothesis or by others. The iterative nature of scientific investigation and
the concomitant evolution of our understanding of an observation can be
illustrated by sampling headlines about scientific discovery. Tracking news-
paper headlines associated with the effects of oat bran consumption on
cardiovascular health illustrates this point.
In 1986, typical headlines referred to oat bran as the “next miracle
food,” and the public was advised to “know your oats.” Then, in the early
1990s, some headlines declared, “Oat bran claims weakened,” or they spoke
of the “rise and fall of oat bran.” But as that decade progressed, so did our
understanding of eating oat bran and its implications for cardiovascular
health. Results of further work began to convince the scientific community
that regular consumption of oat bran has positive effects. We learned that
the soluble fiber in oat bran absorbs bile salts in the intestinal tract, exert-
ing an effect on cholesterol homeostasis and probably lowering cholesterol
blood levels. From this comes the reasonable expectation of decreased ath-
erosclerotic plaque formation in blood vessels—a clear benefit to cardio-
vascular health. And so the headlines once again changed, reporting that
“Oat bran study says cholesterol lowered” and “Lots of oat bran found to
cut cholesterol.” One headline reflected the frustration the public must
have felt: “Confused about oat bran?” But this seemingly confusing stream
of information is just an example of science working as it often does. The
very nature of scientific investigation makes the accumulation of new in-
formation and the interpretation of existing data subject to change.
4 Chapter 1
Work in this area continues to yield new and sometimes surprising

information. The plant product psyllium is used in humans as a
bulk-forming laxative. This material is high in soluble fiber, like oat bran.
When taken in relatively small dietary amounts, it can lower cholesterol,
presumably in a manner similar to that mediated by the soluble fiber con-
tained in oat bran. Its lower dose (about 10 grams/day) compared with
oat bran consumption is easily administered by mixing it with water or
fruit juice. However, in the past several years disclaimers have appeared
on the psyllium bottles found on the shelves of retailers. They caution
users that psyllium and related bulk-forming products should be taken
either 2 hours before or 2 hours after taking medications. The concern is
that psyllium may bind or trap other molecules—like medications—be-
sides bile salts in the intestinal tract. This reduction in bioavailability
would reduce the efficacy of the prescribed drug. A test of this hypothesis
using mice indeed showed that simultaneous administration of soluble
fiber (oat bran in this case) with atorvastatin significantly reduced the
cholesterol-lowering effects of this drug. A better understanding of the
exact mechanisms in play here is needed, but this postscript to the oat
bran story further underscores the iterative nature of the discovery pro-
cess. New facts and interpretations can change our understanding of the
question we seek to answer. Equally important, they may open new doors
and lead us to unexpected knowledge that may be unconnected to our
initial hypotheses.
Scientists recognize that this is how science usually works, but in gen-
eral, people outside of science do not have this same understanding. Dis-
agreements, errors, and new interpretations of results are sometimes
reported to the public by the media. It is easy for such reporting to be
misinterpreted. The debate about emerging or evolving scientific knowl-
edge can be seen as confusion or interpreted as accusation. This may even
cause some to question the integrity of the science. Compounding this
problem is the commonly held stereotype that David Goodstein calls the
“myth of the noble scientist.” This myth holds that scientists must be vir-
tuous, upright, impervious to human drives such as personal ambition, and
incapable of misbehaving. Goodstein recognizes science as a human ac-
tivity that has hypocrisies and misrepresentation built into it. As scientists,
we become accustomed to such behaviors and often don’t even recognize
misrepresentations. Goodstein argues that this myth of the noble scientist
does science a disservice because it blurs the “distinction between harmless
minor hypocrisies and real fraud.” In summary, the human behavior that is
a part of scientific research may influence how that research is done. It may
also lead to misunderstandings that may confuse acceptable activities with
inappropriate behavior.
Scientific method
Textbooks teach us that scientific research proceeds according to “the scien-
tific method.” According to this method, a gap in knowledge is identified
and questions are posed. Existing information is studied, and a h ypothesis—a
prediction or educated guess—is formed to explain certain facts. Informa-
tion is gathered, analyzed, and interpreted in the process of testing the hy-
pothesis. Results may support or refute a hypothesis, but a hypothesis cannot
be proved. Indeed, a hypothesis can only be disproved. Further testing of
specific hypotheses and their derivatives strengthens their support and leads
to the genesis of a theory. Theories take into account a strongly supported
hypothesis or set of hypotheses and encompass a broadly accepted under-
standing of a natural concept. It follows that, since they are based on hy-
potheses, theories can eventually be disproved but they cannot be proved.
When hypotheses are not supported, the results obtained are often used to
refine or construct other hypotheses, and the process begins anew. A hy-
pothesis that has been unequivocally rejected on the basis of the interpreta-
tion of experimental evidence can provide the inspiration for a new
hypothesis, which may survive the test of repeated attempts to reject it. The
value of a hypothesis resides in its ability to stimulate additional thinking
and further research, rather than in its initial correctness.
Henry Bauer has written about what he terms the “myth of the scientific
method.” He contends that scientific research rarely proceeds by the orga-
nized, systematic approach that is reflected in textbook presentations. Ap-
proaches to solving problems and answering questions involve various
blends of empiricism and theorizing. Depending on the scientific discipline
and on the intellect and personality of the scientist, research is conducted
with considerable variations on the scientific method. Bauer argues that sci-
ence varies immensely in its characteristics, and he proposes two categories:
textbook science and frontier science. Textbook science has withstood the
scrutiny of time and is not likely to be subject to frequent change. Frontier
science is often termed “cutting-edge” science. It is volatile, sometimes un-
reliable, and subject to considerable change. Bauer correctly points out that
textbook science fails to reveal the true workings of scientific exploration,
because it teaches us only about successful science. Hence, it is not an accu-
rate portrayal of the often convoluted pathway that leads to accepted and
relatively stable scientific results. Such end products of research are com-
monly the result of several experimental pursuits that use different lines of
intellectual thought and technological approaches. Such efforts can occur
over long periods of time, during which corroborative or contradictory evi-
dence must be addressed and, where necessary, reconciled. Textbook science
evolves to a point of general acceptance with the caveat that future knowl-
edge may further refine, modify, or even disprove it. To attempt to explain
6 Chapter 1
this process as the result of the systematic implementation of a single, pre-

scribed scientific method sheds little light on the way science actually works.
Bauer’s concept of frontier science is relevant to scientific integrity.
Frontier science invites close examination. Methods, data, interpretations,
and conclusions are scrutinized as part of the process. Issues like “honest
error” and differences in judgment emerge. Unfortunately, the rigorous
analysis of frontier science can lead to erroneous perceptions and misun-
derstandings that can translate to accusations of scientific misconduct. Sci-
entists’ intuition and their judgments and decisions may be subjected to
scrutiny in ways that can take on an air of investigation. Who’s to say that
a scientist’s intuition about a problem constitutes bad judgment or sloppy
science, as opposed to deliberate deception? Deciding to discount enzyme
assay data that were obtained from protein preparations extracted from
what a biochemist might call “unhealthy cells” serves as a hypothetical case
in point. Can intuition be relied upon to recognize potentially flawed data?
Such are the gray areas that scientists, both as practitioners and as critics,
must address. Clearly, scientific intuition can be applied to a problem in a
way that allows the investigator to make a major conceptual advance. In
withholding their support for a report of the National Academy of Sci-
ences, Responsible Science: Ensuring the Integrity of the Research Process, How-
ard Schachman and Keith Yamamoto cited that the report “fails to convey
the overriding importance of intellectual freedom and trust in a creative
process that has been remarkably successful.”
It is rational to conclude that there is no single scientific method. Scien-
tists use many different strategies and methods in their exploration of na-
ture. Rarely, if at all, is the process orderly, even though scientific
publications present information in a way that suggests a logical and or-
dered progression of the research. Bauer submits that we should view the
classic description of the scientific method as an ideal rather than a specific
formula for performing research. He further suggests that the projection
of the concept of a prescribed scientific method provides society with un-
realistic expectations of science and scientists.
Finally, against the backdrop of the writings of Goodstein and Bauer, let
us remember that the practice of science is far from the stereotypical ob-
jective and dispassionate behavior that society generally believes to charac-
terize the research process. The objectivity of science that the naive
onlooker assumes to be integral to the process begins to evaporate quickly
at the stage of formulating the hypothesis. The formation of hypotheses
will be affected by the knowledge, opinions, and resources of the investiga-
tor. Furthermore, hypotheses are subject to experimental testing by means
of technologies and observational methods selected by the scientist. The
decision to test a hypothesis means a commitment of time, energy, and
money. In the past, these decisions were usually made by an individual, but
the increasing complexity and collaborative nature of scientific research

frequently mean that these decisions are made collectively. In either event,
the process is profoundly human in nature, and both “gut feeling” and in-
tellect are used in making decisions.
Thus, defining a universal scientific method with which to measure the
integrity of the research process is neither practical nor logical. Schachman’s
blunt assessment of the prosecution of scientific misconduct carries this
message: “it is inappropriate, wasteful, and likely to be destructive to sci-
ence for government agencies to delve into the styles of scientists and their
behavioral patterns.” In his book On Fact and Fraud: Cautionary Tales from
the Front Lines of Science, Goodstein cautions against the notion that scien-
tists conform to uniform strategies in the conduct of their research. He
points out that early federal definitions of scientific misconduct included
“practices that seriously deviate from those that are commonly accepted
within the scientific community.” In fact, there is no single set of accepted
practices that scientists use in conducting their research. The intellectual
freedom mentioned above allows scientists to express themselves cre-
atively. They think “out of the box,” exploit serendipitous events, and even
make mistakes that later have an impact on the research path they are nav-
igating. Assuming that there are commonly accepted practices that define
the scientific method blurs the line between the unappreciated or misun-
derstood activities of the researcher and the egregious transgressions of
fabrication, falsification, and plagiarism.
Reporting science
In 1963, Sir Peter Medawar wrote a provocative essay entitled “Is the Scien-
tific Paper a Fraud?” Referring to scientific communications published in
journals, Medawar’s use of the word “fraud” refers to misrepresentations of
the thought processes that led to the work reported. He points out that the
results section is written to present facts without any mention of signifi-
cance or interpretation. These are saved for the discussion section. Medawar
snickers that this is where scientists “adopt the ludicrous pretense of asking
yourself if the information you have collected actually means anything” and
“if any general truths are going to emerge from the contemplation of all the
evidence you brandished in the section called ‘results’.” Here, Medawar is
attacking the idea that scientific discovery proceeds by an inductive process
in which unbiased observations are made and facts are collected. From these
experimental raw materials, generalizations emerge. He concludes that this
inductive format of scientific reporting should be discarded, because it fails
to convey the fact that experimental work begins with an expectation of the
outcome. This bias extends to which investigational methods are chosen or
discarded, why certain experiments are done and others are not, and why
some observations are considered to be relevant while others are not. Many
8 Chapter 1
years later, Goodstein’s perspective on the scientific paper is captured in his

description of the “noble scientist”:
every scientific paper is written as if that particular investigation were a tri-
umphant procession from one truth to another. All scientists who perform
research, however, know that every scientific experiment is chaotic—like
war. You never know what is going on; you cannot usually understand what
the data mean. But in the end, you figure out what it was all about and then,
with hindsight, you write it up describing it as one clear and certain step af-
ter the other. This is a kind of hypocrisy, but it is deeply embedded in the
way we do science.
The research writings and scientific memoirs of François Jacob further

examine and illustrate the contrast between actual research and the report-
ing of it. In his memoirs, Jacob recounts his research with Sydney Brenner
and Matthew Meselson, which was aimed at the identification and charac-
terization of the “X factor” now known as mRNA (messenger RNA). Such
a factor had been proposed as an intermediary in protein synthesis, despite
the absence of a chemical basis for it. Jacob and his collaborators pursued
this elusive factor, and he writes in his memoirs that they were “sure of the
correctness of their hypothesis.” But their initial work was uniformly un-
productive as they attempted to demonstrate the X factor attached to ribo-
somes. So with their “confidence crumbled,” Jacob and Brenner retreated
to a Pacific Ocean beach, where Jacob describes Brenner as suddenly leap-
ing up and shouting: “The magnesium! It’s the magnesium!”
Jacob and Brenner returned to the lab and repeated the experiments
again, this time with “plenty of magnesium.” And, indeed, it was the mag-
nesium that enabled them to demonstrate “factor X” associated with bacte-
rial ribosomes. They had been using too low a concentration of magnesium,
resulting in the dissociation of the mRNA from the ribosomes. So Bren-
ner’s critical insight on the beach provided the key to demonstrating the
existence of this short-lived intermediate that carries the message of the
genes in DNA to the ribosomes, where protein synthesis occurs. However,
the presentation of these results in their 1961 Nature paper does not por-
tray events as told in Jacob’s autobiography. Instead, Brenner’s insight is
translated into a series of control experiments in which ribosomes, their
subunits, and the mRNA were dissociated or associated, depending on the
concentration of this divalent cation! Jacob eloquently offers his perspec-
tive on such behaviors when he compares writing about research to de-
scribing a horse race with a snapshot or penning the history of a war using
only official press releases. Jacob says scientific writing transforms and for-
malizes research. Scientific writing “substitute(s) an orderly train of con-
cepts and experiments for a jumble of disordered efforts. . . . In short,
writing a paper is to substitute order for the disorder and agitation that
animate life in the laboratory.”
So, what if you decided to dismiss the usual modus operandi of scientific
manuscript writing and relate the work exactly as it happened? For open-
ers, you might begin your paper with the words “This is the story . . .” Jon
Beckwith and his colleagues did exactly that in a manuscript in which they
believed that describing the tortuous history of the project would provide
a perspective that would be instructive to the reader. Beckwith relates the
reaction to this paper, citing comments of the referees who variously re-
ferred (negatively) to the manuscript as a “personal memoir” and a “fairy
tale,” written in “the exotic style of a story.” Beckwith says that although
the stylistic issues may not have been the principal reason, the paper was
rejected by two journals. The paper ultimately was published in the Pro-
ceedings of the National Academy of Sciences. Although we’d be hesitant to
make a sweeping conclusion from a single “experiment,” the prospects for
this style of writing catching on don’t seem to be looming on the horizon.
For the time being, we expect that scientific papers will continue to read
like paragons of logic. They’ll describe cleverly crafted experimental ap-
proaches applied in the most timely and compelling ways. But, in keeping
with Goodstein’s “myth of the noble scientist,” scientific papers for the
most part will not represent the true chronology of events or the intrica-
cies of assembling and interpreting facts that have led to the conclusions.
We won’t expect to read about the wrong turns, dead ends, and “broken
test tubes” that may have been crucial to the overall body of work. Scien-
tific papers rarely describe or put into perspective the pure luck and mis-
takes that were also part of the work being reported. Frederick Grinnell,
discussing the writing of Medawar, describes the scientific paper’s purpose
and in doing so provides us with some closing perspective: “Other re-
searchers will expect to be able to verify the data and the conclusions, not
the adventures and misadventures that led to them.”
Scientific Misconduct
Historical perspective
Questionable or controversial behavior by scientists is not confined to
modern times. Louis Pasteur’s pioneering work in the 1880s led to the
development of effective vaccines for anthrax and rabies. An examination
of Pasteur’s data books revealed that the anthrax vaccine used in a famous
inoculation trial on sheep was prepared by a chemical inactivation method
developed by his competitor, Henri Toussaint. But publicly, Pasteur
claimed that in these trials he employed his own method, which used oxy-
gen to inactivate the anthrax bacilli. In the early 1900s, Robert Millikan’s
selective publication of data on the electric charges of oil drops led to an
understanding of the particulate nature of electric charge. Millikan intui-
tively discounted data involving the migration of electrically charged oil
10 Chapter 1
drops that did not conform to his expectations, because they had “some-
thing wrong” with them. Scholarly writings on this subject abound. Some
have argued that Millikan was simply exercising scientific judgment. Oth-
ers disagree. Most recently, David Goodstein in his book On Fact and
Fraud: Cautionary Tales from the Front Lines of Science retells the story in
detail based on his examination of Millikan’s data books. The debate about
Millikan’s experiments centers on whether or not he published all of his
data. At issue is not that Millikan discarded certain data gathered from
some of the oil drops, but that in his published work on the subject he
wrote that he presented all of his available data. Goodstein asserts, based
on his firsthand analysis of Millikan’s recorded data, that “a careful reading
of Millikan’s words in context greatly diminishes their apparent signifi-
cance as evidence of misconduct.”
Investigation and prosecution of several cases of alleged scientific mis-
conduct in the last decades of the 20th century significantly increased
awareness of such matters. Facilitated by widespread print and electronic
reporting, the high-profile nature of these cases caught the attention of
reporters, politicians, scientists, and the public. The public’s eyes were
opened to the potential existence of scandal in science! The public recog-
nized that science could fall victim to the unethical and inappropriate ac-
tions of some of its practitioners. The importance of this issue was
underscored in the early 1980s with congressional hearings on fraud in
biomedical research. During this decade, some congressional members ag-
gressively pursued certain cases, further fueling zealous media coverage.
Today, reports on alleged misconduct in science appear with regularity in
the electronic and print media. Televised “news magazine” programs have
featured ongoing and closed cases, and a variety of websites and online
blogs specialize in the topic of “scientific fraud.” Newspapers, magazines,
and trade publications run stories on cases and commentaries on the topic.
And a number of the cases have been memorialized in books.
These high-profile cases prompted a federal response that was mani-
fested in policy development, the creation of new requirements, and in the
passage of new laws. In 1985, the U.S. Congress passed the Health Research
Extension Act. Although almost all of this law is concerned with the organi-
zation and authority of the National Institutes of Health (NIH), Section
493 addresses scientific conduct. This section is titled “Protection against
Scientific Fraud,” and it mandates that any entity receiving financial support
from the NIH must have an established administrative process to review
reports of scientific fraud. Reporting “substantial” investigations of alleged
scientific fraud is also a requirement. Furthermore, it mandated that the di-
rector of NIH establish a “process for the prompt and appropriate response
to information” concerning scientific fraud for any funded project. Finally, it
authorized “taking appropriate action with respect to such fraud.”
In 1989, the Public Health Service (PHS) created the Office of Scien-
tific Integrity in the Office of the Director of the NIH (an agency of the
PHS) and the Office of Scientific Integrity Review in the Office of
the Assistant Secretary for Health. The NIH Revitalization Act of 1993
combined both of these offices into a single entity called the Office of
Research Integrity (ORI) and established it as an independent entity
within the U.S. Department of Health and Human Services (DHHS).
This removed the responsibility for processing allegations of misconduct
from funding agencies and placed it under the authority of the ORI. This
act also replaced the term “scientific misconduct,” which had already re-
placed “scientific fraud,” with “research misconduct.” Two other seminal
events occurred in 1989. First, the NIH announced a requirement that “a
program in the principles of scientific integrity be an integral part of the
proposed research training” for all National Research Service Award in-
stitutional training grant applications, effective July 1, 1990. All activities
relating to instruction in the responsible conduct of research had to be
described in the application. Second, a report titled The Responsible Con-
duct of Research in the Health Sciences, prepared by the Committee on the
Responsible Conduct of Research, was published by the Institute of
Medicine. In response to its charge, the committee discussed issues per-
taining to standards of research and the process of investigation of alle-
gations especially in light of the emergence of federal regulations in the
late 1980s. It also addressed the need for mechanisms to promote ethical
standards in research. The committee developed 16 recommendations
aimed at three different sectors of the research enterprise: recommenda-
tions for the NIH, recommendations for universities and other research
centers, and recommendations for professional organizations and scien-
tific journals. The common recommendations across each of these groups
were that they develop policies, standards, and practices to promote and
ensure the responsible conduct of research.
The NIH Revitalization Act also mandated the formation of a Commis-
sion of Research Integrity to review the research enterprise and advise the
Secretary of Health and Human Services and the U.S. Congress about
ways to improve the PHS response “to misconduct in biomedical and be-
havioral research receiving NIH funding.” The committee’s 1995 report,
Integrity and Misconduct in Research, became commonly known as the Ryan
Commission Report, after Kenneth J. Ryan, the chair of the commission.
Among its recommendations, the committee called for a uniform federal
definition of research misconduct; a whistle-blower’s bill of rights; ex-
panded federal requirements for education in responsible research con-
duct; the development of codes of ethics by professional societies; and
defined processes in oversight, investigation, and adjudication of allega-
tions and in the imposition of sanctions.
12 Chapter 1
Defining research misconduct

Defining research misconduct has been an evolutionary process that is il-
lustrated by examining the definitions that have been used by the DHHS
since the 1980s. These have been variously termed the “DHHS defini-
tion,” the “PHS definition” (an agency of DHHS), and the “NIH defini-
tion” (an organization within the PHS). Among the first of such definitions
of research misconduct was one published in the July 18, 1986, issue of the
NIH Guide for Grants and Contracts.
“Misconduct” is defined as (1) serious deviation, such as fabrication, falsifica-
tion, or plagiarism, from accepted practices in carrying out research or in
reporting the results of research; or (2) material failure to comply with Fed-
eral requirements affecting specific aspects of the conduct of research—e.g.,
the protection of human subjects and the welfare of laboratory animals.
The appearance of such a definition signaled a response to concerns

resulting from misconduct allegations of the previously mentioned
high-profile cases. In 1989, a revised PHS definition published in the Fed-
eral Register (August 8, 1989) removed the “material failure to comply with
Federal requirements” clause and asserted that honest error or differences
were not misconduct.
Misconduct or Misconduct in Science means fabrication, falsification, pla-
giarism, or other practices that seriously deviate from those that are com-
monly accepted within the scientific community for proposing, conducting,
or reporting research. It does not include honest error or honest differences
in interpretations or judgments of data.
In 2000 (Federal Register, December 6, 2000), the United States Office of

Science and Technology Policy (OSTP), an Executive Office of the Presi-
dent of the United States, issued its own definition accompanied by a list
of conditions that must be used to arrive at a finding of misconduct.
Research misconduct is defined as fabrication, falsification, or plagiarism in
proposing, performing, or reviewing research, or in reporting research
results.
A finding of research misconduct requires that:
• There be a significant departure from accepted practices of the rel-
evant research community; and
• The misconduct be committed intentionally, or knowingly, or reck-
lessly; and the allegation be proven by a preponderance of evidence.
This definition was part of the OSTP federal research misconduct policy
and applied to all federally funded research. This policy did not limit au-
thority of research institutions or other entities “to promulgate additional
research misconduct policies or guidelines or more specific ethical guid-
ance.” Indeed, a number of federal agencies that conduct or fund research
have published their own definitions of research misconduct. We’ll review
the current research misconduct definitions used by the NIH and the
National Science Foundation (NSF) at the end of this chapter.
Today, definitions of scientific misconduct typically forbid fabrication,
falsification, and plagiarism. Fabrication is making up data; falsification is
any manipulation that introduces inaccuracies into the research record; and
plagiarism is using someone’s ideas, processes, results, or words without giv-
ing attribution or credit. Definitions containing phraseology that catego-
rizes deviations from accepted scientific practices as misconduct continue to
promote debate in the scientific community. The notion that there are ac-
cepted practices causes problems for some as it treads on the previously
mentioned arguments of the use of intuition and the importance of trust in
the research process. Early in the debate, Howard Schachtman, then presi-
dent of the Federation of American Societies of Experimental Biology, said
in congressional testimony that
It is our view that this language is vague and its inclusion could discourage
unorthodox, novel, or highly innovative approaches, which in the past have
provided the impetus for major advances in science. It hardly needs pointing
out that brilliant, creative, pioneering research deviates from that commonly
accepted within the scientific community.
Innovation, creative expression, intuition, and other subjective activities do

have a role to play in research, but so do elements that are objective. Stan-
dards exist about which there can be no question as to their application
and practice in the conduct of research. Written codes, laws, and policies
have existed for some time. These include policies for the use of humans
and animals in research. In other areas, like conflict of interest, written
codes have emerged relatively recently. Codes that define the basis of au-
thorship credit and responsibilities are being promoted by publishers, sci-
entific societies, and other organizations. And standards that deal with data
sharing and with issues of collaborative research are now readily available.
Guidelines that cover responsible research conduct, reflecting extant and
emerging national and international policies and guidance, are becoming
commonplace at universities and research institutes. Many of these will be
discussed in later chapters of this text.
Incidence of misconduct
Scientists commonly assert that misconduct in research is rare. However,
news reporting today frequently suggests that the incidence of misconduct
is on the rise. What baseline information can we use to make such a mea-
surement? Scholarly writings and analyses on this topic generally fall into
two categories: (i) comparing the number of misconduct cases or events to
some estimate of the number of practicing or funded researchers and (ii)
conducting surveys that directly ask scientists if they have committed
14 Chapter 1
misconduct or know of someone who has. Let’s examine in turn how each
of these informs the scope of the problem.
Nicholas Steneck, in ORI Introduction to the Responsible Conduct of Research,
used a 10-year window of data to compare confirmed cases of misconduct to
the total number of funded researchers. In his assessment, he combined mis-
conduct cases handled by the PHS-ORI and the Office of the Inspector
General of the NSF (NSF-OIG). Public records allow the capture of the
number of confirmed misconduct cases from both agencies, and the num-
bers of funded investigators in each year may be obtained from agency data-
bases. Over a decade that began in the mid-1990s, Steneck posited the
annual occurrence of misconduct in research to be approximately 0.01%.
But he cautions that this value is likely affected by underreporting of mis-
conduct in general. That is, researchers failing to report inappropriate be-
havior will have an impact on the number of convictions for research
misconduct. Other factors that could affect this assessment include allega-
tions of misconduct that are incorrectly dismissed following a preliminary
inquiry and the approximation of the number of researchers used in the
calculation. For example, a funded researcher may oversee several pre- and
postdoctoral trainees, and this amplification would not be reflected in the
assessment. Taking this low frequency to mean that research integrity is
necessarily high is potentially flawed. Specifically, Steneck cautions that at-
tempts to quantitate misconduct yield a value that is a minimum threshold.
In fact, the overall health of the research enterprise depends on adherence
to conduct that is guided by many different policies, regulations, laws, and
best practices. Looking at recent data reveals that Steneck’s assessment has
not changed as we move through the early years of the second decade of the
millennium. In aggregate, numbers of confirmed cases by the PHS-ORI
and the NSF-OIG continue to display similar patterns in the several years
since the Steneck analysis. The total number of misconduct findings still
averages between 20 and 30 a year, with each agency occasionally reporting
more than a dozen annual confirmed cases. The number of funded research-
ers has increased during recent years, which would also lower the previously
obtained value. In summary, using this approach to estimate the frequency
of misconduct has pitfalls that can create a misleading, if not inaccurate, es-
timation. Steneck’s use of “assessment” to express the result of his study is
prudent and appropriate. This approach is important because it provides
context and perspective, not because it offers an indisputable value of the
frequency of misconduct incidence.
This perspective clearly demonstrates that research misconduct is a re-
ality occurring at relatively stable baseline levels. It is further illuminated
by examining the annual reports of the ORI for the number of reported
allegations and the number of inquiries and investigations processed by
that agency. The average annual number of the allegations during the pe-
riod from 2001 to 2010 was 212, which was 23% higher than for 1994 to
2000. In a different comparison using the same time frames, the number of
inquiries and investigations jumped 88%, from 45 to 85 per year.
In the past 2 decades, there have been at least two dozen published re-
ports on surveys designed to examine the landscape of research conduct and
misconduct. Such publications variously report researchers’ admission of
committing misconduct, considering misconduct, or witnessing others
commit acts of research misconduct. Attitudes toward defined behaviors,
questionable or otherwise, have also been probed. The target cohorts across
these surveys have varied and have included trainees as well as scientists at
different chronological stages in their careers. Issues that have been raised
with interpreting survey results are manifold and can be controversial. For
example, published surveys of trainees and scientists frequently reveal a frac-
tion of respondents who claim that they have observed scientific misconduct
at some time in their careers. But such studies are subject to the criticism
that participant responses depend on personal knowledge, perceptions, and
interpretations that may differ enormously according to the training and
professional experience of the individual. Responses of participants can also
depend on the wording of survey items. For example, an item may have
ambiguous meaning or may be missing needed context that would cast the
validity of the response into doubt. Another example would be a survey item
that lumps together multiple components of differing value but requires an
absolute answer. Consider the case where a survey item has mixed three ele-
ments, X, Y, and Z. X and Y are consistent with unacceptable behavior, but Z
may be deemed appropriate behavior. In the case where the response is
based on Z, the association with X and Y yields a result that was not in-
tended by the survey participant. Thus, interpretation of surveys that collect
self-reported information or attitudes must be carefully done. Statistical
analysis must be rigorous, but equally important, the actual survey items and
background or instructional narrative provided to the respondents must be
critically examined. These caveats aside, survey data repeatedly suggest that
scientists and trainees admit to contemplating, committing, or observing
misconduct. The levels of these reported activities have differed from survey
to survey, and intersurvey comparisons have been difficult owing to a num-
ber of variables. However, Daniele Fanelli published a metastudy in 2009
using 18 different surveys. His approach was to extract information from
each of the surveys yielding responses that indicated behaviors or observa-
tions of behaviors that distorted scientific knowledge, namely fabrication
and falsification. He concluded that 1.97% of those surveyed admitted to
fabricating or falsifying data at least once. Fourteen percent answered that
they had observed such behavior in colleagues. About one-third of the sci-
entists in his analysis admitted to committing questionable research prac-
tices less serious than fabrication or falsification.
The PHS-ORI and the NSF-OIG investigate scores of misconduct al-
legations every year. Such investigations have led to the conviction of
16 Chapter 1
scientists, trainees, and technicians. Although we may debate how to calcu-

late the true incidence of research misconduct, there seems to be no deny-
ing the fact that it’s a problem. Survey results, also debatable and sometimes
controversial, support this assertion.
No matter what the magnitude of the baseline, if misconduct can be
measured, we are ill-advised to ignore or dismiss it—even if our position is
that it’s rare. The trust that society places in the research enterprise—
demonstrated in part by its financial support of scientists’ work—must be
earned and sustained. When it comes to demonstrating the value we as
scientists place on our research enterprise, we best serve ourselves and so-
ciety by practicing it responsibly. Broadly, this means holding ourselves to
the highest ethical standards and using best practices in our research; ad-
hering to relevant regulations, policies, and laws; reporting misconduct
allegations when they are brought to our attention; and prosecuting mis-
conduct inquiries and investigations when we are called on to do so. We
also have a moral obligation to be proactive in teaching and mentoring
trainees in the responsible conduct of research.
Perpetrators of misconduct
Arthur Caplan suggests that one who would lie about research data or steal
someone else’s ideas suffers from failed morals. Training and appropriate
socialization in the norms of scientific research are not likely to sway such
an individual. And preventing such individuals from entering the research
arena or weeding them out once they’re in place would be challenging.
So who would perpetrate an act of scientific fraud? In this area we are
long on speculation and short on well-supported conclusions. Sir Peter
Medawar may have summed it up in the fewest possible words. In writing
about a case of scientific misconduct, he sought some lesson or truth from
the incident but in the final analysis concludes that “it takes all sorts to make
a world.” Another Nobel laureate, Salvador Luria, suggests that a peculiar
pathology exists in the personality of one who would cheat in science. He
argues that only a distorted sense of reality could account for someone who
would falsify or fabricate results. Thinking one could get away with such
behavior in science, where external and internal control measures continu-
ally demand verification, would be a delusion. Goodstein has studied a num-
ber of cases of scientific fraud and offers three frequently underlying motives
or risk factors: (i) career pressure, (ii) the belief that one “knows” the answer
and can take shortcuts to get there, and (iii) the notion that in some fields
experiments yield data that are not precisely reproducible.
Goodstein’s notions provide an interesting substrate for investigating
drivers of misconduct. The metastudy of Fanelli lends support to the “ca-
reer pressure” hypothesis. He found that papers published by U.S. scien-
tists are more likely to report “positive” results—i.e., support for a
hypothesis—if the corresponding author’s state was identified as being

more competitive and productive according to the NSF data. The NSF
criterion here was the production of academic papers per capita. He re-
ports that scientists from competitive environments are more productive
and more frequently publish results supporting their hypotheses. The im-
plication is that academic competition and pressure to publish may in-
crease bias. With regard to thinking one “knows the answer,” there is some
anecdotal evidence to support this in that it has been reported as a factor
by some who have been convicted of misconduct. The issue of lack of data
reproducibility in some fields has intrinsic merit and is attractive, but sub-
stantive evidence is not available. Here, according to Goodstein, variability
in the data obtained may provide “cover” for someone tempted to cheat.
He proposes this as a reason for the large number of cases in biology, due
to the inherent variability in biological systems.
Finally, Nobel laureate Sydney Brenner offers yet another hypothesis.
He blames what he calls the “work structure” in modern science. That is,
the hierarchy of many laboratories involves a manager-worker relationship
that is complex, with the lab chief at the top and postdocs, trainees, and
technicians forming a network within which reporting relationships can
sometimes be unclear. In these cases, the connection between the lab chief
and the lab bench is not direct. So, suppose someone makes an honest mis-
take and the results from this errant work pique the interest of the lab
chief. The chief, in turn, proposes more experiments based on these re-
sults, suggesting his favored outcomes. Or, as Brenner puts it: “That means
such and such. . . . Now, if you go and do the following experiment and you
get the following answer, then it could mean this and that.” So the person
does as directed, but doesn’t get the expected results. Because the supervi-
sor has expectations, the person then “massages” the results, an act that
Brenner claims is not fraud, but “embezzlement.” Situations like this can
amplify themselves over time. Bad goes to worse, and before you know it,
fabrication and falsification have reared their ugly heads. The disconnect
between the lab supervisor and the work results in what Brenner calls “a
kind of co-operative crime.” For sure, “pressure” is involved as a catalyst
here, but it’s different from the “career pressure” mentioned above, which
is frequently self-imposed in response to a competitive environment.
Impact of research misconduct

The impact of confirmed research misconduct is broad. In some cases, it
begins well in advance of a conviction. First, an investigator convicted of
misconduct may have sanctions placed on him or her that can disrupt or
even destroy his or her career. At the extreme, a conviction for research
misconduct can result in a prison sentence. Others convicted of miscon-
duct may have restrictions placed on them preventing their engagement in
18 Chapter 1
certain activities like submission of proposals to funding agencies or ser-

vice on national review committees. Regardless of formal sanctions, a con-
viction is likely to place a stigma on the work of the investigator and
undermine the credibility of his or her future work. Not only may there be
a negative effect on the investigator, but uninvolved trainees may have
their reputations tarnished because of their association with the lab. If a
whistle-blower was involved in the genesis of the case, he or she may be-
come a target of criticism or may even be drawn into the investigation. In
such cases, he or she may suffer unjustifiable career harm. When fraudu-
lent results are published, they can have a negative impact on the scientific
community, causing time, money, and resources to be wasted as others try
to confirm or build on the bogus work. Any formal misconduct investiga-
tion puts a stressful and expensive burden on the institution. Taking faculty
and administrative time and effort into account, a single investigation of
misconduct may involve costs amounting to hundreds of thousands of dol-
lars. In the case of clinical research, including clinical trials, fabricated or
falsified data may result in physical harm to humans. When fraudulent data
are published, they corrupt the scientific record, and their eradication may
be difficult. Misconduct in research hurts the reputation of the scientific
enterprise. Society feels betrayed that its tax or philanthropic dollars have
been wasted. Politicians become incensed that the governmental infra-
structure that supports research has been abused. In short, research gets a
“black eye” when misconduct is discovered.
Responsible Conduct of Research
Today, we speak of “RCR courses,” “RCR training,” and “RCR require-

ments.” But it is important to keep in mind that when we say “responsible
conduct of research” we are invoking an overarching philosophy of behav-
ior. Conceptually, RCR encompasses four areas: subject protection, re-
search integrity, environmental and safety issues, and fiscal accountability.
• Research subjects include human beings and nonhuman animal species.
In both cases, federal laws govern the use of these subjects in scien-
tific research. We must seek and receive approval from institutional
committees before beginning any work with research subjects. Our
proposed use of research subjects must be precisely described and
appropriate in terms of applicable regulations and policies. Inappro-
priate deviations—violations of omission or commission—can have
serious consequences for investigators and their institutions.
• Research integrity encompasses several areas. The first involves matters
pertaining to data: its collection, management, storage, sharing, and
ownership. Institutions or funding agencies frequently have guidelines
or policies that apply to these issues. The second area is authorship and
publication practices. Guidelines that describe proper or expected

conduct are published by institutions (standards-of- conduct docu-
ments), professional societies (ethics codes), and publishers (instruc-
tions to authors). Related to this area is that of peer review, including
the review of journal manuscripts or grant applications. Guidance here
increasingly comes in the form of written policies from publishers, sci-
entific societies, and granting agencies. Third is mentoring: the rela-
tionship between mentor and protégé that not only underlies the
training phase of a scientific career but continues in various forms
throughout the career of a scientist. Mainly institutional guidelines
provide help in defining this relationship in terms of behaviors and
responsibilities. The last area is collaborative research, with a focus on
the duties and responsibilities of the collaborators. Collaborative sci-
ence has seen explosive growth in recent decades owing to the rise of
interdisciplinary approaches to research problems. Sharing data, de-
ciding on coauthorship, and addressing intellectual property matters
are but a few issues that are relevant here, with guidance coming from
many of the previously mentioned sources.
• Environmental health and safety is an area that applies to the use in
scientific research of materials, procedures, and processes that fall
under some type of government or agency regulation. The employ-
ment of radionuclides under the auspices of an institutionally granted
authorization or license is an example. The use, storage, and disposal
of radioisotopic compounds are strictly governed by law, and failure
to comply can result in various penalties, from fines to imprison-
ment. The same can be said for possessing or working with other
biohazardous or chemically hazardous substances or agents in the
research laboratory.
• Fiscal accountability involves two principal areas. First and foremost is
financial conflict of interest. Scientists must recognize, declare, and
manage financial conflicts of interest that could compromise any as-
pect of their research. The second is the proper and responsible use
of research funds. Obviously, this applies to research that is sup-
ported by any type of grant. The grantee (usually an institution) and
the principal investigator (the scientist) have a responsibility to spend
the awarded funds in compliance with relevant rules and regulations,
and in keeping with the goals and objectives of the work proposed in
the grant application.
PHS and NSF: dealing with misconduct

The NSF and the PHS definitions of research misconduct and related pol-
icies were issued in 2002 and 2005, respectively. Both appeared as addi-
tions to the U.S. Code of Federal Regulations (CFR) and may be accessed
20 Chapter 1
online (see Resources, Online, below). Both were inspired by the 2000
OSTP definition mentioned earlier in this chapter. The PHS definition is:
Research misconduct means fabrication, falsification, or plagiarism in pro-
posing, performing, or reviewing research, or in reporting research
results.
(a) Fabrication is making up data or results and recording or reporting
them.
(b) Falsification is manipulating research materials, equipment, or pro-
cesses, or changing or omitting data or results such that the research
is not accurately represented in the research record.
(c) Plagiarism is the appropriation of another person’s ideas, processes,
results, or words without giving appropriate credit.
(d) Research misconduct does not include honest error or differences of
opinion.
Requirements for findings of research misconduct.

A finding of research misconduct made under this part requires that—
(a) There be a significant departure from accepted practices of the rele-
vant research community; and
(b) The misconduct be committed intentionally, knowingly, or reck-
lessly; and
(c) The allegation be proven by a preponderance of the evidence.
The core wording of the PHS and NSF definitions is almost identical,
with the exception of some specific references to the NSF in its definition.
Both contain the assertion that honest error and differences of opinion do
not constitute research misconduct. Both agency documents have exten-
sive narrative on the investigation and prosecution of research misconduct.
Both deal with reporting requirements, initial handling of allegations, and
the roles of these federal agencies relative to that of the institution at which
the allegation has occurred. These federal agencies place the responsibility
for identification, investigation, and adjudication of misconduct allegations
with the institution. However, the PHS and the NSF have the right to re-
view both the process and findings of the institution. Both agencies also
may forward allegations to other federal agencies, and they may respond
directly to an allegation—i.e., conduct their own investigation.
It should be noted, however, that institutions that accept PHS or NSF
funding are mandated to have their own policies in place for dealing with
research misconduct. The ORI offers a model policy on its website for
guidance to institutions in preparing their own policies. Scientists and
trainees should be familiar with their own institution’s policy. Briefly
stated, such policies typically allow for anyone to bring an allegation to the
institution. Reporting an allegation triggers a series of actions that begin
with an inquiry-based process in which fact-finding is meant to establish
whether a full investigation should be launched. If the inquiry panel finds
that a full investigation is warranted, a second committee is selected to

carry out that phase of the process. If this investigative committee con-
cludes that misconduct has been committed, then the accused, often called
the respondent, is usually given the right to an appeal. Although the usual
time frame for an investigation is 3 to 4 months, the process can take sig-
nificantly longer owing to time needed to constitute an investigatory com-
mittee if appointees are challenged for cause by the respondents. In the
case of any specific deadlines, requests for extension in timing can be
sought and obtained. Finally, if an appeal is instituted, a significant amount
of time can be added to the process. Such factors could extend this entire
investigative process to a year or longer. In sum, the time and effort that is
needed to complete the investigation of an allegation of research miscon-
duct places a significant burden on the institution.
Conclusion
The practice of science has always encompassed values that include honesty,
objectivity, and collegiality. The progress of modern-day science reflects the
success of the research enterprise. There is nothing fundamentally wrong
with the conduct of science. However, emphasis on the workings of science
and the conduct of scientists has shifted considerably in recent years. Gov-
ernmental oversight and definitions of scientific misconduct sometimes lead
one to believe that scientific integrity is a new concept. It is not. In this book,
we strive to provide existing and emerging thinking and resources about the
responsible conduct of research. As part of this learning process, we aim to
challenge the student with cases that require a problem-solving approach.
Bertrand Russell made a cogent point. To paraphrase him, we trace “the evils
of the world” to moral defects and lack of intelligence. We know little about
eliminating moral defects and unethical behavior, but we can improve intel-
ligence through education. So we seek to improve intelligence rather than
morals. Russell’s argument is relevant to the teaching of scientific integrity.
Both practicing scientists and scientists-in-training must continually exam-
ine the subject and standards of responsible conduct of research. The prac-
tice of their science needs to adhere to those mandated and accepted
standards. Where appropriate, scientists need to play a role in refining exist-
ing standards and contributing to the development of needed standards.
Discussion Questions
1. Why do you think scientists would fabricate, falsify, or plagiarize?

2. Is including the phrase “significant departure from accepted prac-
tices of the relevant research community” in the definition of re-
search misconduct a good idea? Why or why not?
22 Chapter 1
3. Who may be harmed by an act of scientific misconduct?

4. What punishments are appropriate for scientists who have been con-
victed of scientific misconduct?
5. Should retaliation against a whistle-blower be considered an act of
research misconduct and added to the definition of research
misconduct?
6. Using your institution’s policy on misconduct in research, present
and explain each step in the process from the reporting of an allega-
tion to the final appeal.
Resources
Print
Barnbaum DR, Byron M. 2001. Research Ethics: Text and Readings. Prentice-Hall,
Inc., Upper Saddle River, NJ.
Bauer H. 1992. Scientific Literacy and the Myth of the Scientific Method. University of
Illinois Press, Chicago, IL.
Beckwith J. 2002. Making Genes, Making Waves: A Social Activist in Science. Harvard
University Press, Cambridge, MA.
Brenner S. 2001. My Life in Science. Science Archive Limited, London, United
Kingdom.
Brenner S, Jacob F, Meselson M. 1961. An unstable intermediate carrying infor-
mation from genes to ribosomes for protein synthesis. Nature 190:576-581.
Bulger RE, Heitman E, Reiser SJ. 2002. The Ethical Dimensions of the Biological
and Health Sciences, 2nd ed. Cambridge University Press, New York, NY.
Caplan A. 1998. Due Consideration: Controversy in the Age of Medical Miracles. John
Wiley & Sons, Inc., New York, NY.
Committee on Science, Engineering, and Public Policy. 2009. On Being a Sci-
entist: A Guide to Responsible Conduct of Research, 3rd ed. National Academies
Press, Washington, DC. http://www.nap.edu/openbook.php?isbn=0309119707.
Crewdson J. 2002. Science Fictions: A Scientific Mystery, a Massive Cover-up, and the
Dark Legacy of Robert Gallo. Little, Brown, and Company, Boston, MA.
D’Angelo J. 2012. Ethics in Science: Ethical Misconduct in Scientific Research. CRC
Press, Boca Raton, FL.
Elliott D, Stern JE (ed). 1997. Research Ethics: A Reader. University Press of New
England, Hanover, NH.
Fanelli D. 2009. How many scientists fabricate and falsify research? A systematic
review and meta-analysis of survey data. PLoS One 4:e5738. doi:10.1371/journal
.pone.0005738.
Fanelli D. 2010. Do pressures to publish increase scientists’ bias? An empirical sup-
port for US states data. PLoS One 5:e10271. doi:10.1371/journal.pone.0010271.
Geison GL. 1995. The Private Science of Louis Pasteur. Princeton University Press,
Princeton, NJ.
Goodstein D. 1991. Scientific fraud. Am Scholar 60:505-515.

Goodstein D. 2010. On Fact and Fraud: Cautionary Tales from the Front Lines of Sci-
ence. Princeton University Press, Princeton, NJ.
Grinnell F. 1992. The Scientific Attitude. The Guilford Press, New York, NY.
Grinnell F. 1997. Truth, fairness, and the definition of scientific misconduct. J Lab
Clin Med 129:189–192.
Grinnell F. 2009. Everyday Practice of Science. Oxford University Press, New York,
NY.
Jacob F. 1988. The Statue Within. Basic Books, Inc., New York, NY.
Kevles DJ. 1988. The Baltimore Case: A Trial of Politics, Science, and Character. W. W.
Norton & Company, Inc., New York, NY.
Luria S. 1975. What makes a scientist cheat. Prism, May, p. 15–18, 44. (Reprinted
in Beckwith J, Silhavy T. 1992. The Power of Bacterial Genetics. Cold Spring Har-
bor Laboratory Press, Cold Spring Harbor, NY.)
Medawar PB. 1991. The Threat and the Glory: Reflections on Science and Scientists.
Oxford University Press, New York, NY.
Michalek AM, Hutson AD, Wicher CP, Trump DL. 2010. The costs and under-
appreciated consequences of research misconduct: a case study. PLoS Med
7:e1000318. doi:10.1371/journal.pmed.1000318.
National Research Council. 1989. The Responsible Conduct of Research in the Health
Sciences. National Academies Press, Washington, DC.
National Research Council. 1992. Responsible Science, vol I. Ensuring the Integrity
of the Research Process. National Academies Press, Washington, DC.
National Research Council. 2002. Integrity in Scientific Research: Creating an Envi-
ronment That Promotes Responsible Conduct. National Academies Press, Washing-
ton, DC.
Pensler RL (ed). 1995. Research Ethics: Cases and Materials. Indiana University
Press, Bloomington, IN.
Reich ES. 2009. Plastic Fantastic: How the Biggest Fraud in Physics Shook the Scientific
World. Palgrave Macmillan, New York, NY.
Resnik DB. 1998. The Ethics of Science: An Introduction. Routledge, New York, NY.
Schachman HK. 1993. What is misconduct in science? Science 261:148–149, 183.
Shamoo AE, Resnik DB. 2009. Responsible Conduct of Research, 2nd ed. Oxford
University Press, New York, NY.
Steneck NH. 2007. ORI Introduction to the Responsible Conduct of Research. U.S.
Government Printing Office, Washington, DC. http://ori.hhs.gov/sites/default
/files/rcrintro.pdf
Stewart CN Jr. 2011. Research Ethics for Scientists: a Companion for Students.
Wiley-Blackwell, Oxford, United Kingdom.
U.S. Department of Health and Human Services, Public Health Service,
Commission on Research Integrity. 1995. Integrity and Misconduct in Research:
Report of the Commission on Research Integrity. U.S. Department of Health and
Human Services, Washington, DC. http://ori.hhs.gov/images/ddblock/report
_commission.pdf.
24 Chapter 1
Online
Definitions of Scientific Misconduct
Public Health Service Policies on Research Misconduct—42 CFR Part 93—

June 2005. (Final Rule. May 17, 2005. Fed Regist 70:28370-28400.) Online at:
http://ori.hhs.gov/sites/default/files/42_cfr_parts_50_and_93_2005.pdf
National Science Foundation 45 CFR 689 Research Misconduct. March

18, 2002. Fed Regist 67:11936-11939. Online at:
http://www.gpo.gov/fdsys/pkg/FR-2002-03-18/pdf/02-6179.pdf
45 CFR 689 NSF Research Misconduct Code (2002):

http://www.nsf.gov/oig/resmisreg.pdf
The Professional Ethics Report, published by the American Association for

the Advancement of Science, which runs articles dealing with professional
ethics in science:
http://www.aaas.org/page/professional-ethics-report-archives
Canadian Tri-Agency Framework: Responsible Conduct of Research. The

Canadian Institutes of Health Research (CIHR), the Natural Sciences and
Engineering Research Council (NSERC), and the Social Sciences and
Humanities Research Council (SSHRC) use this policy to support their
legislative mandates in promoting responsible conduct of research:
http://www.rcr.ethics.gc.ca/eng/policy-politique/framework-cadre/
National Science Foundation (NSF) Research Misconduct web page:

http://www.nsf.gov/oig/misconscieng.jsp
Office of Research Integrity Model Policy for Responding to Allegations

of Scientific Misconduct:
http://www.onlineethics.org/Topics/RespResearch/ResEssays/5664/mod.aspx
United Kingdom Research Integrity office, an independent agency that

provides advice and guidance on the responsible conduct of research:
http://www.ukrio.org/
U.S. Public Health Service Office of Research Integrity website:

http://ori.hhs.gov/
chapter 2
Ethics and the Scientist

Overview • Ethics and the Scientist • Science as a Profession
• Underlying Philosophical Issues • Utilitarianism • Deontology
• Values of the Scientific Community • Critical Thinking and
the Case Study Approach • Moral Reasoning in the Conduct of
Science • Conclusion • Discussion Questions • Case Studies
• Principles and Responsibilities of Research Conduct • Resources
Overview
M any of the decisions that scientists make in their day-to-day activ-

ities are pragmatic ones. Scientists make observations, study facts,
and then interpret them on the basis of established knowledge and
accepted principles. For example, when planning a surgical procedure
involving a rabbit, one must decide on the type and dose of anesthetic to
be used. This decision is determined by professional judgment, pub-
lished recommendations, and consultation with the appropriate animal
experts. It is also strongly influenced by the formal rules and policies
that govern the use of animals in research. On the other hand, the deci-
sion to use a rabbit in the first place has both pragmatic and moral com-
ponents. Most scientists conduct a particular medical experiment on
animals because the risk to humans is unacceptably high. Although
some members of our society question whether this decision is an ethi-
cal one, the majority accept the necessity of animal research but insist
that it be conducted in a humane manner. Here we have entered the
realm of moral reasoning. These decisions are based on our judgment
of what we ought to do—and we want to do the right thing. But deter-
mining what is morally (as opposed to legally) right and wrong in such
cases is not always assisted by guidelines or a policy manual. There are a
number of past research studies that, while conducted in accordance
with acceptable practices at the time, are widely viewed today as having
doi:10.1128/9781555818487.ch2
25
26 Chapter 2
been unethical. To avoid repeating such errors, we must all strive to

carefully examine the moral d imensions of our current research
practices.
As will be discussed later in this chapter, today we commonly encoun-
ter codes and policies that guide scientists in decision making. Institu-
tional standards of conduct, codes of ethical behavior adopted by scientific
societies, and instructions to authors published in scholarly journals are
but a few examples of the kinds of written guidance available to scientists.
On the other hand, there are many examples of decision making in sci-
ence that are not underpinned by clear-cut accepted standards. For ex-
ample, which of our data do we publish? In this connection a National
Academy of Sciences panel report asserts that “the selective use of re-
search data is another area where the boundary between fabrication and
creative insight may not be obvious.” With whom and under what circum-
stances do we share our research data? When, if ever, is it acceptable not
to share research data? Guidelines and policies about sharing publication-
related data are becoming increasingly available, but this is not the case
for the sharing of unpublished data.
In contrast to the pragmatic decisions about the choice of anesthetic in
an experiment, these are ethical decisions. Ethics is typically defined as the
study of moral values. What do we mean by moral values? These are ex-
pectations about beliefs and behaviors that we judge ourselves and others
by; they provide the framework for guiding us toward what we ought to
do. When we talk about ethics as the study of moral values, we are describ-
ing the critical consideration and clarification of such values, integrating
and prioritizing them as needed so we make a decision we consider to be
“right.” This is ethical decision making. The words “ethics” and “morals”
are frequently used interchangeably. However, we are better served to
maintain the distinction between the two. Ethics is about analyzing our
values in seeking a decision on how to act. Morals, specifically moral val-
ues, emanate from our inner convictions; they provide the substrate that
our conscience uses to distinguish right from wrong. In common use, mo-
rality often implies conformity with a behavioral code that is generally ac-
cepted in some defined setting or culture. Ethical behavior in the workplace
implies the adherence to a collection of moral principles that underlie
some specific context or profession and is commonly referred to as applied
ethics, or as professional ethics.
The case studies included throughout this book will give rise to dis-
cussions that will help students reason through problems that require
ethical decision making. In this chapter we shall briefly discuss some as-
pects of ethical decision making, focusing first on two general ethical
theories. We shall also discuss elements of moral reasoning and critical
thinking that are likely to facilitate the analysis and resolution of the
Ethics and the Scientist 27
cases. Finally, we’ll selectively review a growing body of scholarly writ-

ings that provide a foundation of values that apply to the conduct of sci-
entific research.
In his book A Practical Companion to Ethics, Anthony Weston rhetorically

asks, “Who needs ethics?” Why isn’t it enough just to follow our feelings or
to make ethical decisions instinctively? Our feelings and moral intuitions—
Weston calls them our passions—form the beginning of an ethical decision.
But the questioning that arises during the decision-making process may in-
form our feelings and may redirect or even change them. At the core of the
typical scientific misconduct definition are three categories of transgression:
fabrication, falsification, and plagiarism. In other words, scientists should not
lie, cheat, or steal in the course of doing their work. But these are moral val-
ues that apply to society in general and, arguably, provide instinctive direc-
tion. However, the specialization and complexities of scientific research
create a novel context in which scientists must apply moral judgments. Sci-
entists face dilemmas and are challenged by problems that require them to
make decisions and take actions based on their own morals. But this decision-
making process demands the use of knowledge and experience, which in
many cases are unique to the scientific endeavor and may not be appreciated
or understood by those outside the profession. On the other hand, some
ethical arguments transcend the scientific community and the public. The
use of animals in scientific research is an example at the forefront of this
discussion and debate. Should animals be used in research at all? Should
some animals but not others be used in research? Should animals be allowed
to suffer pain as research subjects? These are important questions that face
scientists. They must be addressed with ethically defensible answers.
Given the training and specialized knowledge and skills of scientists,
let’s argue that science is a profession. From this it would follow that scien-
tists are subject to unique professional ethics. That is, how scientists use
their knowledge and skills is subject to specific standards and accepted
practices. Such behavior would ensure the integrity of the research process
and have important implications for the impact that scientific research
may have on society.
Science as a Profession
Scholars who write about the characteristics of professions frequently

invoke the idea of strong differentiation as a defining characteristic. This
differentiation distinguishes a profession from an occupational group. As
an example, in her book Computer Ethics, Deborah Johnson uses the
28 Chapter 2
example of police officers in the profession of law enforcement. A distin-

guishing feature in this case is that police officers “can use force of a kind
for which ordinary citizens would be arrested.” They are granted special
rights and responsibilities as members of the law enforcement profes-
sion. A police officer may decide to use a firearm against someone who,
in his judgment, is threatening the life of an innocent hostage. This use
of force and deliberate infliction of harm on the part of the officer in-
volves a morality unique to the profession of law enforcement. The spe-
cial morals that the police officer uses in this situation translate to powers
and privileges that do not apply to anyone outside the profession of law
enforcement.
The characteristics of professions are further described by Johnson and
as well as by Adil Shamoo and David Resnick in their book Responsible Con-
duct of Research. Johnson offers five key characteristics of professions. The
first is mastery of an esoteric body of knowledge, typically obtained through
formal higher education and marked by continued learning and training.
Clearly, education and training are critical to the practice of science. Many,
if not most, scientists hold terminal degrees (e.g., Ph.D.s), regularly read
the scientific literature, attend scientific meetings, take specialized courses,
and periodically go on educational leaves (e.g., sabbaticals). The second is
autonomy, both at the individual and the collective levels. Scientists usually
enjoy a great deal of autonomy in their work, making decisions on what
problems to study and how to study them. At the collective level, there are
professional societies representing scientific disciplines that have consider-
able impact on the organization and the practice of the profession. Publish-
ing codes of ethics and establishing criteria and standards for practice of the
discipline are examples of some of the activities of professional societies.
The third characteristic is that professions have formal organization. John-
son is explicit in mentioning the kind of organization that may control ad-
mission to the profession (e.g., the American Bar Association for lawyers) or
be involved in licensing and standard setting (e.g., the American Medical
Association for physicians). Such practices may or may not be within the
realm of the activities of scientific societies. Some scientific societies have
registration and certification programs for both individuals (attaining status
as a certified clinical technician or counselor) and for education and train-
ing programs. Fourth, professions generally have ethics codes or documents
that prescribe standards of conduct. Most scientific societies publish such
codes and standards. The fifth characteristic Johnson calls “a culture of
practice.” This culture grows from the working conditions of the practi-
tioners and from what are recognized as the values and purposes for the
existence of the profession. Implicit in this is that the profession’s culture
has a role to play in society. Certainly, in the case of any research that has
implications for the betterment of humankind (most notably biomedical

research), the argument for social function is compelling.
Its general congruence with these five characteristics makes a strong case
for scientific research being a profession rather than a simple, undifferenti-
ated occupation. On the issue of formal organization (the third characteristic
cited above), we note that scientists don’t have to belong to any scientific
society to do their research or to be considered members of the profession.
And certainly there is no single organization that administers an “admissions
test” and grants a license to practice science. So the case for fulfillment of
this characteristic at the global level is arguably weak. Nonetheless, there is
an overriding consideration that involves the context in which scientists
practice their profession. In discussing computer experts, Johnson points out
that this group does not seem at face value to have any special powers and
privileges. However, this idea must be considered in terms of what Johnson
calls efficacy. This concept refers to the computer expert’s “ability and capac-
ity to affect the world.” In the context of employment, the computer profes-
sional or the research scientist can use knowledge and skills to create and
interpret new information, which in turn may be translated into applications
that have an effect (positive or negative, expected or not) on society. Johnson
argues that because computer experts have this efficacy, they bear special
responsibility. This argument can be extended generally to scientists because
through their knowledge and skills they have an ability to affect the world in
ways other cannot. With this comes a responsibility to ensure their work
does not harm others.
There are clear examples of special rights and powers that scientists use
in the course of their work. Maintaining confidentiality over patients’
records, properly treating humans and animals undergoing medical exper-
imentation, and doing research that involves the handling of biohazardous
substances are but a few activities in which scientists must use judgment
based on standards and morals that are not generally applicable to society.
Working under the authority of the Animal Welfare Act, scientists may
subject animals to procedures that could get a layperson arrested under an
animal cruelty statute. Recognizing and understanding how to work
through dilemmas that crop up in the course of scientific research requires
knowledge about the laws, policies, and guidelines that govern the conduct
of research. Making the right ethical decisions will ensure that we carry
out our research in a responsible and accountable fashion.
Finally, there are deeper issues surrounding the awareness of the re-
sponsibility to do research that is aimed at producing new knowledge that
will be used for the good of society. Anticipating the use of scientific
knowledge is a knotty problem that is addressed in our discussion of “dual
use” research in chapter 11.
30 Chapter 2
Underlying Philosophical Issues
It is unfortunate that many of those working in the biomedical and other

sciences have had little formal introduction to the field of ethics, because
they may as a consequence have little appreciation for its power as a disci-
pline. Occasionally, scientists are suspicious that disciplines such as moral
philosophy lack the same type of academic rigor displayed by their own
fields. It is not uncommon for scientists to criticize animal rights activists
for being excessively emotional and insufficiently rational. Yet scholars like
the animal rights activists Peter Singer and Tom Regan are respected for
their rational, not emotional, arguments in favor of granting animals far
more moral weight than society currently allows them.
Some people believe that ethical opinions are mere preferences akin to
expressing a taste for a flavor of ice cream or a type of music. For these peo-
ple there is little basis (or reason) for differentiating between ethical posi-
tions. However, few philosophers would seriously argue for such a strongly
subjective view of ethics. We make rational decisions about our ethical posi-
tions in a way that we do not make decisions about ice cream. If a friend
expressed a preference for strawberry, none of us would feel compelled to
argue the merits of chocolate. This would not be the case for a friend ex-
pressing intent to commit murder. However, ethics are also not strongly
objective in the manner of many scientific principles. Scientists anywhere
around the world (or at any time throughout history) who seek to measure
the density of pure gold will find, within the error of their instruments, the
same result. Yet there is no comparable experiment that we could perform to
assess the morality of a practice, such as polygamy, that is acceptable in some
cultures and taboo in others. Ethics falls in between these extreme positions.
Ethical issues are neither matters of taste nor immutable physical constants
that can be objectively determined irrespective of time and culture.
Ethics is usually subdivided into two areas known as normative ethics
and metaethics. Normative ethics seeks to establish which behavior is mor-
ally right or wrong; that is, it seeks to establish norms for our behavior.
Normative ethics is persuasive in that it attempts to set out a moral theory
that can be used to determine which views are acceptable and ought to be
adopted. This differs from metaethics, which concerns itself with an anal-
ysis of fundamental moral concepts, for example, concepts of right and
wrong or of duty. We will not discuss metaethics but will focus instead on
some of the normative ethical theories that attempt to persuade us to rede-
fine our behavior.
While not all philosophers advance identical ethical theories, this fact
should not be attributed to any inherent weakness in the discipline. It is
not at all uncommon for two biomedical scientists to disagree on the im-
plications of a certain data set. It is quite possible that the two scientists are
approaching the problem with different hypotheses in mind. Likewise,
given an ethical dilemma, one will often find ethicists who reach differing
conclusions as to the best course of action. The difference of opinion may
be attributable to the fact that each ethicist has tried to solve the dilemma
using a different normative ethical theory. Alternatively, each may have
used a similar ethical theory and yet differed greatly in the amount of
weight each ascribed to the various components of the problem. In addi-
tion, there can be disagreements over the empirical facts of a case (for ex-
ample, whether an animal feels pain during a given procedure). The point
is that moral problem solving, like biological problem solving, is an ex-
tremely complex process, and we should not be surprised to find that dif-
ferent people do not always arrive at the same conclusion.
However, it is equally important to realize that while many ethical di-
lemmas may not have a single “right” answer, there are answers that are
clearly wrong. Who would seriously argue that a coin toss should decide
ethical questions, or that abortions should be considered moral on Mon-
days and immoral on Tuesdays? Ethical positions can be evaluated and
compared using techniques that are not entirely foreign to those in the
sciences. Ethical theories can be evaluated on their rationality, their consis-
tency, and even on their usefulness.
While the evaluation of competing ethical theories is a difficult task, there
are areas of general agreement where we might begin. Ethical theories, like
any other, are expected to be internally consistent. No theory should be al-
lowed to contradict itself. Similarly, theories that are unclear or incomplete
are clearly less valuable than theories that do not suffer from these flaws.
Simplicity could also be considered an advantage. If all else were equal, it
would be preferable to employ a simple theory over one that is complex or
difficult to apply. We should also expect an ethical theory to provide us with
assistance in those dilemmas where intuition fails to give us a clear answer.
Most real-life ethical dilemmas are considered as such precisely because
compelling moral arguments can be made in support of each side of the is-
sue. These types of situations are those in which we most require the guid-
ance of a moral theory. Additionally, ethical theories should generally agree
with our sense of moral intuition. Who would wish to adopt an ethic that,
although consistent, complete, and simple, advocated murder for profit?
However, it is more difficult to decide about a theory that runs counter to
our moral intuition in an area less clear-cut than murder, or in a number of
minor areas. This is where the evaluation process becomes extremely diffi-
cult. How are we to decide whether it is the theory or our intuition that is
out of line? We may decide that if a theory is rational, is well designed, and
gives answers that correspond to our moral intuition on a large range of is-
sues, then in a particular instance it is our intuition that is in error.
Those in the natural sciences have something of an advantage over
moral philosophers. Usually, we can design an experiment to discern which
32 Chapter 2
of two competing hypotheses is more strongly supported. Philosophers do

not have the luxury of performing an experiment and letting the data de-
cide between the competing theories. However, ethicists do continually
subject their own philosophies, and those of their colleagues, to “thought
experiments” involving real or hypothetical ethical dilemmas. This process
involves using a particular ethical theory to perform the moral calculus
needed to answer a problem. It is sometimes found that the rigorous ap-
plication of an ethical theory will lead to an outcome that is unacceptable,
either to the philosopher or to the larger society. The philosopher may
then decide to modify the theory in hopes of increasing its acceptability or
choose to stick with the theory and instead suggest that society itself ought
to be modified.
Utilitarianism
Ethical theories are generally divided into two major categories. The first
of these is called either teleological or consequentialist, and the second is
referred to as deontological. Teleological theories focus exclusively on the
consequences of an action in order to determine the morality of that ac-
tion. Thus, to determine if a particular act is moral or immoral, one deter-
mines whether the consequences of that act are considered good or bad.
Those theories that do not exclusively evaluate the consequences of an act
to determine its morality are called deontological. Deontological theories,
considered in the next section, are commonly referred to as “duty-based,”
in contrast to the “outcome-based” nature of teleological-consequentialist
theories.
The best-known example of a teleological theory is utilitarianism. Jer-
emy Bentham (1748–1832) was the first person to articulate the theory
under that name, and John Stuart Mill (1806–1873) was also influential in
its development. Utilitarianism acknowledges the fact that many acts do
not produce purely good consequences or purely bad consequences, but
some combination of the two. To decide whether a particular act is moral,
a person must sum up all of the consequences, both good and bad, and as-
sess the net outcome. Moral actions are those that cause the best balance of
good versus bad consequences.
In addition, utilitarianism requires a person to consider the interests of
everyone. It is not permissible to merely consider what is best for you
personally. Suppose that you are considering lying about the results of an
experiment that you have performed. You reason that lying about the ex-
periment will greatly increase the chance of your paper’s being accepted
into a prestigious journal. This will, in turn, enhance your career, your
salary, and your family’s security. However, utilitarianism requires that
you also consider the impact of your decision on other people. You must
consider the fact that the scientists who read your paper and are misled
by its fabricated results may be harmed by your decision. Some of them
may decide to initiate a new series of experiments or to cease a line of
investigation based on your fabricated data. This can result in wasting
precious resources. If your research has direct clinical relevance, it is pos-
sible that patients may be directly injured or killed by your deceit. If you
are caught in your lie, still more harm will accrue both to you directly and
to the public’s confidence in science. If you consider the cumulative neg-
ative impact of your lying, and not just the positive benefits that you are
seeking, it will become apparent that the net outcome is a bad one. Ac-
cording to utilitarian theory, this act of deceit is immoral and you ought
not to carry it out.
Now let’s imagine a very different situation. A relative of one of your
colleagues has escaped from a mental institution and shows up at the lab
where you both work. Waving a scalpel and screaming that he wants to kill
your friend for “ruining his life,” he asks you to tell him where she is work-
ing. Although you know exactly where she is, what should you do? After
performing the same type of utilitarian calculus as above, it is clear that
you should lie to the escaped patient. The good and bad consequences that
will flow from this particular act of deceit provide a net outcome that is
markedly different from that in the previously described scenario. Thus, in
utilitarianism we find ethical decisions that change as circumstances
change. An act that is deemed immoral under one set of circumstances can
become morally obligatory under another. But exactly what are we to con-
sider when we try to evaluate good and bad consequences? According to
Mill, the only good is happiness and the only bad is unhappiness. Bentham
thought that pleasure was the only good and that pain was the only bad.
These terms are defined somewhat more broadly than you might imagine.
Pleasure includes satisfaction of desires, attainment of goals, and enjoy-
ment, while pain includes, in addition to physical discomfort, things such
as the frustration of one’s goals or desires.
Utilitarianism, like all other ethical theories, has its critics. One criti-
cism is that it is excessively burdensome to employ. Utilitarianism requires
that we all evaluate how each of our actions will impact everyone. How is
it possible to actually do this? How is it possible to predict the conse-
quences of even a fairly simple action on everyone? If we are required to
do this for each of our actions, how will we be able to get anything accom-
plished? The advice to use our common sense does not seem to be very
helpful. Another criticism of utilitarianism is that it would appear to con-
done, or even mandate, some actions that most of us would find horren-
dous. Suppose we find a patient who has a lymphoma that is producing a
substance of tremendous use in the treatment of AIDS. However, the pa-
tient is totally uncooperative, refusing either to accept treatment for his
34 Chapter 2
illness or to allow samples of his cells to be taken for research purposes.

Utilitarianism might allow us to kill this person and divide his cells among
the interested research labs. While one person would die, many AIDS pa-
tients would live. Utilitarianism is potentially at odds with our concept of
individual human rights.
Deontology
The second of the two major categories of ethical thought, deontology,

does not depend exclusively on the consequences of an action to determine
its morality. This does not necessarily mean that consequences play no role
whatsoever in deontological theories. Those theories that admit to the rel-
evance of consequences, in addition to other considerations, have been re-
ferred to as “moderate” theories, while theories that maintain that
consequences must not be considered at all are called “extreme.” The best-
known deontological theory is that developed by the German philosopher
Immanuel Kant (1724–1804). His theory is an example of an extreme de-
ontological position in that the consequences of an action are not consid-
ered in establishing its morality. Kant believed that using the utility of an
act to determine whether it is right or wrong is a terrible mistake. He real-
ized, as we have already seen, that such a standard compels the moral per-
son to perform a particular act in one situation while forbidding it in
another. This changing standard of morality was unacceptable to Kant,
and so he developed a theory based on a principle that, unlike utility, would
not change from one situation to another.
The principle that Kant developed to accomplish this purpose is called
the categorical imperative. Kant formulated this principle in a number of
different ways that he maintained were all equivalent. One of these formu-
lations advises us to “act only on that maxim through which you can at the
same time will that it should become a universal law.” How does this prin-
ciple guide and constrain our actions? To determine if a particular act is
moral, we must first ask ourselves if we would wish that the rule governing
our action be made a universal law—that is, if we would wish for every-
body to follow the same course of action. If we cannot truthfully desire
that anyone else be permitted to perform the action that we are consider-
ing, that act is immoral.
Let’s, once again, suppose that you are considering lying about the results
of certain experiments that you have performed. Before doing this, the cate-
gorical imperative requires that you first ask yourself whether or not you
can honestly wish that your deed be universalized into a rule. This rule
would permit all scientists to submit fraudulent data as genuine. Clearly,
such a rule would destroy the credibility of all scientists and preclude the
ability of the scientific community to make organized advances (as well as
having much broader implications for the general concept of truthfulness).

No one could legitimately wish that such a rule be universalized—therefore
the act is immoral. Note that there is no consideration of the consequences
of your contemplated act of deception. Whether or not you might benefit
from your deed never enters into the moral calculus.
A second formulation of Kant’s categorical imperative is more frequently
encountered in discussions of medical ethics. This formulation advises us to
“act in such a way that you always treat humanity, whether in your own
person or in the person of any other, never simply as a means, but always at
the same time as an end.” This statement makes it clearer that Kant’s prin-
ciple also requires a certain respect for persons. Note that Kant does not
demand that we never use a person as a means to an end, just that we do not
use a person solely as a means. When a physician treats paying patients, she
is clearly using them as a means through which she can achieve an end for
herself (earning a living). Yet if this is the physician’s sole consideration in
treating patients, she will be acting immorally toward them. Patients, and
all other persons, are to be treated as ends as well as means. Patients have
interests independent of those of the physician from whom they have
sought treatment. In other words, patients are their own ends. A physician
who prescribes “snake oil” is acting immorally because she fails to treat the
patient as an end. The physician who provides her patients with the best
care available treats them as both a means and an end.
While it is interesting and useful to understand how moral philosophers
approach ethical problems, it is not essential to understand the intricacies
of utilitarian or deontological theory to make good moral decisions. The
end-of-chapter cases in this book consider ethical dilemmas that may be
encountered by working scientists. By discussing the issues involved and
solving the problems posed in the case studies, students will be better pre-
pared to make positive contributions in their chosen profession.
Values of the Scientific Community
As mentioned above, codes of conduct and values held by the community

of science may be published by professional societies. These are often spe-
cific to the society membership, although similarities in responsibilities
and core values do exist across disciplines. A collection of such ethics codes
published by professional and academic societies and associations may be
found on the Ethics Collaborative Online Resource Environment (Ethics
CORE) website maintained by the University of Illinois and sponsored by
the National Science Foundation. Another online compilation is published
by the Illinois Institute of Technology’s Center for the Study of Ethics in
the Professions. Codes vary in scope and detail. They may include general
statements embracing the obligation of scientists to promote and uphold
36 Chapter 2
integrity in their research. At the same time, they may include specific re-
sponsibilities that address a range of topics from authorship credit to im-
plications of conflicts of interest.
Many universities and research institutes also affirm their commitment
to responsible conduct in research through their own internal policies.
Such policies may be found on the institution’s website, and an example of
a federal research institute guideline for the conduct of research is found in
Appendix III. This policy of the National Institutes of Health is specific to
that agency’s research mission of biomedical, life science, and health-
related research. University policies are typically broader as they address
research and scholarship across an institutional array of disciplines that
may span a variety of sciences, engineering, the humanities, and the arts.
Early in the first decade of this millennium, publications began to ap-
pear that listed values, norms, and recommendations for responsible re-
search conduct. This trend continues and has given rise to a foundation of
material that serves to provide ethical guidance for scientists augmenting
the codes of professional societies and individual institutions. Sources of
such material include government agencies, national scientific academies,
private and independent research councils, and independent scholarly
writings. The “Resources” section of this chapter presents a selected list of
several of these publications with links or citations to provide access to any
of the complete works. The following presents an edited compilation of
overarching concepts and commonly occurring elements taken from many
of these cited readings.
Integrity in research is envisioned as a collective responsibility of the
community of science. It is useful to think of integrity at the level of the in-
dividual scientist as well as at the level of the institution. At the level of the
individual, scientists must embrace the values and best practices of respon-
sible research, apply them habitually, and pass them on to trainees through
instruction and by example. The responsibility of institutions in promoting
responsible research centers on establishing and maintaining a culture that
is predicated on standards, trust, and compliance. Compliance means not
only adhering to laws, policies, and regulations but providing education
needed to facilitate that compliance.
The Council of Canadian Academies’ Expert Panel on Research Integ-
rity report defines research integrity as “the coherent and consistent ap-
plication of values and principles essential to encouraging and achieving
excellence in the search for, and dissemination of, knowledge.” The re-
port’s definition goes on to invoke values that include honesty, fairness,
trust, accountability, and openness. These have been frequently cited in
independent writings that have added yet other values to the list. These
publications include The European Code of Conduct for Research Integrity, the
Irish Council for Bioethics’ Recommendations for Promoting Research Integ-
rity, the Australian Code for the Responsible Conduct of Research, the Singapore
Statement on Research Integrity, the U.S. Department of Health and Human

Services Office of Research Integrity monograph ORI Introduction to the
Responsible Conduct of Research, and the U.S. National Research Council’s
publication Integrity in Research. Culling these documents with the intent
of generating a list of annotated core values yields the following.
• Honesty. This applies to all aspects of the research process including

proposing, performing, reviewing, and reporting research. It requires
that conduct across these areas be free from fraud and deception.
Honesty requires being responsible for one’s actions, being truthful,
and being obligated to meet any and all commitments to the research
process and to others.
• Trust. This value reflects confidence in the research across a spec-
trum that covers investigator conduct, methods used, data analysis,
interpretation, and reporting. Trust is earned at the level of both the
individual scientist and the institution by the conduct of research
that is lawful and compliant with applicable policies, regulations, and
guidelines.
• Fairness. This value reflects behavior characterized by sound and im-
partial judgment. Being fair as a scientist includes providing appro-
priate credit to the work of others, citing the literature accurately
and responsibly, providing appropriate recommendations, conduct-
ing objective peer review, and sharing data.
• Openness. Openness is characterized by forthright discussion with and
accessibility to the scientific community and to the public. It applies to
individual scientist’s conduct, conflict disclosure and management,
communication with the scientific and public communities, reporting
of research results, and acknowledgment of research contributions.
• Accountability. Scientists are required to be accountable for and are
answerable for their actions in proposing, performing, reviewing,
and reporting research.
• Stewardship. This is expressed in a variety of ways to include efficient
and nonwasteful use of resources, responsible use of research funds,
duty of care in conducting research that involves human or animal
subjects, and responsibility for the training and preparation of future
generations of scientists.
• Objectivity. Objectivity requires that interpretations be based on facts
and evidence that have been properly collected and rigorously ana-
lyzed and that conclusions are free of improper bias.
• Accuracy and reliability. These values involve exercising care to avoid
errors in the performance of research and precise reporting and com-
municating of the research process, the results, and the conclusions.
• Impartiality and independence. Scientists establish their impartiality by
being proactive in the identification of conflicts of interest, and then
38 Chapter 2
by disclosing and reporting them as appropriate to their institutions,

sponsors, and the scientific publication and review enterprise. Where
necessary, scientists work with the appropriate bodies to create and
implement management plans to reduce or eliminate perceived or
real conflicts. This process affirms the scientist’s independence in his
or her proposing, conducting, reporting, or reviewing research by
insulating their work from the inappropriate connection to outside
interested parties, from ideological or political pressure groups, and
from economic interests that might lead to bias in judgment.
This compilation of values provides a context for research integrity.
Further, the source of these values is a collection of documents of inter-
national origin, underscoring the importance of core values applied to
research regardless of the site of its performance. The international fla-
vor of the list suggests a global framework for research ethics and has
important implications for the individual investigator as well as for teams
involved in collaborative research. A common understanding of the val-
ues and guiding principles of research integrity serves the scientific com-
munity and the public who largely support research with their taxpayer
and philanthropic dollars.
Two of the documents used to generate this list of values, the Singapore
Statement on Research Integrity and the Canadian Academies report of the
Expert Panel on Research Integrity, spell out fundamental principles and
responsibilities that specifically link most of them to various aspects of re-
search conduct and activities. These have been grouped accordingly and
are presented in Table 2.1 at the end of this chapter (see “Principles and
Responsibilities of Research Conduct”).
Critical Thinking and the

Case Study Approach
Scientists should strive to make certain that each of their professional deci-
sions, whether pragmatic or ethical, is sound. Ideally, ethical decisions will,
like strong hypotheses, endure the test of time. But we must also acknowl-
edge that ethical standards are sometimes revised over time as a result of
continuing scrutiny and reinterpretation in the face of emerging knowledge
and new technology. To analyze and deal with the problems that challenge
us in our daily activities, we need to be well grounded in the rules and stan-
dards of conduct expected of us as scientific professionals. We have already
mentioned the importance of written codes that govern scientific behavior.
Documents on human and animal experimentation, authorship, conflict of
interest, and general codes of conduct are critical resources. But knowledge
of such resources is only the first step in fostering responsible research
practices. An understanding of how to apply the existing codes, as well as an

ability to reason beyond their explicit language, is needed for problem solv-
ing in the real world. The instructional format of this text affords opportu-
nities to improve these skills by providing short case studies. The discussion
of these cases will allow students to practice solving realistic problems by
interpreting and correctly applying appropriate standards.
These short case studies are designed to get the discussants to think
critically as they analyze and problem-solve. “Critical thinking” has be-
come a mantra in some academic circles as the problem-based learning
approach has permeated the curricula of undergraduate, graduate, and
professional programs. But what do we mean by critical thinking? Why is
it important that we be critical thinkers?
Critical thinking is a cognitive process that clearly identifies issues and
evidence related to a problem, thereby allowing defensible conclusions to
be made. When discussing case studies like those found in this book, stu-
dents should first separate the relevant issues from the nonrelevant ones.
Relevant issues must then be analyzed, and the factual matters, backed up
by evidence, must be distinguished from nonfactual ones. Students must
also decide how to weigh the nonfactual matters, such as statements of
opinion or expression of personal values.
Critically thinking about cases means that one must apply both factual
knowledge and an understanding of appropriate scientific behavior to the
problems encountered. This must be augmented by a careful assessment of
assumptions, insightful questioning, and open-mindedness throughout the
process of case analysis. It is important to remember when discussing cases
that a consensus answer may not emerge. Nevertheless, several acceptable
solutions to the problem may be found. Acceptable solutions must always be
in compliance with standards related to global considerations (e.g., issues
related to plagiarism or human rights). Solutions to cases always need to be
examined to be sure they cannot be misinterpreted. In other words, they
should not contain any loopholes. Examples of unacceptable solutions in-
clude violations of specific standards, guidelines, or rules and regulations.
Solutions that are inconsistent with the written or unwritten ethical stan-
dards for scientific conduct generally accepted by the profession are also
unacceptable. (See “Note to Students and Instructors” at the front of this
book for a detailed discussion of how to approach case studies.)
Moral Reasoning in the Conduct of Science
The cases in this book will challenge you to analyze situations and make
decisions based on information and evidence. Many of them will also re-
quire you to employ moral reasoning to reach your decision. But as men-
tioned earlier, using intuition or basing your solution on your feelings alone
40 Chapter 2
will not be enough. Specialized knowledge and information, applied in con-

text to the specific situation, is needed to inform your decision. In their
monograph Moral Reasoning in Scientific Research, Muriel Bebeau and her
colleagues suggest four psychological processes that are consistent with be-
having morally. These were initially proposed by James Rest, Bebeau, and
Joseph Volker and have been referred to as Rest’s Four-Component Model
of Morality. These components are:
• Moral sensitivity. The individual faced with a situation makes inter-
pretations concerning what actions are possible, who would be af-
fected by these actions, and how these actions would be regarded by
the affected parties.
• Moral reasoning. The individual makes a judgment about what course
of action is morally right (or fair, or just, or good), thus prescribing a
potential course of action regarding what ought to be done.
• Moral commitment. The individual makes the decision to do what is
morally right, giving priority to moral values above other personal
values.
• Moral perseverance (or moral implementation). The individual imple-
ments the moral course of action decided upon, facing up to and
overcoming all obstacles.
Bebeau et al. point out that although these four processes can interact
with and even influence each other, in practice they also can be indepen-
dent of one another. For example, a person may be quite adept at inter-
preting the ethical issues of a situation but unable to develop good
arguments for the proposed moral judgment. When discussing cases, we
can usually recognize and appreciate the skills involving moral sensitivity,
moral reasoning, and moral commitment. In fact, the case discussions can
enhance these skills. Because the cases reflect realistic situations, practice
will improve the ability to recognize and reason through actual moral
dilemmas in scientific research. For example, one can be expected to dis-
cover and use written codes of conduct and to better appreciate and apply
normative standards. On the other hand, evaluating moral perseverance
(implementation) is usually not possible when discussing case studies.
Obviously, the true measure of this crucial component lies in what an in-
dividual actually does—something that is very difficult to play out in a
case study. Nevertheless, it is sometimes possible to guess what an indi-
vidual would do in a situation. We have encountered case discussions and
write-ups in which a student, acting as the protagonist in the scenario,
displays appropriate moral sensitivity, reasoning, and commitment. But
then, in bringing the case to closure, the discussant describes some per-
sonal action that, in effect, portrays him or her as “walking away” from
the situation. In other words, the discussant discloses an action that
clearly indicates an unwillingness to implement the plan (and deal with

its consequences).
Conclusion
The activities of scientific research provide a basis of meaningful differen-

tiation that allows it to be classified as a profession. The conduct of re-
search creates new knowledge that can be translated to have an impact on
society. The expectation is that such impact will be beneficial. Thus, scien-
tists must conduct their research responsibly and with accountability.
These and a growing number of other values articulated by various quar-
ters of the scientific infrastructure provide a basis for promoting scientific
integrity. Accordingly, scientists should be expected to embrace these val-
ues in their work. These values and the foundation of general policies and
regulatory concepts presented in this book should be used to solve cases
provided to the reader. Moral sensitivity, reasoning, commitment, and per-
severance will all be needed in addressing the dilemmas raised in these
cases found in subsequent chapters. We affirm the guidance provided by
the criteria of Bebeau et al. for making well-reasoned moral responses to
dilemmas in scientific research. First, your response to the case should ad-
dress all issues and points of ethical conflict. Move beyond just labeling
issues and clearly articulate the conflicts emanating from the various ele-
ments of the case. Second, be sure your response considers the legitimate
expectations of all interested parties. Keep in mind that parties may be af-
fected who are not specifically invoked in the case narrative. Third, recog-
nize that your proposed actions will have consequences. Clearly describe
the probable consequences, their effects, and how they were incorporated
into your decision. Fourth, identify and discuss the obligations or duties of
the protagonist of the case. What professional duty is at issue, and why
does the scientist have that duty?
1. Are there moral values that are unique to the conduct of scientific
research? Describe them and their implications in terms of doing
research responsibly.
2. Should scientists be accountable for their choice of research pursuits
if their published results are used by others for evil purposes?
3. Do you believe that some kinds of scientific research should be for-
bidden? If you do, provide examples.
4. Do scientists have a moral obligation to explain the implications of
their research to society? Why?
42 Chapter 2
Case Studies
Case 2.1 below deals with research ethics as generally discussed in chapters
1 and 2. The remainder of the cases correspond to the topic areas covered
in chapters 3 to 11. Try your hand at solving these cases even before cover-
ing the material in the subsequent chapters. Then return to the case after
reading the appropriate chapter and having classroom discussion of the
topic, and solve the case again. Discuss any differences between your two
solutions.
Research conduct and ethics (chapters 1 and 2)
2.1 Donna Mills is an associate professor who been accused of data

falsification in a federal grant application. The allegation was made
to the dean of her school by someone outside of her institution. Following
a preliminary evaluation of the allegation, the dean formed an inquiry
panel that delivered a finding of suspected misconduct as alleged. Based on
this, an investigative panel has been constituted by the dean. Professor
Sarah Uba-Kalu is one of five senior faculty members on the investigative
panel. Although the panel members have not yet completed their report, it
is clear to Sarah that the panel will be unanimous in its decision to find
Donna guilty of falsification. Sarah has just received a written request to
provide a recommendation for Donna, who is being considered for a posi-
tion at another university. Sarah was unaware Donna was looking at other
job opportunities and does not remember being asked to serve as a refer-
ence. Because the panel’s work is confidential, Sarah decides to delay re-
sponding to the request, knowing that a guilty verdict is imminent. Then
she plans to place a call and disclose Donna’s conviction. She describes her
intentions to you, arguing that she will have a moral obligation to report
Donna’s misconduct to a potential employer. Sarah asks your opinion of
her plan. What will you tell her? If you disagree with her proposed course
of action, what, if any, alternative would you offer?
Mentoring (chapter 3)
2.2 Ashton Malone is a second-year graduate student conducting her

dissertation research in environmental science under your supervi-
sion. During the fall semester, Ashton not only takes a full course load, but
spends long hours in the lab and works as a teaching assistant for one of
your undergraduate classes. Her grades are stellar and she is an exemplary
teaching assistant. After the winter holidays, however, you begin to notice
a change in Ashton. Her grades begin to drop, she often appears distracted,
and you rarely see her in the lab. One afternoon while you are analyzing
air samples, Ashton arrives to do some work. You notice she is not her
usual cheerful self; in fact, she seems frenzied, almost manic racing around
the lab. While working at your bench, you glance over and notice Ashton
taking several pills from a bottle without a prescription label. Concerned
that she may be ill, you ask Ashton how she is feeling. Ashton hastily tells
you that she is not sick and the pills in the bottle are for a migraine. When
you suggest she take the afternoon off to help relieve her headache, she
becomes defensive, telling you she does not have time to go home and rest.
You are not the only one who has noticed a change in Ashton. In fact, you
have had several other graduate students tell you that they have seen Ash-
ton taking pills from a bottle regularly, and many have commented on her
mood swings. As Ashton’s mentor, how would you handle this situation?
What, if any, actions need to be taken?
Authorship and peer review (chapter 4)
2.3 An East Coast geneticist and a West Coast biochemist are engaged
in a productive, well-defined collaborative project. The geneticist
prepares an abstract, approved by his collaborator, for submission to a large
international genetics meeting. The scientific content of the abstract reflects
equal contributions of both collaborators. Within 1 month, the biochemist
prepares an abstract of the same work to be submitted to a national bio-
chemistry meeting. The two abstracts have different titles and different
wording, but they report the same experiments and same results and inter-
pretations. The abstracts submitted to both of these meetings will be pub-
lished in journals of the respective societies as “meeting proceedings.” Have
these investigators acted appropriately in reporting their research?
Use of humans in biomedical experimentation (chapter 5)
2.4 An institutional review board (IRB)-approved clinical trial of a new

cancer drug is under way at the cancer center of an academic medi-
cal center. The participants in this study, all of whom are adults in the early
stages of leukemia, are seen twice per month for treatment and follow-up.
Their clinic visits take place in the cancer center building, which also con-
tains research labs and teaching facilities. Due to security measures recently
put in force, the study participants must sign a logbook prominently placed
at the reception desk when they enter and leave the building. They also
must wear name tags. A research coordinator working on this study is con-
cerned that these procedures provide inappropriate public access to patient
identification and are inconsistent with patient confidentiality stated in the
IRB research protocol. She brings her concerns to you, the director of the
cancer center. What, if anything, will you do?
44 Chapter 2
Use of animals in biomedical experimentation (chapter 6)
2.5 Myron Castillo is a new graduate student in Dr. Jessica Ripka’s lab.
Dr. Ripka instructed Myron to complete the university animal
training program within his first 2 weeks of being in the lab. Six weeks af-
ter Myron begins his lab work, Dr. Ripka personally begins training My-
ron in performing specialized injections in rats being used in her research.
During an injection, Myron is bitten by one of the rats, resulting in a sig-
nificant laceration of his thumb. Dr. Ripka instructs Myron to go to the
student health clinic where he was screened for possible animal allergies at
the conclusion of his animal-use training. Myron confesses that he has not
had time to complete the animal-use training, nor has he been screened for
allergies at the student health clinic. Dr. Ripka chastises Myron for failing
to tell her he had not completed the training and for not disclosing this
before engaging in the specialized injection training with her. Dr. Ripka is
worried that if Myron goes to the student health clinic, the report that will
ensue from the visit will be filed with the institutional animal care and use
committee. She fears this will lead to sanctions being placed on her animal-
use authorization, thus impeding her research progress. She instructs My-
ron to get the bite wound sutured at the emergency room of a nearby
community hospital. Later in the day, Dr. Ripka shares the incident and
her response to it with you over a cup of tea. She asks you if she did the
right thing. What is your analysis of the situation, and what do you tell
her? If she has not acted appropriately, what should she have done?
Managing competing interests (chapter 7)
2.6 Professor Ella Blackfeather has just published a new book on sta-
tistics for social scientists. She wants to use the book as a text in her
undergraduate course in social science methods. Ella has a lucrative roy-
alty deal based on book sales, and the book is relatively expensive, retailing
for $150. The course she teaches is popular and typically enrolls about 200
students. She knows that use of the book in her course will generate a
handsome royalty. There are similar texts on the market, but she considers
hers to be superior to the competition in terms of content and instruc-
tional format. She is a faculty member at a private university that does not
have an explicit policy on faculty-authored textbook use, but several of her
faculty colleagues use texts they have authored in their own courses. Con-
templating her decision, she comes to you for advice. She asks you to com-
ment on the pros and cons of using her text. What, if any, conflict-of-interest
issues may emerge from the use of her book? If she decides to use the
book, are there things she can do to mitigate or manage concerns that
might arise? What are they? Ultimately, what advice do you give her about
using her text in her course?
Collaborative research (chapter 8)
2.7 Scientists at a large southeastern research university in the United

States are attempting to preserve an endangered species of animal
from a developing island nation in the South Atlantic. Because of scientific,
political, and social considerations, it is both desirable and necessary to study
these animals at the research university in the United States. The office of
research at the university is in discussions with the Ministry of Science of
the island nation to create an agreement to carry out these studies. The doc-
ument drafted by the Ministry of Science stipulates that specimens of the
endangered species will only be shipped to the university under the condi-
tion that scientists from the island nation be listed as authors on any publi-
cations reporting on this important species. The university scientists know
that, unfortunately, the scientists from the island nation are unlikely, and
possibly unable, to provide any significant contributions to the research.
The university has just published a standards-of-research-conduct docu-
ment that details criteria for authorship of scholarly works. Criteria for au-
thorship of this document are clearly inconsistent with what the Ministry of
Science is asking the university to do. What, if any, are possible solutions
that would balance the responsibility to preserve this species with the re-
sponsibilities for authorship?
Ownership of data and intellectual property (chapter 9)
2.8 A predoctoral student working in the laboratory of her mentor is

gathering data for a federally funded project on which the mentor
serves as principal investigator. The student is, of course, going to use the
data for her dissertation work. The student and mentor have a terrible
falling out. The student leaves the lab and finds a new advisor. The advisor
notices that data and materials related to the student's project are missing.
The student readily admits to removing the tissue sections, gels, and com-
puter disks but asserts that they are “hers”—the product of her sweat and
blood. Do these data and resources rightfully belong to the student? What
data ownership issues apply to this situation?
Scientific record keeping (chapter 10)
2.9 Ming Shu, biochemistry graduate student from China, can speak
and write in English, but her speed at each task is relatively slow.
46 Chapter 2
Every few weeks Dr. Andrekia Keys, Ming’s graduate mentor, meets with
her to discuss research and to generally inquire as to how her transition
into academic life in the United States is progressing. This week Dr. Keys
asks Ming to leave her research notebooks out so that she can stop by the
lab and inspect them. When Dr. Keys arrives at the lab, Ming has left for
the day, but she finds the notebooks lying on her desk. Upon inspection,
she finds that several of the notebooks are written in Chinese. Upon fur-
ther investigation, she discovers that Ming is recording her initial obser-
vations in Chinese in one notebook and then translating them into
English at a later time. Furthermore, when Dr. Keys examines both sets of
notebooks, she observes that the current English notebook is approxi-
mately 3 weeks behind the Chinese counterpart. Dr. Keys comes to you
for advice. Is Ming guilty of improper notebook-keeping practices? Can
the notebooks written in English be considered valid records of her re-
search thus far? What advice on how to handle this situation do you have
for Dr. Keys?
Science, technology, and society (chapter 11)
2.10 Jacob Moscowitz is a 66-year-old English professor at State Uni-

versity. He voraciously reads science and health news, as well as the
popular scientific literature. He is a habitual exerciser and adheres to
healthy dietary practices. Recently he has developed an interest in the ser-
vices offered by personal genetics companies. He has decided to use one of
these companies, gotGENES, to have his genome analyzed. Using DNA
extracted from cells in his saliva, gotGENES will analyze a representative
sampling of Jacob’s entire genome. These data will be provided to Jacob
and his physician. The company advertises that the analysis will provide
information on thousands of genes that will allow prediction of risk for
genetic disorders and other valuable information that can inform Jacob’s
overall health care. Jacob and his wife of 41 years have three married chil-
dren and seven grandchildren. He has confided in you, his faculty col-
league, that he is expecting the gotGENES saliva collection kit in his office
mail within a few days and he plans to have his DNA analyzed. You ask him
if he’s had a family discussion about having the analysis done and the im-
plications of the results. Jacob is taken aback by your question, and re-
marks that he has not had such a discussion with his wife, their children, or
any other family members. He asserts: “These results are between me and
my physician. This is all about personalized medicine, not ‘family medi-
cine’!” How do you respond, and what arguments, if any, might you offer
to Jacob for disclosing his intentions to his family? Should his family mem-
bers be involved in the decision and with the use of the testing data? Is
Jacob taking any personal risks in having his DNA analyzed? If so, what
are they?
Principles and Responsibilities

of Research Conduct
Using the recommendations of the Council of Canadian Academies’ Ex-
pert Panel on Research Integrity report and the Singapore Statement on Re-
search Integrity, Table 2.1 organizes the principles and responsibilities that
provide a framework for research conduct. The first column designates 12
general categories into which the recommendations of the two reports
have been placed based on their relatedness. The second column contains
the verbatim recommendations from the Canadian Academies report. The
numbering system corresponds to that presented on page 39 of the report.
The parenthetical material after each of the recommendations in the sec-
ond column corresponds to the appropriate core values as designated by
the expert panel. The third column contains the 14 responsibilities con-
tained in the Singapore Statement on Research Integrity appropriately grouped
according to the topics listed in the first column of the table. The number-
ing of the items corresponds to that found in the Singapore Statement on
Research Integrity.
Resources
Print
Bebeau MJ, Pimple KD, Muskavitch KMT, Borden SL, Smith DH. 1995.
Moral Reasoning in Scientific Research: Cases for Teaching and Assessment. Poynter
Center for the Study of Ethics and American Institutions, Indiana University,
Bloomington, IN. http://poynter.indiana.edu/files/8713/4572/7960/mr.pdf.
Expert Panel on Research Integrity. 2010. Honesty, Accountability and Trust:
Fostering Research Integrity in Canada. The Council of Canadian Academies,
Ottawa, ON, Canada.
http://www.scienceadvice.ca/uploads/eng/assessments%20and%20publications
%20and%20news%20releases/research%20integrity/RI_report.pdf.
Goldman AH. 1980. The Moral Foundations of Professional Ethics. Rowman and
Littlefield, Totowa, NJ.
Johnson DG. 2009. Computer Ethics, 4th ed. Prentice Hall, Inc., Upper Saddle
River, NJ.
National Academy of Sciences. 1992. Responsible Science: Ensuring the Integrity of
the Research Process, vol. I. National Academies Press, Washington, DC.
National Research Council. 2002. Integrity in Scientific Research: Creating an
Environment That Promotes Responsible Conduct. National Academies Press,

Washington, DC.
Table 2.1 Research conduct recommendations
48
Category Expert Panel on Research Integrity, Singapore Statement
Council of Canadian Academies
Chapter 2
Conduct 1. Conduct research in an honest search for knowledge: a fair, 1. Integrity: Researchers should take responsibility for the
open, and reliable approach to all activities that support, trustworthiness of their research.
fund, or otherwise encourage research. (Honesty; Fairness;
Trust; Openness)
Competence 3. Know your level of competence and your limitations; act 3. Research Methods: Researchers should employ appropriate
accordingly: Ensure you have the appropriate expertise research methods, base conclusions on critical analysis of
and experience to participate in a given area of research the evidence and report findings and interpretations fully
or research administration. (Honesty; Trust; Accountability) and objectively.
Environment 2. Foster an environment of research integrity, accountability, 2. Adherence to Regulations: Researchers should be aware of
and public trust: Individuals and organizations at all levels and adhere to regulations and policies related to
should take responsibility for creating, implementing, research.
maintaining, and complying with policies and practices
13. Research Environments: Research institutions should create
designed to ensure accountability and the maintenance of
and sustain environments that encourage integrity
public trust. (Trust; Accountability)
through education, clear policies, and reasonable
standards for advancement, while fostering work
environments that support research integrity.
Funds 5. Use research funds responsibly: Individuals and organizations

at all levels should ensure the responsible allocation and
management of research funds in accordance with sound
academic and financial principles. (Honesty;
Accountability)
Conflicts 4. Avoid conflicts of interest, or if they cannot be avoided, 9. Conflict of Interest: Researchers should disclose financial
address them in an ethical manner: Personal and and other conflicts of interest that could compromise the
institutional conflicts of interest, or the appearance of trustworthiness of their work in research proposals,
conflict of interest, should be avoided. When unavoidable, publications and public communications as well as in all
each instance should be identified, disclosed, carefully review activities.
examined, and managed in such a way as to avoid any
corruption of the research process. (Trust; Accountability;
Openness)
Records 8. Treat data with scholarly rigor: The highest levels of 4. Research Records: Researchers should keep clear, accurate
exactitude should be ensured in proposing, performing, records of all research in ways that will allow verification
recording, analyzing, interpreting, reporting, publishing, and replication of their work by others.
and archiving research data and findings. The
appropriate authorities, as mandated by applicable
standards or regulations, should retain a copy of research
records. (Honesty; Accountability)
Subjects 9. Treat everyone involved with research fairly and with

respect: All individuals and institutions directly affected
or involved in research, including human subjects and
animals, should be treated fairly and with respect.
Relevant regulations and applicable Tri-Council and
institutional policies should be followed and guided by
common principles and values. (Fairness; Trust)
Reporting 7. Report on research in a responsible and timely fashion: 5. Research Findings: Researchers should share data and
Publications, including clear statements of data and findings openly and promptly, as soon as they have had
methodology, as well as research activities and research an opportunity to establish priority and ownership claims.
results, should not be unduly delayed or intentionally
6. Authorship: Researchers should take responsibility for their
withheld. These considerations should be configured
contributions to all publications, funding applications,
within each discipline’s own timeframe. (Trust; Openness)
reports and other representations of their research. Lists
10. Acknowledge all contributors and contributions in research: of authors should include all those and only those who
All contributors and contributions to research and meet applicable authorship criteria.
research results, including financial contributions, should
7. Publication Acknowledgement: Researchers should
be acknowledged fairly and accurately whenever
acknowledge in publications the names and roles of those
research is communicated. (Fairness; Accountability;
who made significant contributions to the research,
Openness)
including writers, funders, sponsors, and others, but do

not meet authorship criteria.
Review 6. Review the work of others with integrity: Individuals and 8. Peer Review: Researchers should provide fair, prompt and
organizations should engage in, and organize, peer rigorous evaluations and respect confidentiality when
review and the evaluation of the work of others in a reviewing others’ work.
manner that reflects the highest scholarly, professional,
and scientific standards of fairness and confidentiality.
(Fairness; Trust)
(continued)
49
Table 2.1 (continued)
50
Category Expert Panel on Research Integrity, Singapore Statement
Council of Canadian Academies
Chapter 2
Trainees 11. Engage in the responsible training of researchers: Research
investigators, particularly new scholars, should have
access to education, mentoring, and support to develop
and maintain the skills and capacities required for
conducting and managing research in accordance with
relevant scholarly and ethical standards. An individual’s
level of responsibility should be commensurate with his
or her competence and experience. (Fairness; Trust)
Society 10. Public Communication: Researchers should limit

professional comments to their recognized expertise
when engaged in public discussions about the application
and importance of research findings and clearly
distinguish professional comments from opinions based
on personal views.
14. Societal Considerations: Researchers and research

institutions should recognize that they have an ethical
obligation to weigh societal benefits against risks
inherent in their work.
Misconduct 11. Reporting Irresponsible Research Practices: Researchers

should report to the appropriate authorities any
suspected research misconduct, including fabrication,
falsification or plagiarism, and other irresponsible
research practices that undermine the trustworthiness of
research, such as carelessness, improperly listing authors,
failing to report conflicting data, or the use of misleading
analytical methods.
12. Responding to Irresponsible Research Practices: Research
institutions, as well as journals, professional organizations
and agencies that have commitments to research, should
have procedures for responding to allegations of
misconduct and other irresponsible research practices and
for protecting those who report such behavior in good
faith. When misconduct or other irresponsible research
practice is confirmed, appropriate actions should be
taken promptly, including correcting the research record.
Rest JR. 1986. Moral Development: Advances in Research and Theory. Praeger Pub-
lishers, New York, NY.
Steneck NH. 2007. ORI Introduction to the Responsible Conduct of Research. U.S.
Government Printing Office, Washington, DC. http://ori.hhs.gov/sites
/default/files/rcrintro.pdf.
Weston A. 2010. A Practical Companion to Ethics, 4th ed. Oxford University Press,
New York, NY.
Online
A collection of ethics codes published by professional and academic socie
ties and associations may be found at the following websites.
The Singapore Statement on Research Integrity, produced by the 2nd World

Conference on Research Integrity in 2010, at:
http://www.singaporestatement.org/
Ethics Collaborative Online Resource Environment (Ethics CORE) web-

site, maintained by the University of Illinois and sponsored by the Na-
tional Science Foundation at:
http://nationalethicscenter.org/
Center for the Study of Ethics in the Professions at the Illinois Institute of
Technology website:
http://ethics.iit.edu/
The Online Ethics Center for Engineering and Science website:

http://www.onlineethics.org/
In addition to Council of Canadian Academies Report and the Singapore

Statement, referenced above, the following resources were used to compile
information on values of the scientific community contained in this
chapter.
For information on the European Science Foundation’s Member Organi-

sation Forum on Research Integrity, which produced The European Code of
Conduct for Research Integrity:
http://www.esf.org/coordinating-research/mo-fora/research-integrity.html
52 Chapter 2
The Irish Council for Bioethics’ Recommendations for Promoting Research

Integrity:
http://irishpatients.ie/news/wp-content/uploads/2012/04/Irish-Council-of
-Bioethics-Research_Integrity_Document.pdf
(Note: the Irish Council for Bioethics ceased to exist in 2010. The PDF referenced
here—archived on the Irish Patients Association website—may still be downloaded.)
The Australian Government National Health and Medical Research

Council’s Australian Code for the Responsible Conduct of Research:
http://www.nhmrc.gov.au/guidelines/publications/r39
chapter 3
Mentoring
Francis L. Macrina
Overview • Characteristics of the Mentor-Trainee Relationship
• Choosing a Mentor • Foundations of Mentoring • Diversity,
Research, and Research Training • Learning Mentoring Skills
• Conclusion • Discussion Questions • Case Studies • Resources
Overview
History
The word “mentor” has its origins in the poetic epic The Odyssey, written
by Homer more than 2,500 years ago. In Homer’s story, Odysseus, king of
Ithaca, sails off with his army to do battle in the Trojan War. Before leav-
ing, Odysseus entrusts the care and education of his son Telemachus to his
faithful friend Mentor. Mentor’s responsibilities become enormous in
scope and duration. The war lasts 10 years, and Odysseus’ return trip takes
another decade as he encounters one astounding adventure after another.
Meantime, Penelope, Odysseus’ wife, is being courted by noblemen in her
husband’s absence. Thinking that Odysseus will never return, these suitors
waste his possessions by staging numerous feasts and parties. Throughout
all of this, Mentor faithfully performs his oversight duties. His efforts are
manifested in the young man Telemachus, who ultimately demonstrates he
is worthy to be the son of Odysseus. And so the word “mentor” has come
to mean a loyal and trusted friend, enlightened advisor, and teacher.
Modern-day mentors in research and research training

During the 1970s, the terms “mentor” and “mentoring” came on the scene
in professional environments including that of scientific research. Com-
mon descriptions of a mentor were of a person who “imparted wisdom,”
“nurtured,” “sponsored,” “criticized,” and, in general, “cared for” someone
else. The recipient of the mentor’s actions was variously called a trainee, a
protégé, a mentee, or an apprentice. Mentors are characterized as being
doi:10.1128/9781555818487.ch3
53
54 Chapter 3
senior— professionally, chronologically, or both— to the person being

mentored, as often found in modern dictionary definitions: e.g., “some-
body, usually older and more experienced, who provides advice and sup-
port to, and watches over and fosters the progress of, a younger, less
experienced person.”
In scientific research, a mentor provides guidance in one or more areas
that include intellectual development and academics, technical expertise,
and ethical responsibilities and behavior. As team leaders or principal in-
vestigators, scientists may be mentors to a variety of individuals including
undergraduate students, graduate students, postdoctoral trainees, technical
staff, and even their peers (e.g., other faculty). Mentoring between and
among individuals representing these cohorts is also possible. For example,
a postdoctoral trainee may take on the role of mentor to a graduate or un-
dergraduate student. In the world of academics, sometimes “mentoring” is
used to describe the role of the faculty advisor. But the traditional aca-
demic advising of students—typically undergraduate—does not include
many things that happen in mentoring. Mentoring entails greater inter-
personal engagement and is more complex than traditional advising. Al-
though “mentor” and “advisor” may be used interchangeably, not all
advisors are mentors. Advising at the undergraduate level involves guid-
ance that is largely focused on the academic progression and matters re-
lated to completion of a curriculum to achieve a degree. Another
distinguishing feature is the role of informed choice in establishing the
mentor-trainee relationship. An academic advisor and advisee are brought
together because educational institutions usually mandate that students
have faculty advisors. Usually, there is little choice afforded the partici-
pants when entering into this relationship. But such a relationship may
develop into a mentoring relationship, with the mentor engaging in some
or all of the above-mentioned activities. In this case, a conscious choice has
led to the emergence of a mentor-trainee relationship, and it’s a choice that
both members are party to. In the case of either a graduate degree or a
postdoctoral training experience, the formation of the relationship is typi-
cally steeped in mutual consent between the mentor and the trainee. The
nature of the selection process, the scope of activities, the time invested by
both parties, and the expected outcome of preparation for a specific pro-
fession predestine the formation of a mentor-trainee relationship.
In this chapter, our focus will be on the mentor-trainee relationship in-
volving pre-and postdoctoral trainees. The substantive elements of the
mentor-trainee relationship have much in common for both of these co-
horts. Career mentoring at later professional stages (between faculty or
between principal investigators and technical staff) depends on many of
the basic principles and strategies that are employed in mentoring trainees
that will be discussed here.
Mentoring 55
The canons of scientific integrity derive their life from effective men
toring in graduate and postdoctoral training programs. Mentors inform, in-
struct, and provide an example for their trainees. The actions and activities
of mentors affect the intellect and attitude of their trainees. The educational
transfer process may be obvious or subtle, but the effects are rarely in dis-
pute: trainees emerge from their programs with an intellectual and ethical
framework strongly shaped by their mentors. Indeed, trainees often assume
the traits and values of their mentors. Thus, mentors are the stewards of
scientific integrity. Yet the young faculty member who has just accepted his
or her first trainee into the lab is not likely to have had much formal educa-
tion in the principles of mentoring and is very likely to have no experience
at all. The direct experience of dealing with trainees improves mentoring
skills. To be sure, the skills and responsibilities of mentoring sometimes
elude precise articulation and definition, because, as a human activity, there
is great variation in the practice of mentoring trainees. There are many ef-
fective styles, and although common traits may be shared, there is no one
prescribed method.
Characteristics of the
Mentor-Trainee Relationship
A growing body of literature discusses and analyzes mentoring in profes-
sional settings, including the university and the research laboratory. In ad-
dition, many academic and research institutions now publish policies or
guidelines on mentoring, and these have been used to inform the following
discussion of mentor-trainee relationship characteristics. In the sciences
and related professions there are several general categories of activities
that describe the mentor-trainee relationship and the roles of its partici-
pants. These apply universally—to a greater or lesser extent—to mentor-
trainee or mentor-protégé relationships at any level.
Mentors teach content-specific knowledge and methodology

A primary role of a mentor is that of teacher, and the delivery of specific
knowledge is achieved in a variety of ways. The experience and scientific
competence of a mentor serves as the foundation from which new knowl-
edge is directly transmitted to the trainee. But knowledge and skills are
also transmitted indirectly as the trainee observes the mentor as a role
model. In such cases, mentors share their talents for defining problems,
asking questions, and selecting the means for solving problems and getting
answers. This may be done in a calculated way wherein a novice is guided
through a problem with considerable assistance from the mentor. Alterna-
tively, mentors may convey their style and methods for problem solving by
example, allowing trainees to observe the process. What is learned may
56 Chapter 3
range from how the mentor formulates a hypothesis to how he or she

keeps up with the literature and developments in the field. It is rare for the
mentor not to make an impression in this setting, and the trainee usually
assimilates some of the ways in which the mentor deals with the theoretical
and practical aspects of doing research. These mentoring issues can remain
in play throughout one’s career, applying both to the young scientist doing
postdoctoral training and to the seasoned faculty member doing a research
sabbatical.
Mentors evaluate and critique scientific research

There are many opportunities for mentors to convey to trainees “how
things are going.” Whether reviewing results in a data book; listening to a
presentation, lecture, or seminar; or critiquing a manuscript or disserta-
tion, the mentor can and should provide constructive criticism. Such activ-
ities give the mentor a chance to identify problems and propose remedies
and to challenge the trainees to refine their research skills. In practical
terms, these opportunities often allow the mentor to help improve the
trainee’s communication skills. These activities also continue throughout a
career. For example, scientists may develop mentor-protégé relationships
with colleagues who read and critique their proposals, manuscripts, or
other writings.
Mentors foster the socialization of trainees

Mentors provide information to trainees about the workings of science.
This may involve familiarizing trainees with policies, guidelines, and regu-
lations about the conduct of research. Normative standards pertaining to
authorship, peer review, data sharing, and collaboration are things that
trainees often hear about first from their mentors. Mentors make trainees
aware of the ethical responsibilities of scientists and provide by example
and instruction the tenets of responsible conduct in research. In short, the
trainees’ entry into the profession involves learning appropriate behaviors,
and mentors take an active role in this process.
Mentors promote career development

Mentors are advocates. They look out for the professional health and well-
being of their trainees. Mentors can help with insight, information, and
advice about career planning. They can help trainees understand and prac-
tice networking by encouraging them to communicate with other scien-
tists and by introducing them to other scientists. Mentors help trainees
develop and refine appropriate interpersonal skills like negotiation, media-
tion, persuasion, and poise. Later in a career, mentors may promote
protégés by suggesting their names as speakers or conference organizers or
by recommending them for service assignments that are part of good
Mentoring 57
professional citizenship. Nominating trainees or protégés for awards also

can be done to foster and enhance their careers.
Mentors perform different duties at different times

The primary duties of a mentor change over time, and at any moment they
may involve different aspects of the relationship. Switching from the role
of mentor-advisor to that of mentor-confidant or mentor-critic might oc-
cur over the span of a day. Being responsive to the changing demands of
the mentor role requires critical attention and oversight. Mentoring is a
one-on-one activity. Typically, it is an intense relationship that demands
continued personal and intellectual involvement on the parts of both men-
tor and trainee. Mentoring relationships work best in an atmosphere of
mutual respect, trust, and compassion. Mentoring is dynamic and complex.
It has multiple dimensions that often interconnect, and no one dimension
alone defines what a mentor does. A mentor is not just an academic advi-
sor, nor is mentoring just a means of linking trainees to an academic infra-
structure. Mentors are not just teachers or sources of resources or
information to trainees. Mentors are not just supervisors, as in individuals
who oversee dissertation research. Nor are they solely role models. In-
stead, these and other activities are often applied in various combinations
and receive different emphasis depending on specific circumstances and
the changing needs of the trainee.
Trainees depend on mentors

A unique aspect of predoctoral— and to some extent postdoctoral—
mentoring is the dependence of the trainee on the mentor. Often, this de-
pendence is grounded in finances, because the mentor’s grant provides
stipend support and tuition and fee payments. Often the mentor’s grant
provides the resources that are critically needed for trainees to perform
and complete their research projects. Moreover, the mentor is usually di-
rectly or indirectly involved in providing or securing the resources for
trainees to attend meetings or workshops that are important to their train-
ing experience. Finally, trainees are critically dependent on their mentors
for a position when they finish their programs. Such positions might entail
postdoctoral training or employment in universities, industry, or govern-
ment. Such dependence on the mentor’s evaluation continues well into the
trainee’s career; for example, applying for a position beyond a postdoctoral
training experience usually means that the predoctoral mentor provides a
letter of recommendation.
Thus, a predoctoral trainee is profoundly dependent on his or her
mentor, and a similar dependence is encountered in the postdoctoral
trainee-mentor relationship. This dependence means that the trainee is
vulnerable to abuses of power. Although such abuse would seem
58 Chapter 3
antithetical to the basic premise of mentoring, trainees do fall victim to

such circumstances. Abuses of power can take the form of acts of com-
mission as well as acts of neglect. The trainee usually finds himself or
herself in a difficult position when such situations arise. The very person
who should be available to solve the problem at hand turns out to be at
the heart of the problem. Nonetheless, the mentor should be approached
directly if such problems are perceived by the trainee. Communication
between mentor and trainee can be an effective way to resolve the situa-
tion. In addition, graduate advisory committees, other faculty, and de-
partmental chairs can usually help. Dependence on their mentors at
a time when they feel abused by the same person presents trainees with a
dilemma that is not easily resolved. However, avoiding the problem is a
virtual guarantee that the problem will get worse.
The mentor-trainee relationship is an exclusive one

Although graduate programs usually mandate that each predoctoral trainee
be guided by an advisory committee, the mentor usually chairs the com-
mittee and is the trainee’s principal advocate in this forum. The exclusive
and intense nature of the mentor-trainee association in science is under-
scored by the usual longevity of such relationships. Predoctoral mentoring
in graduate research usually marks the beginning of a relationship that
significantly outlives the time spent in formal training. Trainees may con-
tinue to rely on their graduate mentors for advice and counsel as they
progress through the beginning stages of their professional careers.
Staying aware of the academic status, intellectual development, and re-
search progress of a trainee requires regular oversight, information ex-
change, and frequent and regular interpersonal communication. One critical
issue is the size of the research group. As the number of people in a research
group increases, there is less time to conduct a proper and effective mentor-
trainee relationship. Mentors need to face up to this reality as they weigh
commitment, take on additional responsibilities, and develop their research
training programs. There is a point of diminishing returns in the number of
trainees who can be effectively mentored. When that threshold is crossed,
the ability to responsibly guide trainees is compromised and the viability of
the training experience is put in jeopardy. Poorly mentored trainees can un-
knowingly cut corners, make mistakes, or not recognize errors. Over time,
such behavior can come back to haunt the mentors by jeopardizing the
credibility of their research programs. Thus, neglect of mentoring responsi-
bilities and duties can harm both mentors and trainees.
At times, members of the graduate advisory committee or even other
faculty may assume transient mentoring roles. For example, a trainee in
biochemistry may need to produce antibodies against a protein she has
isolated. To achieve this goal, she may be scientifically mentored by an
Mentoring 59
immunologist who is a member of her advisory committee. Mentoring ac-

tivities in this case might involve instruction and advice regarding compli-
ance with regulations concerning the use of animals in research, the
handling of animals in the called-for experiments, and training in relevant
immunological methods.
The mentor-trainee relationship is built on trust

Certain fundamental characteristics must be evident in the actions of both
the mentor and the trainee. Personal respect is absolutely necessary on
both sides of the mentoring relationship. Mutual trust is another essential
ingredient. Throughout the relationship, trainees must trust their mentor’s
advice and actions. Most students at the early stages of their programs de-
pend strongly, if not exclusively, on their mentor’s knowledge and expertise
in helping them select a viable dissertation research project. A mentor who
has developed a reputation for recommending changes in a trainee’s dis-
sertation project at the least sign of failure may have difficulty attracting
and keeping students in the lab. Such actions tend to lessen confidence and
undermine trust in the mentor’s scientific decision-making style. Mentors,
for their part, must cultivate a trust in the caliber of work performed by the
trainee over the course of the dissertation research project. In an active
mentoring relationship, the mentor is able to gauge a trainee’s perfor-
mance by four principal means: (i) direct laboratory observation, (ii) view-
ing the trainee’s raw and analyzed research data, (iii) listening to trainees
present their ideas and data, and (iv) reading the candidates’ reports and
manuscripts on their work. Over time, the mentor develops a degree of
confidence in the trainee’s operating style based on these observations. Di-
rect laboratory observation is usually a significant component in the early
stages of training but may wane or even disappear as the trainee progresses
and matures. Data observation and related discussion take place through-
out the course of graduate training. This activity should be characterized
by regular face-to-face meetings, with data books and other relevant mate-
rials at hand. The mentor should observe trainees as they give seminars,
write research reports, or lead journal clubs. This activity, which should
persist throughout the training experience, serves two functions. It allows
for continuing assessment of student progress in scientific thinking and
analysis, and it provides an excellent forum for the mentor to critique the
scientific communication skills of the trainee.
Free and open communication flows from an atmosphere of mutual re-
spect and trust in a successful mentor-trainee relationship. Good mentors
are critical and demanding of their trainees, and these characteristics
should be explicit in all forms of communication with the trainee. When it
is combined with compassionate personal support and enthusiasm for the
work, trainees are likely to recognize helpful criticism and guidance and
60 Chapter 3
not confuse these messages with displeasure, hostility, or intimidation.

Such an interchange, in turn, cultivates a collegial relationship between the
participants as together they share and analyze information, critique each
other’s ideas, and solve problems with each other’s help. Attribution of
credit and recognition of accomplishments should be clearly articulated.
Taken together, these activities are the important first steps in the broad-
based socialization of a young scientist.
Choosing a Mentor
Forming mentor- trainee relationships that involve an established re-
searcher and a predoctoral (or masters level) or postdoctoral trainee is a
two-way street. In general, the prospective trainee starts by narrowing the
selection process according to the field of work of possible mentors. On
the one hand, this part of the process is steeped in the trainee’s educational
and professional goals and objectives. These must be compatible with the
skills and expertise of a mentor. For predoctoral trainees the selection pool
includes faculty in their home departments, or in other departments in the
case of multidisciplinary training programs. For prospective postdoctoral
students, meeting professional goals and objectives is a critical driver in
seeking a mentor. But once they have decided on the nature of the schol-
arly training they are seeking, candidates may undertake a national or in-
ternational search for the desired person. Whether seeking a predoctoral
or postdoctoral mentor, trainees typically use both subjective and objective
criteria in the selection process. These include:
• Active publication record in high-quality, peer-reviewed journals.
Online tools for evaluating this include the Web of Science, PubMed
and PubMed Central, and Google Scholar. Individual and institu-
tional websites of mentor candidates under consideration are good
sources of such information, too.
• Extramural financial support base: competitiveness and continuity of
support. Publicly available databases of grants made by the National
Institutes of Health (NIH), the National Science Foundation (NSF),
and other federal funding agencies are helpful here. Many private
foundations also list grants awarded, including the name of the prin-
cipal investigator. Also useful in this category are curricula vitae or
biosketches that may be posted on the candidate mentor’s personal
websites.
• National recognition: meeting and seminar invitations, invited pre-
sentations, consultantships, and honors. As above, these may be
found in online biographical documents or in online departmental or
institutional reports.
Mentoring 61
• Rank, tenure status, and proximity to retirement age.

• Prior training record: time it takes trainees to complete a degree,
number of trainees, and enthusiasm for previous trainees’ accom-
plishments.
• Current positions of individuals who have completed training over
the past 5 to 10 years.
• Recognition for trainee accomplishments (e.g., coauthorship prac-
tices).
• Organizational structure of the laboratory and direct observation of
the laboratory in operation.
Although a considerable amount of the information mentioned above
can be collected passively, there will come a point in the selection process
where active engagement must occur. Predoctoral trainees will need to
meet in person with prospective mentors to exchange information that will
help each make an informed decision. Such meetings may be extended to
include members, including trainees, of the prospective mentor’s research
group. It is in the best interest of the potential mentor and the trainee to
meet on several occasions and to thoroughly discuss the practical issues of
dissertation research possibilities and the logistics of selection of a project.
It is also appropriate to discuss issues such as mentoring style (supervision,
general expectations, and goal setting) and other personal and academic
issues related to graduate training. Candid discussion at this point not only
provides the basis for intelligent decisions on the part of both the prospec-
tive mentor and the trainee but also sets the stage for the free and open
communication that must support the trainee-mentor relationship going
forward. Talking with lab members about their view of the training envi-
ronment provides a valuable perspective for the trainee seeking a mentor.
The training climate, enthusiasm of other trainees, and corroborative in-
formation on the mentoring style can make the trainee more comfortable
with the prospect of selecting this person as a mentor, or they can raise
more questions that will need to be answered by the prospective mentor.
Often formal research group rotation programs are options for this
information gathering. These involve the trainee spending up to several
weeks doing a short-term project. These programs provide a firsthand
view of the operation of the research lab and its personnel dynamics, in-
cluding mentor-trainee relationships. For many entering graduate train-
ees, this encounter is often their first exposure to the day-to-day workings
of a research environment. This exposure allows prospective trainees to
directly assess the climate they will encounter in their training experi-
ence. Does the mentor provide much direct supervision, or are techno-
logical skills and data analysis and interpretation relegated to another
senior lab member? Has the training environment changed much over
62 Chapter 3
time in the experience of the current trainees? Have the methods of

training used by the mentor been successful over time? The rotation sys-
tem also allows the mentor to view the prospective trainee at the research
bench and thus to acquire useful, albeit brief and casual, impressions of
the trainee’s potential.
In the case of postdoctoral training, direct engagement of interested
parties typically involves written or telephonic communication to begin an
information exchange that will guide the decision-making process from
the perspective of both the trainee and the mentor. A visit to the potential
mentor’s lab to enhance this process and to meet with other members of
the research group is highly recommended. Having an in-person meeting
at a scientific conference is a reasonable substitute for this. Mentors rarely
accept postdoctoral trainees without seeking references—verbal, written,
or both—in support of the candidate trainee.
Finally, in the case of mentoring undergraduates, many of the elements
mentioned above may come into play. Undergraduate research mentoring
may be part of a structured program within the institution. In these cases,
undergraduate trainees may have little say in the selection of mentors be-
cause the assignment mechanism is prescribed within the operating proce-
dures of the program. Examples of such structured arrangements range
from university- coordinated undergraduate research opportunity pro-
grams to grants that specifically support research experiences for under-
graduates. However, a certain fraction of undergraduate research
engagements are the result of purely ad hoc processes where undergradu-
ates seek out opportunities by approaching researchers directly or through
intermediaries. In these cases, information gathering on the part of the
undergraduate may follow processes described above, with the potential
mentor assessing the undergraduate on a case-by-case basis with informa-
tion gained from academic records, interviews with the student, or based
on recommendations from colleagues who know the student.
In summary, selection of a mentor usually requires both formal and
informal activities coupled with thoughtful analyses on the part of both
mentor and trainee. However, even the most thoughtful decisions, based
on the careful collection of facts and data, can result in mentor-trainee
relationships that do not work. Conflicting personal styles that emerge
over time, disenchantment with a general area of research, and evolving
changes in aspects of mentoring responsibilities or discharge of duties all
can cause a mentor-trainee relationship to degenerate. When this hap-
pens, resolution at an early stage is the best course of action for all in-
volved. Candid mentor-trainee discussion of problems may need to be
augmented by third-party mediators (e.g., departmental chairs; graduate
program directors; or institutional experts in conflict resolution, such as
university ombudsmen). Intractable problems should be recognized and
Mentoring 63
accepted; switching mentors in either predoctoral or postdoctoral train-

ing programs may be the only way to solve some problems. To be sure,
prolonging problems by failing to face up to them often creates tension
in the training environment and is likely to unnecessarily lengthen the
duration of the training program and negatively affect its overall quality.
Foundations of Mentoring
Institutional commitment
Effective mentoring is built on a foundation of institutional commitment.
As stressed in the Association of American Medical Colleges (AAMC) train-
ing compacts for predoctoral and postdoctoral trainees, institutions must be
committed to a training environment comprising the highest educational,
scientific, and ethical standards. Institutional commitment requires clear
policy, organizational structure, and oversight to foster a research mentor-
ing environment. Such institutional commitment ensures consistency and
openness that benefits both mentors and trainees. For predoctoral mentor-
ing, this involves sustaining high-quality academic programs, providing ex-
plicit guidance on trainee expectations, and promoting mechanisms for
monitoring trainee progress. To achieve this, graduate training programs
must be well developed and supported. That the institution puts a premium
on graduate education must be self-evident to trainees and mentors alike.
For postdocs, institutional commitment means providing a user-friendly en-
vironment that is designed to ensure that trainees finish their programs fully
prepared for the next step in their professional careers. The need for admin-
istrative infrastructure to support postdocs is being increasingly recognized,
and a growing number of institutions have created central offices that pro-
vide postdoctoral services and support training-related activities. Such of-
fices often are involved in creating and maintaining policies that govern
postdoctoral training and address such things as conditions and method of
appointment, salary levels, benefits, and grievance procedures. The National
Postdoctoral Association (NPA) has become a voice for postdocs, and it pro-
vides resources for helping institutions develop the administrative infra-
structure to enhance the training experience.
Institutional support can also play a role in the mentoring of under-
graduates and in peer-to-peer mentoring relationships. Institutional initia-
tives that coordinate and oversee research opportunities for undergraduates
provide a portal for undergraduates seeking to do research. Usually orga-
nized as institutional offices, these initiatives ensure matches between
mentors and students, creating an environment that encourages and nur-
tures undergraduate mentoring. Such initiatives often celebrate the men-
tored undergraduate experience by sponsoring special lectures, programs
featuring undergraduate research, and social events. All of these heighten
64 Chapter 3
the awareness of research opportunities under the guidance of a mentor

but require a commitment of resources on the part of the institution.
In peer-to-peer (or peer-to-near peer) mentoring, participants are pro-
fessionally independent, having completed their formal training. At some
institutions, departments are encouraged to assign an experienced faculty
member to mentor a new faculty member. In these relationships, the men-
tor can provide advice and counsel on topics such as networking and col-
laborative research, setting goals and objectives, promotion and tenure
preparation, and balancing work and personal life, just to name a few. For-
mal mentoring programs that promote and support such relationships also
need resources, and there is a clear role for the institution in forming and
sustaining such programs.
Finally, institutional commitment for the mentoring enterprise is man-
ifest in general mentoring guidance documents either written by the insti-
tution or adopted from other organizations or agencies. We’ll review some
common elements of these documents in the following section. In addi-
tion, the “Resources” section at the end of this chapter will direct the
reader to examples of relevant guidance and policies that reflect the pro-
grams cited throughout the chapter.
Mentoring guidance
Guidance on mentoring in research training exists in various forms. Fre-
quently, institutional policies on academic standards or on responsible con-
duct of research include the topic of mentoring. Examples of such policy
statements may be found by searching institutional websites, and represen-
tative samples are found below in the “Resources” section. Some institutions
have prepared position papers or have published mentoring “handbooks.”
Institutions also may publish mentoring policies addressing predoctoral or
postdoctoral mentoring practices and expectations. N ational organizations
such as the Howard Hughes Medical Institute and the AAMC have pub-
lished monographs or position papers that address mentoring practices. The
following is a distillation of mentoring guidance from this genre of sources
to illustrate the spectrum of topics addressed. Categories of information are
not presented in any order of priority, nor is any relative importance implied
based on, for example, the number of times a particular item appears in
these documents. Instead, this summary is meant to fully describe the con-
tent of these documents so as to provide the broadest possible perspective.
Personal characteristics
Desirable characteristics of mentors include being
• Approachable and accessible

• Empathetic and encouraging
• Patient
Mentoring 65
• A good listener
• Constructively critical, including providing regular evaluation of
performance
• Willing to share knowledge
• An exemplar of honesty and ethical standards
• Appreciative of trainee contributions
• Attentive to career development and career counseling, including in-
troducing trainees to scientific colleagues to catalyze networking
• Appreciative of diversity and inclusivity
• Respectful of matters involving trainee confidentiality
Trainees have responsibilities to their mentors that include
• Being proactive in planning and goal setting
• Conscientiously discharging their agreed-upon and assigned duties
in connection with their research projects
• Meeting regularly with their mentors to review data and to be
counseled
• Being respectful of their mentors and their mentors’ time
• Being thankful
• Maintaining research records according to best practices for their
disciplines
• Engaging their mentors in open and timely discussions of research
data, including review of data books and sharing data with others
• Taking appropriate responsibility for reporting research in the liter-
ature according to relevant policies and best practices
• Conducting research involving human or animal subjects or biohaz-
ards in full compliance with relevant regulations and policies
• Fully disclosing competing interests that might create a real or per-
ceived conflict of interest in relationship to the trainee’s research or
the research agenda of the mentor
Assignment of a mentor
For predoctoral trainees, institutional guidelines and policies frequently
describe this as a formal transaction that is vested in the graduate program
administration. It is neither a temporary nor ad hoc assignment, and disso-
lution of the relationship usually requires a second formal transaction in-
volving all the interested parties (trainee, extant mentor, new mentor, and
sometimes the relevant program organization or the institution). The for-
malization of mentorship involving a postdoctoral trainee is usually mani-
fest in the appointment letter signed by the postdoctoral mentor.
General features of the relationship

Elements discussed previously as part of the characteristics of mentor-
trainee relations are often reaffirmed in mentoring guidelines. A central
66 Chapter 3
theme in the narrative is the description of a relationship that is character-

ized by professional courtesy and trust. Both mentor and trainee need to
properly recognize and acknowledge their respective contributions. Men-
tors should always keep the trainees’ best interest in mind. The mentor
should provide enough time for the trainee. Mentors should place value on
diversity and dealing with mentoring issues attendant to diversity. Mentors
are cautioned against conflicts of interest that may interfere with their du-
ties (e.g., familial or personal relationships). One specific admonition
raised in this context is that projects in which the mentor has a monetary
stake or other compelling interest are not acceptable training experiences.
Occasionally, guidelines mention that avenues for problem solving related
to the relationship should be available and that trainees should be aware of
them and not reluctant to use them.
Mentor-trainee ratio
The ratio of mentor to trainees in a laboratory group should be small
enough to foster scientific interchange and to afford supervision of the
research activities throughout the training program. Few would argue
with the assertion that, at some point, the size of a laboratory research
group curtails and may even preclude responsible and effective mentor-
ing. However, defining that point is difficult, because it depends on such
factors as the type of trainee (entry level or advanced, predoctoral or
postdoctoral), the nature of the work being performed, the overall time
commitments of the mentor, and the mentor’s management skills. Some
would argue that active mentoring of more than 10 to 12 trainees is
challenging if not impossible. Larger groups must have a secondary
mentoring network in place, wherein senior members of the lab also
serve as mentors. Such an infrastructure may enable the laboratory head
to delegate mentoring duties, but this practice can be criticized on the
grounds that such systems are not in keeping with some mentoring
guidelines. Specifically, mentoring is predicated on mentor-trainee in-
terchange and, as such, does not afford the latitude for delegation of
such responsibility.
The mentor’s supervisory role

The mentor should have a direct role in supervising the designing of ex-
periments and all activities related to data collection, analysis and interpre-
tation, and storage. The emphasis is on close supervision of the trainee’s
progress, highlighted by personal interaction. In some guidelines, this is
stressed especially for trainees in the early stages of their programs. Some
of the standards-of-conduct documents underscore the importance of di-
rect, active supervision by the mentor.
Mentoring 67
Communication
Collegial discussion among mentors and trainees should pervade the rela-
tionship, and this should be highlighted by regular group meetings that
contribute to the scientific efforts of the group and, at the same time, ex-
pose trainees to informal peer review. The definition of “regular” is usually
not provided in guidelines, although in at least one instance, once a month
was suggested. Group meetings should be augmented by mentor-trainee
meetings that are held regularly and privately. Individual attention pro-
vides the mentor and the trainee with a unique opportunity for uninhib-
ited communication, critical analysis, and problem solving on matters that
may be unique to the trainee or the specific project. Some guidelines noted
that a mentor needs to communicate a clear map of expectations leading to
a trainee’s academic goals.
The mentor is responsible for providing trainees with all relevant rules,
regulations, and guidelines that may apply to the conduct of research (e.g.,
responsible conduct of research, human and animal use documents, radio-
active and hazardous substance use documents, and others). The mentor
has a responsibility for oversight and enforcement in this area, too. Train-
ees must comply with rules and regulations as observed directly or moni-
tored indirectly by the mentor. The breach of any established policy will
come to rest with the mentor as the individual with overall responsibility
for the laboratory group.
In addition to the mentor’s role in ensuring that trainees are aware of
and understand relevant material, some guidelines mention that mentors
should be role models in conducting their research according to these pol-
icies, rules, and regulations.
Career counseling
Institutional guidelines occasionally contain recommendations about the
mentor’s role in promoting the careers of his or her trainees. These span
such things as writing candid letters of recommendation and assisting
trainees in job placement. Mentors should encourage trainees to view job
prospects realistically. Mentors should play a proactive role in facilitating
networking by introducing their trainees to colleagues, potential collabo-
rators, or individuals who might contribute to their professional develop-
ment (department chairs, senior administrators, etc.).
Performance evaluation
Planning and evaluation are vital to the career development of trainees. A
workable training plan should be accompanied by regular monitoring and
evaluation of progress. Plans should reflect expectations and objectives
that are explicit and realistic. In the case of predoctoral trainees, such plan-
ning and performance evaluation is embedded into the structure of the
68 Chapter 3
graduate training program. The trainee’s graduate advisory committee,

along with the leadership of the mentor, typically ensures that a plan exists
and that evaluation is regularly carried out. In the case of the postdoctoral
trainee, there has been an evolution of the planning and evaluation pro-
cess. Historically, the process has been ad hoc and was dependent on both
the mentor and the postdoc being appropriately proactive. In the case of
training experiences supported by a training grant or some type of fellow-
ship award, planning may be articulated to a greater or lesser degree in the
application.
The Federation of American Societies for Experimental Biology (FASEB)
has promoted the use of an individual development plan (IDP) to aid in the
training of postdoctoral fellows. The IDP is a written document that is
crafted by the postdoctoral fellow and his or her mentor. The FASEB IDP
describes a plan for action and forms the basis for periodic evaluation. It is a
flexible document, and its content is modified as the goals and needs of the
fellow change during the training period. The IDP contains both profes-
sional development needs and career objectives for postdoctoral fellows. By
its very nature, the crafting and use of the IDP promote communication
between mentor and trainee. The creation of the IDP is meant to follow
four steps. Step 1 is a self-assessment in which the postdoc is urged to assess
his or her skills, strengths, and areas needing development. Step 2 involves
outlining long-term career objectives, including identification and selection
of career opportunities along with developmental needs and prioritization
of developmental areas. These are done in open and honest discussion be-
tween mentor and postdoc. In step 3, the IDP is drafted, establishing a time
line for training, skill acquisition, and strength development; the draft is
discussed with the mentor and revised as necessary. Step 4 involves putting
the plan into action, remaining flexible and open to change, and reviewing
and revising the plan with the mentor on a regular basis. The FASEB model
calls for (at least) an annual review of performance vis-à-vis the IDP. Ideally
this review should be written.
There are resources that can be used in connection with the IDP ap-
proach encouraged by FASEB. The first two—mentioned earlier in this
chapter—are compacts developed and published by the AAMC. One com-
pact deals with the postdoctoral trainee-mentor relationship and the other
with the graduate student-mentor relationship. Both compacts articulate
core tenets of the respective mentor-trainee relationship. These tenets are
followed by robust lists of commitments of mentors and commitments of
trainees. The scope and specificity of the commitments provide a matrix of
elements that can inform planning of an evaluation of training effective-
ness, performance, and professional development.
Another resource that can be used to augment the planning and evalua-
tion of training has been published by the NPA. The NPA has established
Mentoring 69
six core competencies that can be used to inform the mentor-postdoctoral

trainee relationship and guide both parties in establishing a foundation for
acquiring and demonstrating skills that should be assimilated during train-
ing. These competencies can be used by trainees in performing self-
evaluation of their skills and competencies. Working in concert with their
mentors, trainees can use such self-evaluations to build on strengths or
address professional weaknesses. The competencies also serve as a guide
for mentors and institutions in developing well-organized and effective
mentoring programs for postdocs. In brief, the core competency areas are
(i) discipline-specific conceptual knowledge, (ii) professional/research skill
development, (iii) communication skills, (iv) professionalism, (v) leadership
and management skills, and (vi) responsible conduct of research. NPA re-
sources available in the public domain include a self-assessment tool and
concept paper that details the competencies and includes useful resources.
Finally, the NSF now requires that principal investigators on NSF
grants include a description of the plans for mentoring postdoctoral train-
ees who will be involved in the research. Sample mentoring plans available
at a number of institutional sites as well as the NSF website can be helpful
to mentors, trainees, and institutions in creating frameworks for expecta-
tions, objectives, and performance evaluation.
Diversity, Research, and

Research Training
In the setting of research and research training, the term “diversity” con-
notes a range of human characteristics, traits, and features that are associ-
ated with individuals or groups of individuals. Defining elements may
include things such as race, ethnicity, gender, age, geographic origin, reli-
gion, socioeconomic background, veteran status, sexual orientation, gen-
der identity, and disability. Research funding agencies such as the NIH and
NSF have made strong commitments to diversity and inclusivity in the
scientific workforce. These are reflected in planning and policy documents
and are supported by agency funding programs that seek to attract and
train culturally diverse researchers at various stages of their professional
development.
Diversity adds intellectual power and value to the creative environment.
No matter what their stage of professional development, researchers and
trainees bring their personal beliefs, skill sets, life experiences, and per-
spectives to the research environment. The growing nature of interdisci-
plinary research stands to benefit significantly from a diverse workforce. In
health-related and behavioral research, for example, individuals of under-
represented groups may bring unique perspectives and experience to the
design, conduct, and analysis of some types of research projects. The
70 Chapter 3
National Institute of General Medical Sciences, NIH, articulates in its

statement of the “Societal Benefits of a Diverse Workforce” that
As biomedical research becomes more interdisciplinary and more of a team
endeavor, excellent training will utilize the diversity in the trainee pool and
develop the skills and abilities needed for working with people of different
scientific, social and cultural backgrounds. Research has shown that diversity
in teams fosters innovation and contributes to greater creativity. Diversity bal-
ances biases, providing alternative perspectives and experiences for exploring
new problems. In these ways, diversity contributes to the scientific advances
that improve our nation’s health and maintain its global competitiveness.
In addition, this Institute’s strategic training plan, Investing in the Future,

asserts the findings of published studies that demonstrate that increasing
diversity has beneficial effects for all students as well as those that indicate
that culturally heterogeneous groups have the ability to solve problems
more completely and inventively.
A recent report by the NSF declares women, persons with disabilities,
and three racial/ethnic groups— blacks, Hispanics, and American
Indians—to be underrepresented in science and in engineering. This cate-
gorization is based on the fact that compared with the general population,
these groups comprise smaller percentages of those earning degrees in sci-
ence and engineering as well as those employed as scientists and engineers.
For the reasons given above, federal funding agencies are proactive in
terms of striving to achieve a balance wherein the percentage of scientists
and engineers of underutilized groups reflects the national demographics.
Strategies to do this include requiring institutions that submit training,
career development, and education grant applications to include a plan for
recruitment and retention of individuals whose training and successful de-
velopment will diversify the research workforce. Finally, it is important to
note that because most research funding is traced to the public’s tax and
philanthropic dollars, harmonizing the research workforce with popula-
tion demographics builds public trust in our use of such resources.
In considering the mentor-trainee relationship in research, the goal of
enhancing diversity has a foundational core at the level of the institution.
Institutions must be proactive in providing an environment that embraces
goals and objectives that seek diversity in keeping with its educational and
training missions. Characteristics that are harbingers of this culture in-
clude institutional affirmations on the importance of diversity and explicit
plans for enhancing it. There must be clear endorsement of diversity en-
hancement from institutional senior leadership (university president, pro-
vost, deans, etc.). The existence of an institutional diversity officer or an
office dedicated to diversity issues is important, as are educational pro-
grams that promote awareness of diversity. Training programs that con-
tribute to diversity plan implementation and raise sensitivities to relevant
Mentoring 71
issues must be resourced and promoted by the institution or by major in-

stitutional units. Another proactive role for the institution is to put a pre-
mium on the development of programs that address diversity enhancement.
In the case of the research enterprise, this would include seeking federal or
other grants that support research training aimed at diverse and underrep-
resented trainees.
Institutional workforce and training goals that speak to diversity and in-
clusivity should dovetail with those embraced by federal agencies. In this
vein it is useful to consider the NSF’s Diversity and Inclusion Goals for such
purposes. First, recruiting efforts should be aggressively implemented to at-
tract the most qualified potential applicants representing all sectors of soci-
ety for faculty, postdoctoral, and graduate trainee positions. Second, the
institution, its researchers, and its trainees must be welcoming and inclusive
of its cohorts of diverse individuals, exercising fairness, flexibility, and assis-
tance that will allow these individuals to reach their full potential. Finally,
the institution should promote an infrastructure that will ensure sustainabil-
ity of diversity and inclusivity initiatives. These include the development of
means to equip its individuals to manage and be accountable for diversity by
measuring and analyzing its impact on the research enterprise.
With regard to the role for the individual mentor, some activities have
been recommended by Kathy Barker in her book At the Helm: Leading Your
Laboratory. Barker devotes significant narrative to issues of diversity and
gender. In a section titled “The Balance between Accommodation and
Fairness,” she lists eight principles that provide useful guidance for a re-
searcher (principal investigator) in addressing the issues associated with
directing a research group comprising diverse individuals:
• Set a standard for how you treat everyone.
• Be vigilant about your own behavior.
• Intervene with lab members who have a problem with cultural
issues.
• Bring all lab members into the lab culture.
• Avoid favoritism.
• Show interest in and respect for others’ background.
• Do not allow anyone to be marginalized.
• Treat each person and each situation as a unique one.
This guidance provides a useful framework for research mentors.
Learning Mentoring Skills
Finding yourself in the role of a mentor for the first time is likely to be a
little daunting. The relationship a new mentor establishes with his or her
first trainee is laden with responsibilities for both. For the first- time
72 Chapter 3
mentor, there is sobering reality in the thought that someone has entrusted
you with the oversight and guidance of a critical part of his or her career
development. And what training prepared you for being a mentor? Hope-
fully, you had good mentoring throughout your own training, and you
have learned by observing your mentors as role models. Experiencing be-
ing mentored from the trainee’s side of the relationship will provide bene-
fits in preparing you to be a mentor. You might have read up on the subject,
including book chapters like this one. Although these experiences can
jump-start your role, learning to be a good mentor takes time. Consider
the words of Jo Handelsman, Christine Pfund, Sarah Miller Lauffer, and
Christine Maidl Pribbenow:
Effective mentoring can be learned, but not taught. Good mentors discover
their own objectives, methods, and style by mentoring. And mentoring. And
mentoring some more. Most faculty learn to mentor by experimenting and
analyzing success and failure, and many say that the process of developing an
effective method of mentoring takes years. No two students are the same or
develop along the same trajectory, so mentoring must be continually cus-
tomized, adjusted, and redirected to meet each student’s needs. A skilled
mentor’s decisions and actions are guided by a reflective philosophy, a well-
developed style, and an ability to assess student needs. There is certainly no
book that can tell us how to deal with every student or situation, but a sys-
tematic approach to analyzing and discussing mentoring may lead us to a
method for tackling the knotty challenges inherent in the job.
Guided by this thinking, Handelsman and colleagues, with support from

the Howard Hughes Medical Institute, have created a mentoring seminar to
assist scientists in learning to be mentors. The core of this seminar is a 152-
page manual designed to be used by a facilitator in teaching the seminar,
called Entering Mentoring. Facilitators may be novices (e.g., “new” scientists
with no direct experience in mentoring), experienced mentors, or even
trainees. The authors note that mentoring experience on the part of the fa-
cilitator does not seem to be critical, as the success of the seminar is driven
by the participants, whose contributions are enriched by their experience as
trainees. The eight-session seminar packaged in the manual is built on back-
ground materials, case studies, and discussion questions and exercises that
emphasize interaction and interpersonal engagement to achieve learning.
The seminar provides an excellent platform for learning and honing men
toring skills. The materials to deliver it are available in the public domain
and may be found in the “Resources” section of this chapter.
Conclusion
Mentor-trainee relationships are critical to both the technical training and

professional socialization of young scientists. The mentor-trainee selec-
tion process should involve an informed decision on the part of both
Mentoring 73
participants. The mentor-trainee relationship must be built on mutual

trust and respect. It is a dynamic interpersonal relationship, with both par-
ties having distinct responsibilities. Educational institutions, professional
organizations, and professional societies have taken to formalizing guid-
ance on the mentor-trainee relationship in the past few decades. Such
writings are helpful in presenting the responsibilities and duties of both
mentors and trainees. Candid communication focused on expectations and
performance is critical to successful training relationships.
1. What criteria and sources of information would you recommend

graduate students use in selecting a mentor to guide them through
their dissertation research?
2. What do you believe are the core values of the mentor-trainee rela-
tionship in science?
3. Under what circumstances should a predoctoral trainee consider
changing his dissertation advisor (mentor)?
4. What is your estimate of the maximum number of predoctoral train-
ees a faculty member could effectively mentor at one time? Should
graduate programs or departments limit the number of predoctoral
trainees that can be simultaneously mentored by a faculty member?
5. What programs and resources does your institution provide to edu-
cate mentors about diversity and inclusivity in their role as research
trainers? How do these compare to a few peer institutions of your
choosing?
Case Studies
3.1 Lois Adams is doing her doctoral research in psychology under the
supervision of her mentor, Professor Kali Chaterjee. Her research
is aimed at evaluating strategies that motivate patients over age 50 to get
colonoscopy screenings. Lois has spent the past year designing and validat-
ing a survey to assess behavioral and motivational factors that aim to im-
prove compliance with standards recommended for having this procedure.
Meanwhile, Neo-Med-Care, an ambitious biotechnology company, has
just marketed a noninvasive way to screen for colon cancer by improving
the sensitivity of a fecal blood test. Neo-Med-Care has been trying unsuc-
cessfully to convince patients to try its screening method. Lois has told her
uncle, who works for Neo-Med-Care, about her dissertation project, and
without consulting her mentor offers her uncle a copy of the survey. Sev-
eral months later Professor Chaterjee’s husband is given a printed survey
during his annual physical visit with his primary care physician. He is asked
74 Chapter 3
to take the survey home, complete it, and mail it back to the physician’s
office. Upon returning home, he shows the survey to his wife, who is struck
by the similarity of this questionnaire to the one developed by Lois. Some
of the survey items are identical or nearly identical to those developed by
Lois. And overall, the conceptual basis of the survey is similar to that of
Lois’s. Professor Chaterjee makes a photocopy of the survey and contem-
plates whether she should bring this to Lois’s attention. What should she
do? Given the facts of the case, has Lois done anything wrong? Has
Neo-Med-Care?
3.2 Nicholas Reynolds is a second-year predoctoral student in neurobi-

ology. His mentor, Dr. Gertrude Benke, has helped Nicholas select a
research topic for his dissertation and has been proactive in helping him get
started in the lab. Dr. Benke has provided Nicholas with written guidelines
and benchmark dates for completion of various phases of the project. Nich-
olas recognizes that this project is particularly ambitious and appreciates the
need for the rigid deadlines Dr. Benke has set. Nicholas is concerned that he
may have difficulty meeting these deadlines: his wife is pregnant and he is
overseeing the care of his father, who has early-onset Alzheimer’s disease
and resides in a local adult home. Nicholas has not disclosed either of these
facts to his mentor. He begins the project enthusiastically but after a year is
overwhelmed by the combination of the demands on him coming from both
his research and his personal life. Because his progress has been modest, he
finally tells Dr. Benke about his situation. Dr. Benke is upset with Nicholas
for not providing this information sooner and implies that Nicholas has
compromised the progress of the lab’s overall research program by not be-
ing honest with her when he began as a trainee. Dr. Benke immediately as-
signs Nicholas to a different dissertation research project that does not have
as many time constraints and deadlines. She tells Nicholas that the work he
has completed will be given to a new graduate student in the lab, who will be
able to meet the various deadlines. Dr. Benke mentions that when the work
is completed, she will evaluate Nicholas’s prior contributions and decide at
that point whether Nicholas should be an author on the paper reporting the
findings of the project. Nicholas is distressed by this plan and takes a week
off to regain his composure. During that time he comes to you for advice.
Should he have done anything differently? Should he change mentors now?
Did Dr. Benke behave appropriately? Are there compromises he could sug-
gest to Dr. Benke that would allow him to continue working on his initial
project? If so, what are they?
3.3 Sheila Wood and Professor Omar Deeb have met several times to
discuss possible projects that Sheila might take on as a doctoral
dissertation project. During the last discussion, Deeb recites a series of
rules that he applies uniformly to his graduate trainees. Most of the issues
Mentoring 75
covered are straightforward, reasonable, and come as no surprise to Sheila.

However, one rule surprises and concerns her. Deeb says that he does not
permit his laboratory advisees to enter into romantic relationships with
one another. Should such a relationship develop, he insists that one of the
members of the relationship find a new advisor and a new laboratory.
Sheila questions this, arguing that this is direct interference with personal
matters and that such relationships are of no concern to the mentor. Deeb
counters with the fact that twice in the past 6 years his laboratory has been
significantly disrupted by romantic relationships between trainees in his
group. These situations have resulted in ill will, diminished productivity,
and a negative effect on the overall morale of his laboratory group. Profes-
sor Deeb indicates that he has carefully considered the implications of
such relationships and has decided that the only reasonable thing to do is
to prevent the problems they create by asking those involved to decide
which of the two of them will leave the laboratory. Discuss the issues of
mentorship responsibilities, ethics, and conflicts of interest that you feel
are important to this scenario.
3.4 Kelly Goldstein and Zygmunt Caspar are postdoctoral students in

Dr. Maria Ocha’s lab. By mutual agreement, Kelly and Zygmunt’s
research projects are complementary to one another. In using this strategy,
Dr. Ocha expects that they will independently contribute to an overarch-
ing goal of her research program. All planning and individual project re-
sponsibilities have been painstakingly detailed and clearly defined to
prevent redundancy or inappropriate overlap of the two projects. After a
year of research, both Kelly and Zygmunt have enough data to write man-
uscripts. They have discussed the data and manuscript planning with Dr.
Ocha, who approves. However, shortly after meeting each separately, she
brings them together in her office and suggests that Kelly and Zygmunt
enter into an arrangement whereby each agrees to include the other as a
coauthor on both papers. She argues that this would increase their publica-
tion numbers and make for a more complete research story for them to use
during presentations of their work when applying for future positions. She
further asserts that they will likely find the need to intellectually collabo-
rate in writing their papers and that this would justify coauthorship. Zyg-
munt is immediately enthusiastic about this arrangement, as he is keenly
aware of the expectations for postdocs to publish and is intent on applying
for an independent position in the near future. Though tempted by the
idea of strengthening her publication record, Kelly, on the other hand, is
uncomfortable with the idea of making a “deal” and of being included as an
author on Zygmunt’s publication. Although Ocha’s practical reasons for
coauthorship are tempting, Kelly feels that the notion of intellectual col-
laboration during writing of the papers is not a well-founded justification.
She is feeling some pressure because both Dr. Ocha and Zygmunt strongly
76 Chapter 3
favor implementing this plan. She comes to you for advice on what to do.
What do you tell her?
3.5 Professor Norma Chena is planning a research proposal for sub-

mission to the National Science Foundation (NSF). She invites her
postdoc, Dr. Eleanor Axelrod, to participate in the writing of the proposal.
Dr. Chena explains to Eleanor that such participation will benefit her in
two ways. First, it will provide her with invaluable experience in writing
grant applications, and second, if the proposal is approved and funded, the
grant will secure 3 more years of training support for her. Eleanor enthu-
siastically accepts Dr. Chena’s offer. Dr. Chena asks her to write a portion
of the background section of the proposal and also instructs her to write a
section describing results she obtained under a previous NSF grant on
which Dr. Chena was the principal investigator. They write independently
of one another, but Dr. Chena does the final editing of the assembled pro-
posal. The proposal is submitted, and Dr. Chena anticipates that she will
learn about its disposition in a few months. However, at about the time she
expects to receive the proposal reviews and rating, she gets an e-mail from
the NSF program officer, notifying her that the proposal has been admin-
istratively withdrawn and will not be considered for funding. The program
officer explains that the grant application was found to contain plagiarized
material. In particular, the background section contained several para-
graphs of narrative that were taken verbatim from a review article pub-
lished in a peer-reviewed journal. Further, the preliminary results section
contains an illustration that appears in a presentation found on the website
of another investigator who works in Dr. Chena’s field. It was used in the
proposal with only minor modification and without attribution of its
source. The program officer also indicates that the NSF Office of Inspec-
tor General has been notified of the plagiarism and will conduct an inves-
tigation. The e-mail is copied to the dean of Dr. Chena’s school. Dr. Chena
realizes that the material in question was written by Eleanor, and she plans
to deflect the plagiarism charges by arguing that Eleanor is the culpable
party in this case. She plans to claim that it would not be reasonable to
expect that she could detect this level of plagiarism in the proposal. She
holds that if the allegation results in a conviction, it should be leveled
against Eleanor and not her. If you were the dean, how would you respond
to these arguments? To what extent should mentors be held accountable
for trainees’ misconduct in such cases? What advice do you have for Dr.
Chena in terms of how she should deal with Eleanor?
3.6 Dr. Montel Conrad has received a grant from an industrial source
to do basic research that has implications for commercialization. A
new graduate student, Michelle Lawless, has just joined his lab after
Mentoring 77
completing one semester of graduate coursework. Dr. Conrad outlines

several projects that can be pursued by Michelle in the industrially spon-
sored research program. Dr. Conrad indicates that there is a proviso listed
in the industrial grant agreement that says that all material to be submitted
for publication must first be reviewed by the company. This review must
always be completed within 120 days. Dr. Conrad points out that this pres-
ents only a minimal disruption to the normal publication process as com-
pared with the unrestricted publication of material gathered under federal
research grants. He also mentions that the positive aspects of working on
this proposal include the fact that there is money in the grant for Michelle
to travel to at least two meetings per year. Also, the grant application pro-
vides money for a personal computer that will be placed at Michelle’s lab
station while she is working on the project. Dr. Conrad emphasizes that
working on the project will likely give Michelle an “inside track” with the
company should she want to pursue job possibilities there following grad-
uation. Michelle asks for some time to think before giving Dr. Conrad her
decision. She finds the project exciting and believes it would afford her the
opportunity to gain appropriate research experience. She comes to you for
advice on the pros and cons of doing this project for her master’s degree
thesis research. What do you tell her?
3.7 Dr. Rhonda Archer mentors several predoctoral trainees. One of her
students, Gordon Krol, shows Rhonda data that suggest a novel
property of an enzyme under study. Both Rhonda and Gordon believe this
work has major implications for expanding the knowledge about this en-
zyme. At Rhonda’s request, Gordon repeats the experiments successfully.
Then, because of the important implications of this work, Rhonda ap-
proaches a predoctoral student in the lab and asks her to perform the same
experiments to double-check the results. Rhonda instructs the student not
to discuss the experiments with anyone else in the lab in order to obtain in-
dependent data to confirm Gordon’s potentially important findings. When
the student’s work is done, all data will be disclosed to all parties. Are the
advisor’s actions justified? Why or why not? What other means could be
used to achieve Rhonda’s need to confirm reproducibility?
3.8 Jim Allen has been a postdoctoral fellow in your lab for 3 years.
He is in final negotiations for a tenure-track assistant professor-
ship at another university. He is excited about taking this job, and you are
pleased that the position will allow him an excellent opportunity to grow
into an independent scientist. At the request of Dr. Norbert Wiley, his
prospective departmental chair, Jim has been preparing an equipment list
needed to set up his laboratory. Jim has come to you for advice several
times while preparing this list. This morning he shows up in your office
78 Chapter 3
and you immediately sense he is upset. Last night Dr. Wiley called and
asked him to be sure to include several additional equipment items on his
list. Dr. Wiley told him: “Setting up faculty is our best opportunity to get
equipment money for the department from the dean and vice president’s
office. The department desperately needs a phase-contrast microscope,
an ultraspeed centrifuge, a high-end computer server, and two ultra-low-
temperature freezers. So please add these to your setup list. I promise
that asking for these items won’t compromise our ability to secure the
money for the equipment you actually need for your lab.” In Jim’s present
or planned research, he has no need for such equipment. Jim feels he is
being asked to falsely represent his needs to the university administra-
tion. He is worried that if he objects to or refuses Dr. Wiley’s request, he
may not be offered the job. He asks you for advice on how he should
proceed.
3.9 Hal Sloan, a junior faculty member, has developed a mentor-

protégé relationship with Chet Alexander, a professor in his de-
partment. Over coffee one morning, Hal tells Chet that he is “seeing” a
graduate student in the department. Hal refers to her by a fictitious name,
Diane. Hal tells Chet that he is currently delivering a series of five lectures
in a cell biology course in which Diane is enrolled. Chet cautions Hal that
this may be a conflict of interest. Hal says he has already thought about
this and proposes to solve the problem as follows. He intends to meet with
the course director and give him an answer key to his questions on the
upcoming cell biology midterm test. Hal will ask the course director to use
this key to grade Diane’s answers to Hal’s questions on the midterm. Hal
will, of course, volunteer to grade the answers written by the rest of the
students in the class. Finally, Hal tells Chet that he intends to alert the
departmental chair about his relationship with Diane and ask the chair to
avoid making any assignments that put Hal and Diane in any type of work-
ing or academic relationship (e.g., committee work or other courses).
Speaking as Chet, what comments, advice, or suggestions do you have for
your protégé regarding his plan?
3.10 Mike Morton is a third-year graduate student at Big West Univer-

sity, where he is immersed in his dissertation research in cell biol-
ogy. You are a postdoctoral fellow in the same lab. One fall Saturday
afternoon you are working in the lab when Mike arrives to do some work,
having just attended a Big West home football game. He seems in a jovial
mood as he shuts down a high-voltage electrophoresis apparatus and pre-
pares his gel for processing. He then prepares some samples and starts an
ultracentrifuge run that will take 3 hours. As he works near your bench,
you can smell alcohol, and you conclude that although Mike may not be
Mentoring 79
intoxicated, he has clearly been drinking. You have some passing concern
that Mike could be endangering himself and others by operating poten-
tially dangerous lab equipment following alcohol consumption. The next
day you visit the lab to change some cell culture media, and you discover
that Mike’s centrifuge has completed its run and is sitting idle with Mike’s
samples still in it. You phone his apartment but get no answer, so you send
him an e-mail alerting him to the problem. The next morning the centri-
fuge is still not in operation, but Mike’s tubes are no longer in the rotor.
Sensitized to these events, you take a keen interest in Mike’s behavior. You
notice that you can sometimes smell alcohol on his breath in the mornings
when he comes to the lab. Are you obliged to act on these observations?
What actions, if any, do you take? Should you choose to inform Mike’s
mentor, what would you expect her to do?
Resources
Print
Barker K. 2010. At the Helm: Leading Your Laboratory, 2nd ed. Cold Spring Harbor
Laboratory Press, Cold Spring Harbor, NY.
Blixen CE, Papp KK, Hull AL, Rudick RA, Bramstedt KA. 2007. Developing a
mentorship program for clinical researchers. J Contin Educ Health Prof 27:86–93.
Burroughs Wellcome Fund. 2008. Staffing the Lab: Perspectives from Both Sides of
the Bench. Burroughs Wellcome Fund, Research Triangle Park, NC. http://
www.bwfund.org/sites/default/files/media/files/staffing%20the%20lab.pdf.
Burroughs Wellcome Fund. 2009. Excellence Everywhere: A Resource for Scientists
Launching Research Careers in Emerging Science Centers. Burroughs Wellcome
Fund, Research Triangle Park, NC. http://www.excellenceeverywhere.org/
images/book/excellence_everywhere.pdf.
Burroughs Wellcome Fund. 2009. Moving On: Managing Career Transitions. Bur-
roughs Wellcome Fund, Research Triangle Park, NC. http://www.bwfund.org/
sites/default/files/media/files/Moving%20On.pdf.
Burroughs Wellcome Fund and Howard Hughes Medical Institute. 2006.
Making the Right Moves: A Practical Guide to Scientific Management for Postdocs and
New Faculty, 2nd ed, p 97–111. Burroughs Wellcome Fund, Research Triangle
Park, NC, and Howard Hughes Medical Institute, Chevy Chase, MD. http://
www.hhmi.org/sites/default/files/Educational%20Materials/Lab%20
Management/Making%20the%20Right%20Moves/moves2.pdf.
Training Scientists To Make the Right Moves: A Practical Guide to Developing Pro-
grams in Scientific Management. Burroughs Wellcome Fund, Research Triangle
Park, NC, and Howard Hughes Medical Institute, Chevy Chase, MD. http://
www.hhmi.org/sites/default/files/Educational%20Materials/Lab%20
Management/Training%20Scientists/training-scientists-fulltext.pdf.
Cohen CM, Cohen SL. 2005. Lab Dynamics: Management Skills for Scientists. Cold
Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
80 Chapter 3
Dee P. 2006. Building a Successful Career in Scientific Research: A Guide for PhD Stu-
dents and Postdocs. Cambridge University Press, Cambridge, United Kingdom.
Handelsman J, Pfund C, Lauffer SM, Pribbenow CM. 2005. Entering Mentor-
ing: A Seminar To Train a New Generation of Scientists. University of Wisconsin
System, Madison, WI. http://www.hhmi.org/sites/default/files/Educational%20
Materials/Lab%20Management/entering_mentoring.pdf.
International Union of Biochemistry, Committee on Education. 1989. Stan-
dards for the Ph.D. degree in biochemistry and molecular biology. Trends
Biochem Sci 14:205–209.
Lee A, Dennis C, Campbell P. 2007. Nature’s guide for mentors. Nature 447:791–
797.
McCook A. 2011. Mentoring: on the right path. Nature 474:667–669.
National Academy of Sciences. 1997. Adviser, Teacher, Role Model, Friend: On Being
a Mentor to Students in Science and Engineering. National Academy Press, Wash-
ington, DC. http://www.nap.edu/openbook.php?record_id=5789.
Revillard JP, Celada F. 1992. Guidelines for the Ph.D. degree in immunology.
Immunol Today 13:367–373.
Online
Following are examples of guidance material that deals with mentoring
issues.
Rackham Graduate School, University of Michigan, which provides docu-

ments including How To Get the Mentoring You Want: A Guide for Graduate
Students and How To Mentor Graduate Students: A Guide for Faculty at a
Diverse University.
http://www.rackham.umich.edu/faculty_staff/information_for_programs
/academic_success/mentoring_advising/
Oregon State University:

Mentoring at Oregon State University:
http://gradschool.oregonstate.edu/faculty/graduate-mentoring
Mentoring Undergraduates:
http://oregonstate.edu/students/research/mentoring-undergraduates
The Ohio State University Graduate School Guidelines on Advising and

Mentoring Graduate Students:
http://www.gradsch.osu.edu/DEPO/PDF/MentoringAdvisingGradStudents.pdf
University of California, San Francisco Graduate Division, Office of Post-

doctoral Affairs Web page on mentors:
http://postdocs.ucsf.edu/postdoctoral/mentors
Mentoring 81
Virginia Commonwealth University’s VCU School of Medicine Faculty

Mentoring Guide:
http://www.medschool.vcu.edu/facultyaffairs/career_dev/facultymentoringguide
/index.html
The National Institutes of Health (NIH) has a number of online re-

sources related to mentoring.
The Intramural Research Sourcebook of the NIH includes a section on

ethical conduct and mentoring:
http://sourcebook.od.nih.gov/ethic-conduct/ethical-conduct-toc.htm
Thoughts on Choosing a Research Mentor from the NIH Office of Intra-

mural Training and Education:
https://www.training.nih.gov/mentoring_guidelines
NIH Biomedical Workforce Task Force Web page:

http://acd.od.nih.gov/bwf.htm
Investing in the Future: National Institute of General Medical Sciences

Strategic Plan for Biomedical and Behavioral Research Training 2011, can
be accessed at:
http://publications.nigms.nih.gov/trainingstrategicplan/
National Institute of General Medical Sciences, National Institutes of

Health. Societal Benefits of a Diverse Workforce.
http://www.nigms.nih.gov/Training/StrategicPlanImplementationBlueprint/pages
/SocietalBenefitsofaDiverseWorkforce.asp
The National Science Foundation’s Diversity and Inclusion Strategic Plan

2012–2016:
http://www.nsf.gov/od/odi/StrategicPlan.pdf
(Note: also use the NSF site search engine to access “postdoctoral researcher
mentoring plan.”)
Association of American Medical Colleges (AAMC):

Compact between Postdoctoral Appointees and Their Mentors Web page:
https://www.aamc.org/initiatives/research/postdoccompact/
82 Chapter 3
Compact between Biomedical Graduate Students and Their Research Advisors

Web page:
https://www.aamc.org/initiatives/research/gradcompact/
At the Federation of American Societies for Experimental Biology

(FASEB) website, the FASEB Statement on Including Postdoctoral Men-
toring Plans in Research Grant Applications and Sample Mentoring Plans
and Individual Development Plan for Postdoctoral Fellows:
http://www.faseb.org/Policy-a nd-G overnment-A ffairs/Science-P olicy-I ssues
/Training-and-Career-Opportunities-for-Scientists/Teaching-Advocacy-Material
.aspx
At the National Postdoctoral Association (NPA) website, the NPA Post-

doctoral Core Competencies Toolkit:
http://www.nationalpostdoc.org/competencies
Online resources from the American Association for the Advancement of

Science (AAAS), including news, career advice, job opportunities, diversity
issues, and a variety of other resources:
http://sciencecareers.sciencemag.org/career_magazine
myIDP, an interactive tool for creating an individual development plan,

may be accessed at:
http://myidp.sciencecareers.org/
MinorityPostdoc.org is a Web portal on the minority postdoctoral

experience:
http://www.minoritypostdoc.org/
National Action Council for Minorities in Engineering is a Web portal

featuring resources in education and research for underrepresented mi-
nority students:
http://www.nacme.org/
The Council of Graduate Schools website presents a variety of print re-

sources on mentoring and best practices in the responsible conduct of
research:
http://www.cgsnet.org/
chapter 4
Authorship and Peer Review

Francis L. Macrina
Scientific Publication and Authorship • The Need for Authorship
Criteria • Instructions for Authors • Authorship: Definitions,
Duties and Responsibilities • Peer Review • Publication’s Changing
Landscape • Conclusion • Discussion Questions • Case Studies
• Resources
Scientific Publication and Authorship
P ublication of our experimental work in the peer-reviewed literature

accomplishes several things. In addition to reporting new scientific
findings, it allows evaluation of results and places them in perspective
against a larger body of knowledge. Published work also credits other sci-
entists whose contributions and ideas have been built upon. It also enables
others to extend or repeat work by providing a description of experiments
performed. In doing so, publication is the principal means for verifying the
validity of our research results. The author’s byline on our publications
attributes priority and credit for the work and affirms who accepts respon-
sibility for it. Finally, scientific publication provides the means to archive
our research findings and to make them readily accessible over time.
The publication of research findings is frequently described as the “coin
of the realm” in science, a terminology credited to sociologist Robert K.
Merton. Although that phrase is now widely used to convey variously au-
thorship or publication, Merton’s intent had a deeper meaning. Specifi-
cally, his coin of the realm in science didn’t just mean being an author of a
publication or the publication itself. Rather, it was the associated recogni-
tion that followed from one’s peers. Thus, publishing is the first step in
securing the coin of the realm, but it’s only in others appreciating and valu-
ing the author’s published work that recognition is earned. Throughout
most of its six-edition history, Robert Day’s book How To Write and Publish
a Scientific Paper proclaims, “The goal of scientific research is publication.”
doi:10.1128/9781555818487.ch4
83
84 Chapter 4
In the 6th edition, Day and his coauthor, Barbara Gastel, posit that re-
search as a profession is unique in that it requires that scientists write about
what they do. Doing scientific research means you must report it. In com-
menting on scientific publication, Donald Kennedy says: “All the thinking,
all the textual analysis, all the experiments, and the data gathering aren’t
anything until we write them up. In the world of scholarship we are what
we write.” It follows that we are either recognized or ignored by the per-
ceived importance and the impact of our scholarly writing.
The peer-reviewed scientific literature

What is peer review? In this process, someone who is deemed to be knowl-
edgeable in the subject matter of the reported research offers a written cri-
tique of a manuscript that has been submitted to a journal for publication.
This is typically done anonymously and is overseen by an individual who
has a formal relationship with the journal, e.g., an editor or associate editor.
The reviewer may be an ad hoc volunteer or may be formally associated with
the journal as well, e.g., an editorial review board member. The charge to
peer reviewers varies across journals and publishers, but generally requires
them to provide a critique on the originality and soundness of the work, the
appropriateness of the detail in which it is presented, the sufficiency of the
methodology, the degree to which interpretations and conclusions are sup-
ported by the data, and compliance with applicable standards of the research
including ethics of experimentation and other research-specific issues (e.g,
public data accessibility and plans for sharing research-related materials).
Generally, reviewers’ comments are meant to be seen by the authors of the
paper, but sometimes they may be specifically directed only to an editor.
Finally, the reviewer is usually expected to provide a recommendation to the
editor that can range from accepting the manuscript for publication without
modification to rejecting it. Dispositions along the spectrum created by
these two extremes vary from recommending copyediting to performing
additional experiments in support of the conclusions.
What does peer-reviewed literature look like? In practice, the time-
honored image of bound journals on the shelves of library stacks or in
departmental conference rooms has given way to the computer screen.
Although printed journals are not likely to ever disappear, digital access
to the peer-reviewed literature has become the norm. There are three
platforms for digital scientific publication. The first involves digital cop-
ies of the corresponding print journals maintained by many publishers on
their computer servers. For a personal or institutional subscription fee,
the user accesses a publication and can read it online, save an electronic
file copy, and print the paper if desired. For the cost of a subscription fee
(borne by the reader or by a library site license), this puts the scientific
literature no farther away than the end user’s computer or handheld elec-
tronic device. A second form of digitally accessible scientific literature is
Authorship and Peer Review 85
called open access (OA) and comprises journals that are exclusively digi-
tal, with no printed counterparts. Access to them is free to the end user.
Instead of the cost of publication being paid by subscription fees, the
authors bear the cost of publication. A third form of published research
literature is the electronic repository. Here, papers that have been previ-
ously peer reviewed and published are available for free, electronic access.
Well-known repositories include PubMed Central and related coopera-
tive initiatives, e.g., Europe PubMed Central and PubMed Central
Canada. Operated by the National Center for Biotechnology Informa-
tion, PubMed Central contains papers that report research that has been
supported by grants from the National Institutes of Health (NIH).
Additional discussion on digital publication appears later in this
chapter.
The pressure to publish

In academic settings, publishing helps scientists to successfully compete for
grants and to achieve promotions, tenure, higher salaries, priority of discov-
ery, and professional prestige. For these reasons, there is pressure to publish.
Unfortunately, scientists may sometimes react to these pressures in ways
that lead to questionable practices. The need for that “one more paper” to
add to the progress report of a grant application (to get a grant award) or an
employer’s activity report (to get a raise) or the curriculum vitae (to get a job)
creates pressure to publish. The competitive nature of scientific research
creates a need to be “first.” And establishing the priority of one’s scientific
contributions is accomplished through publication. This priority takes on
additional significance when seeking intellectual property protection like a
patent that would be vital to commercializing your research results. Papers
also publicize research activities, allowing principal investigators to recruit
new trainees and junior investigators to their groups.
The large number of scientific journals provides many options for sub-
mitting papers. Journal quality and reviewing standards vary, so there is al-
ways likely to be a place where research findings can be published. Indeed,
the rapid growth in OA journals has contributed significantly to increasing
publication options, and this has caused concerns for some over the quality
of peer review. The pressures to publish have given rise to euphemisms that
describe what sometimes happens in scientific publishing. “Salami science”
refers to the publication of related results in “slices”: data sets are split and
published separately instead of being presented in a unified way. This prac-
tice increases the number of published papers from the same body of data,
giving the impression of increased productivity. Another phrase used to de-
scribe a related practice is “the least publishable unit,” the smallest amount
of data that can be written as a manuscript and published. Some publications
and editors may be contributing to these practices. Publication categories
termed variously “Notes,” “Short Communications,” or “Preliminary
86 Chapter 4
Reports” accept brief reports of important findings that are intended to

stand their own. When editors and reviewers do not heed their journal’s
policies, such brief publication formats open the door to the “salami slicers”
and the “reductionists.” The ethics of publishing data in a way that maxi-
mizes the number of papers is open to debate. Most would argue that it is
not inherently wrong and that scientists must have the freedom to publish
how and what they see fit. However, the fragmentary nature of such publi-
cations sometimes makes them difficult to evaluate. They can mislead the
reader and create confusion in the field by giving inappropriate emphasis to
one piece of work. Finally, unjustified multiple publications put undue strain
on the peer review process.
The Need for Authorship Criteria
Historically, the scientific community has relied on rather informal, often

unwritten, and sometimes vague or ill-defined criteria for determining au-
thorship on scientific papers. That approach has not served science well. It
can breed misunderstanding, hard feelings, and confusion. However, be-
ginning in the 1980s we have seen wide-scale and continuing change as
institutions, societies, editorial boards, and publishers seek to clarify, de-
fine, and even codify the criteria used to assign authorship and its respon-
sibilities. Funding agencies have also entered the fray, putting forth both
ideas and policies that have an impact on publication practices.
Today in the biomedical sciences, single-authored research publications
have become a rarity. Even at the most fundamental level—the training of
students and postdoctoral fellows—the multiauthored paper is common-
place. Interdisciplinary approaches mandate collaboration. This makes
multiauthorship the norm, and there is no expectation that the number of
coauthors has to be limited. But, no matter the number, authors in the by-
line of a paper all have a stake in their published work. Defining that stake
can be elusive, however, without rational guidelines.
Scientists agree that it would be wrong to include as an author on a pa-
per someone who made no experimental, technical, or intellectual contri-
butions to the work. Similarly, if someone thought of and performed a key
experiment and provided an interpretation of the results, authorship for
that person would be obligatory. These extremes have never really been in
question. But decisions on authoring scientific papers frequently fall in be-
tween these examples. And the responsibilities of individuals whose names
appear on multiauthored papers are not always clear, although this topic is
increasingly debated. “If you are willing to take the credit, you have to take
the responsibility” is a much-used statement that is not so simple to deal
with in every case of coauthored scientific publication. To this end, conver-
sations, guidelines, and policies on scientific authorship have been
increasingly evident in the past few decades. For example, the number of
publications on the subject of authorship of scientific papers has jumped
from a handful in the 1970s to thousands in the present day. Interrogation
of the PubMed database using search terms like “authorship guidelines,”
“authorship criteria,” “ghost authorship,” and “honorary authorship” cur-
rently reveals a plethora of scholarly writing on the subject. A sampling of
topic areas includes authorship responsibilities, ethical publication guide-
lines, management of errors in the literature, the prevalence of ghost and
honorary authorship, and the impact of disclosure of competing interests
on research reporting. Institutions and professional societies have imple-
mented guidelines dealing with authorship and publication. And profes-
sional organizations and scholarly societies continue to study and make
recommendations about authorship and publication practices.
Publication policies and guidance have grown in scope and number
over the past few decades. They continue to evolve, and they merit the at-
tention of novice and seasoned scientist-authors. The following two sec-
tions of this chapter will provide an overview of authorship best practices
derived from a variety of such sources.
Instructions for Authors
The “Instructions for Authors” sections of scientific journals have become

useful places to glean information on authorship and publication stan-
dards. Today, instructions for authors are typically available online at the
journal’s home page. These instructions provide the details of manuscript
preparation required by the journal, its general policies, and often its phi-
losophy of publication. These latter points, although different from jour-
nal to journal, are indeed standards for publication. Sometimes these issues
are reaffirmed after the paper is submitted; for example, they may be stated
in the letter acknowledging receipt of the manuscript, in the acceptance
letter, or in other publication-related correspondence. Prospective authors
should read and be familiar with the instructions for authors of the journal
to which they intend to submit their work. In fact, consulting these in-
structions can assist in the decision on journal selection. Journal publishers
often use this space to state the kinds of research considered appropriate
for publication. This information, along with perusal of the published ma-
terial that appears in the journal, helps with the decision on where to sub-
mit a paper. For novice authors, it is highly recommended to seek the
advice of mentors and experienced colleagues on where to publish.
Details of manuscript preparation

Instructions for authors contain essential information needed to prepare
and submit the manuscript. Details on format, space constraints, or word
88 Chapter 4
limitations; preparation of figures; use of abbreviations and symbols; and

proper chemical, biological, and genetic nomenclature are found there.
For information on symbols and nomenclature, many journals use various
authoritative reference books or guides as their accepted standards. In-
structions for authors often contain housekeeping details such as proce-
dures for submission of the manuscript— these days an electronic
process—and charges associated with publication. (The lay public is often
surprised to find that scientists must pay to publish their work in order to
subsidize the cost of publication.) Finally, some journals provide guidance
on the preparation of the various sections of the scientific paper: the ab-
stract, introduction, materials and methods, results, and discussion.
Authorship criteria
Increasingly, journals provide guidance on the definition of authorship and
its responsibilities. The words frequently come down to the same two is-
sues. First, an author has to make a significant contribution to the work.
Most statements like this leave plenty of room for interpretation and thus
are flexible. Second, statements defining authorship may mention that all
authors on a manuscript take responsibility for its content, or have read
and approved the manuscript, or consent to its submission.
Some journals now require that the contributions of all coauthors be
described in the paper, with this information usually published as a foot-
note. Such contributorship models may list author-associated activities like
formulating hypotheses, experimental design, writing and critical editing,
data collection and processing, analysis and interpretation, and literature
review and citation. Additionally, the identification of the author or au-
thors who take responsibility for the integrity of the work as a whole is
sometimes encouraged (so-called guarantors of the work). The expectation
is that these models reduce the ambiguity about the contributions of au-
thors. This is arguable on the grounds that such disclosure does not allow
assessment of the quality and quantity of contribution and is compounded
by the usual brevity of description (e.g., “data acquisition”), which may add
rather than remove ambiguity. On balance, however, the contributorship
model is useful and meritorious because it demands that investigators who
have a stake in the research be proactive in developing and defending the
basis for their authorship.
Copyright
Copyright is a form of intellectual property that is defined by law in the
United States and many other countries. In terms of a scientific manu-
script, copyright means that an author or authors hold the right to dupli-
cate (copy), distribute, display, or prepare a derivative version of the work.
Copyright protects the expression of the creative work—the exact form of
text, figures, tables, etc.—but it does not protect the ideas or information
conveyed in the manuscript. This is further discussed below and in chapter
9. Historically, a condition of manuscript acceptance for most scientific
journals is that the authors assign the copyright to the publisher. Increas-
ingly, print and online scientific journals are moving from this requirement
by allowing the author(s) to hold copyright of the work while at the same
time granting the publisher an exclusive license to publish the work. This
facilitates the submission of published papers to repositories like PubMed
and the ready posting of authors’ published work to institutional and per-
sonal websites. OA publications use a variety of copyright models but often
allow the authors to retain copyright while abiding by some type of an OA
license that permits users to download, print, and use the content with ap-
propriate attribution to the authors and the publisher. Whatever the copy-
right model, there is a required transaction in which the author(s) and the
publisher form the legal agreement of copyright ownership and use. Fi-
nally, many journals require the authors to obtain permission to use any
copyrighted material that is included in their manuscript, e.g., a diagram
from a previously published paper. This is usually a formality that involves
writing to the publisher who holds the copyright for the work to be in-
cluded and describing its intended use. Many publishers have forms or on-
line interactive sites that can be used in lieu of a letter. Of course, if the
author holds the copyright under any of the models described above, this
process is simplified.
Manuscript review
Matters relating to the peer review of the manuscript often are found in
the “Instructions for Authors” section. Some journals allow authors to sug-
gest the names of impartial reviewers, either ad hoc referees or members of
the editorial board. This helps the editors do their job, and it is wise to take
advantage of the opportunity. Who qualifies as an impartial reviewer?
Opinions vary, and criteria are subjective. Often excluded as impartial re-
viewers are (i) people at the author’s institution, (ii) people who have been
recently associated with the author’s laboratory, and (iii) the author’s col-
laborators or coauthors. Individuals in the latter two categories are consid-
ered in view of the time that has elapsed since the author’s last interactions
with them.
Often a description of the peer review process is found in the instruc-
tions for authors. The process also may be described in a transmission
(usually electronic) acknowledging receipt of the manuscript. Authors
need to read about this process and know how it works. It can vary signifi-
cantly for different journals. Understanding the process helps authors in
dealing with the manuscript during peer review. The typical path of a man-
uscript through the review process is discussed later in this chapter.
90 Chapter 4
Simultaneous submission, prior publication,

and embargos on public disclosure
Submitting the same manuscript simultaneously to two or more journals is
considered unethical. One assumes an author would do this to shorten the
time from manuscript submission to print. In such a scheme, the intention
is to publish in the journal that offers the quickest acceptance, thus accel-
erating reporting the research. At least three problems may emerge from
this practice. First, the journal that published the paper becomes the de-
fault rather than the author’s true choice, and this could affect the impact
of research findings. Second, simultaneous submission puts an unfair bur-
den on the peer-review and editorial processes. Finally, acceptance of the
same manuscript by two or more journals could create copyright disputes
that might have unwanted consequences for publishers and authors alike.
In 1968, the Council of Biology Editors (now called the Council of Sci-
ence Editors) defined a “primary scientific publication” as follows:
An acceptable primary scientific publication must be the first disclosure con-
taining sufficient information to enable peers (1) to assess observations, (2)
to repeat experiments, and (3) to evaluate intellectual processes; moreover, it
must be susceptible to sensory perception, essentially permanent, available
to the scientific community without restriction, and available for regular
screening by one or more of the major recognized secondary services (e.g.,
Biological Abstracts, Chemical Abstracts, Index Medicus, Excerpta Medica,
Bibliography of Agriculture, etc., in the United States and similar services in
other countries).
Although today we’d add PubMed to the list of indexing services, the defi-
nition is relevant almost 50 years after it was first written. Precisely defin-
ing a primary scientific publication is important to the concept of prior
publication.
In light of this definition, agreeing on what qualifies as prior publication
is arguable. There is ambiguity when considering, for example, papers
published in monographs (invited short papers or meeting proceedings). It
is not easy to determine how “readily available” a source may be. How
many copies of a monograph have to be sold or distributed to qualify it as
available? If all copies of the monograph have been distributed in the
United States, is it acceptable to submit essentially the same work to a
journal published in Europe? Some argue that original work published in
conference reports, symposium or meeting proceedings, or equivalent
monographs is by definition preliminary owing to considerations of for-
mat and space. Often methods cannot be fully described, and such work is
usually not subjected to peer review. However, if you are faced with a di-
lemma that impinges on the issue of prior publication, it is advisable to
have a conversation with the editor of the journal to which you intend to
submit your manuscript. Explaining the nature of the dilemma will
provide disclosure to the editor or editorial staff that will yield an answer
on how your particular situation should be handled.
Scientists generally agree that it is wrong to publish the same material
as a primary publication in two different peer-reviewed journals. Using
that philosophy as a guide is highly recommended. The Policy on Prior
Publication of the Proceedings of the National Academy of Sciences of the United
States of America (PNAS) provides additional clarity on the matter.
PNAS considers results to have already been published if they have appeared
in sufficient detail to allow replication, are publicly accessible with a fixed
content, and have been validated by review. A paper has surely been pub-
lished if it has appeared in a journal cited by any widely used abstracting
service, whether in print or online, in English or in any other language. Gray
areas result when two of the three criteria (replicability, public accessibility,
and review) are met or only a portion of an article has appeared before. What
if only one figure has been published previously? That need not doom sub-
sequent publication in PNAS, but the authors must convince us at the time
of submission that the figure is essential for the submitted paper yet not the
major contribution.
Although their use was once limited to medical journals, embargo po-
lices that control the release and the public presentation of in-press papers
are now common in the scientific publishing world. Embargos prohibit the
public release of information about a paper prior to a specific date. Typi-
cally they also include a date only after which the news media may report
on the content of the paper. For example, an embargo may dictate that an
in-press manuscript may be released to the news media no more than a
week before the publication date and that news reports of the work not
appear or be broadcast sooner than 24 hours before the publication date of
the journal. An often-stated rationale in the medical publishing world is
that this affords health care providers and their patients with concurrent
access to the research findings. This enables the health care providers a
window of time to assimilate the findings and be better prepared to answer
patients’ questions. Outside of this medical implication, general rationales
for embargos include that they provide fair and equal access of scientific
papers to the media and allow time for the media to develop well-informed
commentary on the research.
Unpublished information cited in manuscripts

Some journals require proof of permission to cite the unpublished work of
or communications from others. Information provided by a colleague as a
“personal communication” may require a letter granting permission. The
same is usually true for preprints or submitted manuscripts provided by
your colleagues. Although a colleague may have provided a manuscript
that has been submitted for publication, she may not feel comfortable
92 Chapter 4
allowing that work to be cited in another paper before she knows that hers
is accepted. By formally asking her permission, you eliminate any prospect
of misunderstanding.
In the case of the author’s unpublished work—“in-press” or “submitted”
manuscripts—journals may require that copies of such manuscripts ac-
company the new submission so that they can be used if needed during
peer review.
Sharing research materials

In natural science and biomedical journals it has become common for pub-
lishers to include statements about sharing research materials. This includes
various research findings, or products including cell lines, microorganisms,
mutants, plasmids, antibodies, and other biologicals and reagents. There are
usually conditions stated for the release of such materials. For example, ma-
terials must be available at cost (e.g., preparation and shipping), they must be
requested in reasonable quantities, and they must not be used for commer-
cial purposes. Some policies are explicit in affirming that data sharing is
done promptly and unconditionally. Journals may encourage that the paper
denote which author or authors should be contacted to request published
materials. Proper practice dictates that the materials be requested from that
author or authors of the publication in which the material was initially de-
scribed. For example, it is not acceptable to request a cell line from a third
party, even though it may be convenient to do so. A novel cell line needed for
work in Chicago may have been constructed by a scientist in Japan, but a
colleague in a nearby city already has it. It is not appropriate to ask the state-
side colleague to provide the cell line. Ask the Japanese investigator who
made it and published the results. At the very most, you could suggest that
he allow you to get a culture from your conveniently located neighbor.
Data sets associated with scientific manuscripts fall under the umbrella of
data sharing as well. Also included in many instructions for authors is the
requirement that authors deposit specialized data—e.g., nucleic acid and
protein sequences, genomic and proteomic data, microarray data, structural
studies data, and functional magnetic resonance imaging studies—in appro-
priate databases. Sharing research materials and proper deposition of results
into databases are widely listed as conditions of publication.
Other kinds of data that may be prescribed for deposition in public re-
positories include climate data, ecological data, rare specimens, and fossils.
Conflict of interest
The disclosure of personal interests, activities, and associations has be-
come a common required practice in the publication of scientific papers.
Journal policies focus on the disclosure of any association with the poten-
tial to create a financial conflict of interest that might have an impact on
the paper. Of primary concern is that a financial interest of an author

might give rise to bias or the perception of bias in the collection, analysis,
or interpretation of the data reported in the manuscript. Simply disclosing
the nature of the potential conflict provides the reader with a perspective
that better affords the evaluation of the manuscript’s findings and their
interpretation. Financial conflicts may revolve around associations that
connect the author or authors with a corporation whose products or ser-
vices could be affected by the paper. Consider, for example, a paper that
reports positively on a medical device, enhancing the perception of its reli-
ability. There are several ways a financial conflict of interest might be cre-
ated in such a scenario. These could include the following: (i) the company
provided a grant to the author to do the research; (ii) the author is a paid
consultant to the company; (iii) the author is a member of an advisory
committee or the board of directors of the company; (iv) the author regu-
larly gives public lectures or provides other services that are paid for by the
company; (v) the author owns significant equity in the company; and (vi)
the author receives royalty payments from the company for an invention
that has been licensed to the company by the author and/or the author’s
institution.
Reporting associations that represent conflicts is done variously by pub-
lishers. In many cases this information is included in the manuscript, but
sometimes the submission of such disclosures is also done using an elec-
tronic interface or data entry form. Journals may also require that potential
conflicts of interest be reported by their editors, editorial boards, and re-
viewers. This information may be used to guide editorial and reviewer as-
signments. Some journals announce that none of their editors have
relationships with corporations relevant to the subject matter of the jour-
nal, thus minimizing if not removing them from issues of conflict of inter-
est as they relate to the peer review process. Author-declared conflicts
usually appear in a footnote in the published paper.
Subjects protection in research

Some journals require an affirmation regarding the use of humans or ani-
mals in the work reported in the submitted manuscript. This may be a
statement by the authors that institutional approval was sought and ob-
tained from an institutional review board (see chapter 5) or the Institu-
tional Animal Care and Use Committee (see chapter 6). Some journals
require the inclusion of a statement that accepted practices or codes were
followed in the conduct of the research. Some journals mention that a
statement confirming that informed consent was obtained from human
subjects must be included in the manuscript. Approval dates on either hu-
man or animal subjects protocols may have to be provided as well. Other
human subject-related requirements that may be found in instructions for
94 Chapter 4
authors relate to subject privacy and include reminders to strip identifying

data from subject-derived materials or data; at least one journal requires
the use of a consent and release form that must be signed by the subject if
he or she could be recognized from an image or other published content.
A significant number of journals that publish the results of clinical trials
require that they be registered in an accepted clinical trial registry (e.g.,
ClinicalTrials.gov, a site provided by the NIH) before the first subject is
enrolled in the study. This practice was initiated in 2005 by the Interna-
tional Committee of Medical Journal Editors (ICMJE), thus making it a
requirement for the hundreds of journals that used the ICMJE’s Recom-
mendations for the Conduct, Reporting, Editing, and Publication of
Scholarly Work in Medical Journals. In 2007, the U.S. Food and Drug
Administration enacted a federal law requiring that “applicable” clinical
trials be registered on ClinicalTrials.gov. It also required the submission
and posting of results on the website. The origin of this policy revolved
around highly publicized cases of selective data reporting or suppression of
clinical trials data that would otherwise reflect negatively on the research
sponsor’s product. The rationale for registration was grounded in the ex-
pectation that full disclosure of a clinical trial protocol will announce its
existence, afford a comprehensive understanding of its features and char-
acteristics, and, in doing so, reduce the chances of concealment or suppres-
sion of data when the results of the clinical trial are submitted for
publication and, ultimately, published. The benefit of such registration has
also been argued in terms of the public having access to clinical trials, thus
providing them with information on available clinical trials that may be of
direct interest to them, their families, or their friends.
Digital image integrity

The Rockefeller University Press, publisher of three biomedical journals,
was a leader in developing policies that govern the handling of digital im-
ages submitted for publication. Publishers of many other journals have fol-
lowed suit, and their instructions for authors describe both acceptable and
unacceptable practices for dealing with digital images including gels, mi-
crographs, specimen photographs, and other digital data. Implicit in these
policies is that any digital image is data itself and should not be fundamen-
tally changed. The Rockefeller University Press policy on digital image
handling has been adapted or modified by many journals, and a summary
of central elements most commonly found in such polices is as follows.
No specific feature or portion of the image may be enhanced, obscured,
moved, removed, or introduced.
The creation of composite images (e.g., independently obtained images
grouped together using editing software) must be explicitly indicated
by some visual means (e.g., borders or dividing lines) and explained

in the legend to the figure.
Adjustments made to brightness, contrast, or color are acceptable only
if they are made to the entire image (not part of it) and if they do not
have any effect on the information contained in the original image.
Some journals include methods for monitoring and enforcement in
their policies. This may include general or random screening of digital
images for manipulation using software programs or methods for detect-
ing author-created modifications. Undisclosed, deliberate modification de-
tected by these methods may result in the rejection of the paper and
possibly in the notification of the author’s institution or the funding agency
that supported the research.
Biosecurity
Prompted by the 2001 bioterrorism attacks in the United States, the U.S.
National Academy of Sciences and the U.S. Center for Strategic Interna-
tional Studies sponsored a 2003 meeting of editors, scientists, and security
experts to discuss scientific publication and national security. From this
meeting came a position paper authored by a group of editors and authors
that concluded that certain scientific information should not be published
because of its risk of use by terrorists.
The position paper was simultaneously published in Nature, Science,
PNAS, and the journals of the American Society for Microbiology. It con-
tained four concepts: (i) the integrity of the scientific process must be pro-
tected by publishing high-quality manuscripts written in sufficient detail
to ensure reproducibility; (ii) there should be a commitment to deal re-
sponsibly and effectively with safety and security issues that may be raised
by papers submitted for publication, and to increasing capacity to identify
such issues as they arise; (iii) there is need for consideration and imple-
mentation of the appropriate level and design of processes to accomplish
effective review of papers that raise such security issues; and (iv) the recog-
nition that, on occasion, an editor may conclude that the potential harm of
publication outweighs the potential societal benefits. Under such circum-
stances, the paper should be modified or not be published. In keeping with
these concepts, the statement declared that journals and scientific societies
can play an important role in encouraging investigators to communicate
results of research in ways that maximize public benefits and minimize
risks of misuse.
Since that time, a limited number of editorial boards and publishers
have included language in their instructions for authors or editorial poli-
cies that addresses the issue of biosecurity in the peer review process. Such
issues are typically broached under the rubric of “dual-use research of
96 Chapter 4
concern” (DURC), which, for our purposes, may be defined according to

the Office of Biotechnology Activities of the NIH as
research that, based on current understanding, can be reasonably anticipated

to provide knowledge, products, or technologies that could be directly mis-
applied by others to pose a threat to public health and safety, agricultural
crops and other plants, animals, the environment, or materiel.
In general, the language found in the publication policies or instruc-

tions for authors on biosecurity shares some common elements. Some
journals state the expectation that the authors notify the editor if the man-
uscript being submitted reports findings that represent DURC. Policies
typically affirm that the editor, editor-in-chief, or editorial board will eval-
uate the potential of DURC but that outside reviewers or experts may be
consulted in making a decision about the manuscript. Finally, the language
usually contains an implicit or explicit message that a manuscript may be
turned down for publication based on biosecurity concerns.
Publication policies on biosecurity issues are found in multidisciplinary
journals, like Science, Nature, and PNAS; and discipline-specific journals,
like all of the journals published by the American Society for Microbiology
and all of the journals published by the American Phytopathological Soci-
ety. In general, however, the number of biomedical and life sciences jour-
nals that have dual-use peer review policies in place remains low more than
a decade after the events that prompted their genesis. A 2011 survey report
by David Resnik, Dionne Barner, and Gregg Dinse indicated that of 155
journals responding to a question of whether they had a written dual-use
review policy, only 7.7% (about 12 journals) indicated that they did.
Finally, invoking security concerns within the context of the openness
of biomedical research publication has engendered debate in scientific,
publishing, and government circles. While some argue that the research
enterprise is acting responsibly in monitoring and intervening in the pub-
lication of information with dual-use potential, others contend that this is
blatant censorship.
Miscellanies
Some journals also include policies on the handling of disputes once pa-
pers are published. Occasionally, journals are explicit about the option of
having their editors examine original data in the process of dispute resolu-
tion. In addition, many journals describe policies for publishing correc-
tions of author errors (corrigenda), errors made by the journal (errata), or
retractions of papers owing to invalid results. Publishers of a number of
journals have also begun using text-similarity software programs to detect
plagiarism. As part of journal policy, selected submissions may be screened
against a large database of published papers. Plagiarized material found in
a submitted manuscript requires correction. More preemptive action may
be necessary if the plagiarism rises to the level of research misconduct,

copyright infringement, or both. Plagiarism detected in a published paper
can result in the paper being retracted by the journal. Some journals allow
plagiarism analyses of manuscripts to be done by the submitting author on
a voluntary basis. This allows the author to make needed corrections be-
fore the paper is subjected to peer review. Such voluntary review might
uncover self-plagiarism, which otherwise might be flagged by a journal-
initiated plagiarism screen. If the author was not comfortable with the
level of identical text discovered in the screen, this could be corrected or
explained prior to the manuscript entering the peer review process.
Instructions for authors and editorial policies continue to evolve in
response to external factors including new discoveries and knowledge,
new technology, and the implementation of new or modified laws and
policies. A recent example is the emergence of publication policies bear-
ing on the issue of cultured cell line contamination and misidentification.
Such problems result in wasted time and resources and can impede scien-
tific progress. The journals published by the American Association for
Cancer Research have adopted a policy requiring that submitted manu-
scripts must contain information on the origin of cell lines used in the
research. Specifically, the origin of the cells and the date they were ob-
tained must be disclosed, along with whether the cells were tested and
authenticated. The method by which the cells were tested must be pro-
vided, including the last time such testing occurred. The National Insti-
tute of Standards and Technology (NIST) has launched a project to aid in
cultured cell line authentication. NIST is in the process of collecting and
cataloguing such DNA sequence data that will permit precise cell line
identification based on the profiling of short tandem repeat sequences.
The NIST project aims to collect DNA identification data for up to
1,500 human cell lines. These data will be posted in a public database at
the National Center for Biotechnology Information for use by research-
ers in cell line authentication. Short tandem repeat profiling of animal
(mouse and monkey) cell lines is also being developed and can be ex-
pected to expand the scope of molecular identification methods that can
be used to authenticate cultured cell lines. Thus, it is reasonable to expect
that publication policies on cell line authentication will be refined and
adopted by other journals in the future.
Authorship: Definitions,
Duties, and Responsibilities
Defining authorship
Criteria for authorship have been presented variously in journal policies, in-
stitutional guidelines, and professional society statements. Commonly in-
voked is the need for an author to have made a significant contribution to the
98 Chapter 4
work. Such contributions are frequently described as those that have an ef-
fect on the “direction, scope, or depth” of the research. They have also been
stated in terms of “conceptualization, design, execution, and/or interpreta-
tion” of the research. The development of necessary methodologies and data
analysis essential to the conclusions of the project are also sometimes listed
as contributions that justify authorship. Sometimes the language is specific,
and contributions to the project are linked to having a “clear understanding
of its goals.” This leads to the issue of responsibility. Some have addressed
this issue in defining authorship by invoking the need “to take responsibility
for the defense of the study should the need arise” or “to present and defend
the work in context at a scientific meeting.” The challenge of coauthor re-
sponsibility where disparate contributions have been made was addressed in
one case by saying that exceptions to this rule will need to be made when
“one author has carried out a unique, sophisticated study or analysis.” In
other words, in certain collaborative studies, it may not be possible for every
author to be able to rigorously present and defend all aspects of the work.
To illustrate the specificity and detail of authorship definitions, let’s use
two examples. First, let’s examine the widely used definition of the ICMJE.
This definition is found in the ICMJE’s Recommendations for the Con-
duct, Reporting, Editing, and Publication of Scholarly Work in Medical
Journals, which were first published in 1979. Several updated versions of
the Recommendations have appeared since that time. At present these
Recommendations are used, in whole or in part, by more than 1,000 med-
ical and biomedical journals.
The current ICMJE definition (August 2013) for authorship found in
the Recommendations has, at its core, the following elements.
The ICMJE recommends that authorship be based on the following 4
criteria:
1. Substantial contributions to the conception or design of the work; or
the acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual
content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring
that questions related to the accuracy or integrity of any part of the
work are appropriately investigated and resolved.
Further guidance on authorship is offered by the ICMJE Recommenda-

tions in connection with these four criteria. Notable narrative includes the
following.
In addition to being accountable for the parts of the work he or she has done,
an author should be able to identify which co-authors are responsible for
specific other parts of the work. In addition, authors should have confidence
in the integrity of the contributions of their co-authors. . . .
These authorship criteria are intended to reserve the status of authorship

for those who deserve credit and can take responsibility for the work. The
criteria are not intended for use as a means to disqualify colleagues from
authorship who otherwise meet authorship criteria by denying them the op-
portunity to meet criterion #s 2 or 3. Therefore, all individuals who meet the
first criterion should have the opportunity to participate in the review, draft-
ing, and final approval of the manuscript.
The individuals who conduct the work are responsible for identifying
who meets these criteria and ideally should do so when planning the work,
making modifications as appropriate as the work progresses. It is the collec-
tive responsibility of the authors, not the journal to which the work is sub-
mitted, to determine that all people named as authors meet all four criteria;
it is not the role of journal editors to determine who qualifies or does not
qualify for authorship or to arbitrate authorship conflicts. If agreement can-
not be reached about who qualifies for authorship, the institution(s) where
the work was performed, not the journal editor, should be asked to investi-
gate. If authors request removal or addition of an author after manuscript
submission or publication, journal editors should seek an explanation and
signed statement of agreement for the requested change from all listed au-
thors and from the author to be removed or added.
The corresponding author is the one individual who takes primary re-
sponsibility for communication with the journal during the manuscript sub-
mission, peer review, and publication process, and typically ensures that all
the journal’s administrative requirements, such as providing details of au-
thorship, ethics committee approval, clinical trial registration documenta-
tion, and gathering conflict of interest forms and statements, are properly
completed, although these duties may be delegated to one or more co-
authors. The corresponding author should be available throughout the sub-
mission and peer review process to respond to editorial queries in a timely
way, and should be available after publication to respond to critiques of the
work and cooperate with any requests from the journal for data or additional
information should questions about the paper arise after publication. . . .
When a large multi-author group has conducted the work, the group ide-
ally should decide who will be an author before the work is started and con-
firm who is an author before submitting the manuscript for publication. All
members of the group named as authors should meet all four criteria for
authorship, including approval of the final manuscript, and they should be
able to take public responsibility for the work and should have full confi-
dence in the accuracy and integrity of the work of other group authors. They
will also be expected as individuals to complete conflict-of-interest disclo-
sure forms.
Finally, contributions that do not merit authorship are mentioned in the

ICMJE Recommendations:
Contributors who meet fewer than all 4 of the above criteria for authorship
should not be listed as authors, but they should be acknowledged. Examples
of activities that alone (without other contributions) do not qualify a con-
tributor for authorship are acquisition of funding; general supervision of a
research group or general administrative support; and writing assistance,
technical editing, language editing, and proofreading.
100 Chapter 4
Now, let’s look at the current definition found in the information for
authors for PNAS.
Authorship must be limited to those who have contributed substantially to
the work. The corresponding author must have obtained permission from all
authors for the submission of each version of the paper and for any change in
authorship.
All collaborators share some degree of responsibility for any paper they
coauthor. Some coauthors have responsibility for the entire paper as an
accurate, verifiable report of the research. These include coauthors who are
accountable for the integrity of the data reported in the paper, carry out the
analysis, write the manuscript, present major findings at conferences, or
provide scientific leadership to junior colleagues. Coauthors who make
specific, limited contributions to a paper are responsible for their contribu-
tions but may have only limited responsibility for other results. While not
all coauthors may be familiar with all aspects of the research presented in
their paper, all collaborators should have in place an appropriate process
for reviewing the accuracy of the reported results. Authors must indicate
their specific contributions to the published work. This information will be
published as a footnote to the paper. Examples of designations include:
• Designed research
• Performed research
• Contributed new reagents or analytic tools
• Analyzed data
• Wrote the paper
An author may list more than one contribution, and more than one author
may have contributed to the same aspect of the work.
Both the ICMJE and PNAS authorship definitions include many of the
same elements. The ICMJE definition is specific in its conditions and how
they are to be applied. The PNAS definition mentions the requirement for
a substantial contribution and then ties this to examples later in its narra-
tive. The PNAS definition is more explicit in detailing authorship respon-
sibility and accountability when multiple authors are involved. Both
definitions acknowledge that some coauthors may make specific contribu-
tions to the work and are responsible for them. The PNAS definition is
explicit in affirming that some coauthors have responsibility for the entire
paper (the guarantorship model), while the ICMJE definition embraces
the use of the guarantorship model in language preceding the definition in
the Recommendations. Aspects unique to the ICMJE definition involve an
accommodation of multicenter-based, group-authored papers (often clini-
cal trials fit this description). Both definitions address author accountabil-
ity, equating this to the responsibility for authors in the byline to present
the reported research finding in a public setting.
In summary, the ICMJE and PNAS authorship definitions provide a
foundation for appreciating the evolving field of policies and practices
related to authorship. They cover a breadth of scientific disciplines, are

updated regularly, and are, by and large, usefully explicit. Readers should
be aware of other organizations (e.g., World Association of Medical Edi-
tors) and scientific societies (e.g., American Chemical Society, Society for
Neurosciences, American Psychological Association, and American Soci-
ety for Microbiology) that provide a rich array of information on author-
ship and publication practices. Most importantly, authors should rely on
the instructions for authors of the journals in which they plan to submit
their manuscripts.
Classifying authors
Although there is not a universally accepted authorship nomenclature, ad-
jectives are commonly used to describe authors or types of authorships.
Instructions for authors and general guidelines and policies may refer to
these, thus providing context. Here is a synopsis of some of the more com-
monly used authorship terminology.
The senior author. Guidelines often define this person as the principal
investigator, leader of the group, or laboratory director. If the byline of a
paper lists a faculty mentor along with two of her predoctoral trainees and
one postdoctoral trainee, then the mentor is the senior author. The senior
author may be the first author listed in the byline. Most agree that the first
author is defined as having played a major role in generating the data, in-
terpreting the results, and writing the first draft of the manuscript. In many
cases, however, the first author and the senior author are different. When
this is so, it is customary in many disciplines for the senior author’s name
to be last in the byline.
Guidelines often vest senior authors with overarching responsibilities.
What follows is an amalgamation of the typical responsibilities listed in
several documents from universities, research institutions, professional so-
cieties, and publishers.
• The senior author, along with the first author, typically decides who
else will be listed as coauthors. General criteria for making these de-
cisions are discussed below. The senior author is responsible for no-
tifying all coauthors of this decision and for facilitating discussion
and decision making about the order of appearance of the coauthors’
names in the byline.
• The senior author, usually with the help of the first author and some-
times other coauthors, decides on the people to be listed in the “Ac-
knowledgments” section of the paper. The senior author should
notify the individuals to be acknowledged. The senior author also is
responsible for listing in the acknowledgments all sources of
102 Chapter 4
financial support for the work. In short, the senior author is respon-
sible for appropriately acknowledging all contributions to the work
reported in the paper.
• Senior authors often are the guarantors of the work, as defined pre-
viously in the guarantorship model. This means they review all data
contained in the paper and, in doing so, assume responsibility for the
validity of the entire body of work. This assertion may present prob-
lems in regard to specialized work that may be outside the senior
author’s area of expertise. In such cases, one means of handling this is
for the senior author to gain a reasonable understanding and verifi-
cation of the data from the appropriate coauthor. Still, this problem
persists as interdisciplinary research abounds and researchers from
highly technical and specialized fields collaborate and copublish
their results. Nonetheless, some of the guidelines in effect today are
very specific on this point: the senior author must “understand the
general principles of all work included in the paper.”
• The senior author has a responsibility to facilitate communication
among coauthors during the preparation of the manuscript. This
means reviewing raw data and discussing new ideas for additional
work. It certainly means reaching agreement on the part of all coau-
thors as to interpretation of results and conclusions.
• The senior author makes sure that the logistics of manuscript sub-
mission are properly followed. This may be something the senior
author does directly or assigns to another author (see the sections on
the first author and submitting author, below). Such things as manu-
script format and related material and local editorial review (if re-
quired) are included here. Also included are all dealings with the
publisher, e.g., correspondence, execution of copyright assignments
and authorship agreement forms, and, where appropriate, financial
matters such as publication charges.
• The senior author usually coordinates and oversees the responses to
the peer reviewers’ comments if the manuscript has to be revised.
This may a task done collaboratively with or assigned to the first
author, if they are not one and the same. He or she is responsible for
involving the coauthors in this process as appropriate and for seeking
the approval of all coauthors to submit the revised manuscript.
• The senior author is responsible for acting on and honoring requests
to share materials from the research once the paper is published.
Again, these may be assigned by the senior author to another person
in the author byline. Some publication guidelines recommend that
the person or persons to contact for materials reported in the paper
be listed explicitly, usually in the “Materials and Methods” section of
the paper. The senior author is responsible for coordinating and
making responses to general inquiries or challenges about the work.

The senior author assumes responsibility in dealing with the publi-
cation of corrections, errata, or retractions. This includes coordinat-
ing preparation of such items by seeking the comments and
agreement of all coauthors. Finally, the senior author is responsible
for the appropriate retention and storage of all data used to prepare
the manuscript.
The first author. The first author is the author whose name appears first
in the byline of the paper. As mentioned above, the first author is the per-
son who participated significantly in the work by (i) doing experiments and
collecting the data, (ii) interpreting the results, and (iii) writing the first
draft of the manuscript. Some journals allow the first authorship position
to be shared. In other words, if the contributions of two authors (or more
in some journals) are equal or indistinguishable, then it is possible to iden-
tify each in the byline (e.g., with an asterisk) with a notation to that effect.
Because there still is a linear order of names in the byline, the order of the
equal contributors is left to authors’ mutual decision. James Watson and
Francis Crick reportedly used a coin toss to determine author order in
their 1953 classic paper proposing the double-helical structure for DNA.
Footnotes in contemporary papers reveal that the coin toss methodology
has been used in reconciling shared first authorship.
The submitting author. The submitting author is usually the author

who sees the manuscript through the submission process, e.g., letter writ-
ing, coordinating responses to the editor, responding to peer review com-
ments. Sometimes this person is called the corresponding author. This
may be the senior author, but it can be the first author. For example, a
mentor (senior author) may want his postdoctoral fellow (first author) to
gain experience in dealing with the peer review process. It should be re-
membered that certain responsibilities will fall on this author (see above).
Many publishers indicate the submitting author on the first page of the
published article. The responsibilities of the senior author with respect to
correspondence after publication will then fall on the submitting author.
When the submitting author and the senior author are not the same per-
son, there should be a clear understanding of how follow-up correspon-
dence related to the manuscript will be handled.
Other coauthors. Coauthors whose names appear between the first and
last author in the byline of a paper are usually determined by the senior
author and the first author. The order of these coauthors can be based on
the importance of their contributions to the work in descending order
from the first author. Decisions on authorship need to be made before the
104 Chapter 4
paper is written. It may be appropriate to change the order of the authors

as the manuscript preparation progresses. The senior author and the first
author should take the lead in any decision to revise author order, but such
decisions should involve all the coauthors. Sometimes journals require that
any change in authorship of a paper under peer review be accompanied by
a letter of approval signed by all of the coauthors.
Inappropriate authorship
Certain types of unethical authorship are identified by specific terms that
graphically depict the behavior involved. The two most commonly used
designations are ghost authorship and guest authorship. Ghost authors,
although meeting qualifications for authorship, are those whose names
have been deliberately omitted from the byline of the paper. A guest au-
thor, on the other hand, is one who does not qualify for authorship but
whose name appears in the byline. Both ghost and guest authorships are
inappropriate.
Ghost authorship falls into two distinct categories. The first involves
someone who has legitimately participated in some aspect of the research
but whose name is omitted from the byline and the acknowledgments for
various reasons, e.g., their employment by a corporate entity. More com-
monly, ghost authors are actually ghostwriters, who analyze data, compose
data presentations, and write the manuscript. This may be done on a fee-
for-service basis, and a corporate sponsor may even finance this arrange-
ment. Why is ghostwriting wrong? Ghostwriters are removed from the
accountability that is attached to authorship. Moreover, transparency is
further eroded by the inability to critically evaluate possible conflicts and
bias that may be associated with the ghostwriter.
A second meaning of the term “ghost authorship” involves authors who
participated in the research as collaborators in a way that meets authorship
criteria. However, when the paper is published, their names do not appear
in the author byline. This may be the result of deliberate inappropriate
denial on the part of the other authors or confusion, misunderstanding, or
lack of communication between the collaborators. Although this use of the
term “ghost authorship” has a different meaning from the first category
described above, it is also wrong because it denies authorship to someone
who qualifies for and deserves a place in the byline of the paper.
Guest authorship is grounded in the expectation that inclusion of a par-
ticular name in the author byline will enhance the paper’s chances for fa-
vorable peer review and, ultimately, for being published. The guest author’s
status and visibility are expected to elevate the quality of the paper. But
guest authors do not contribute to the paper in ways that justify author-
ship; thus their name in the byline is inappropriate. A nuanced form of
guest authorship is called honorary or gift authorship. In this case, instead
of the author’s name being able to enhance the status of the paper, the
honorary or gift author is afforded a place in the byline by virtue of his or
her position, e.g., a departmental chair or institute director. In fact, this is
an inappropriate courtesy that gives the honorary authors credit where
none is due.
Acknowledgments
The “Acknowledgments” section of a scientific paper is typically described
in guidelines as being reserved for those people whose contributions to the
work do not meet the criteria established for authorship. This might in-
clude someone who provided needed technical help but did not have a full
appreciation of the experimental work. Or it might be someone who pro-
vided writing or editorial assistance but participated in no other aspect of
the work. The ICMJE takes this a step further and recommends the “Ac-
knowledgments” section as the place to include individuals who have con-
tributed “materially” to the work but whose contributions do not justify
authorship, e.g., “scientific advisors” or “clinical investigators.” The ICMJE
recommends that written permission be obtained from anyone mentioned
in this section, as readers are likely to infer their endorsement of the data
and conclusions by virtue of their acknowledgment.
Peer Review
Many scientists are called on to review manuscripts. This happens in two

ways. First, scientists may be appointed as editors or as members of edito-
rial boards of scientific journals, in which case their duties as reviewers are
formalized. Such appointments are made for a defined period of time.
Usually editors (or editors-in-chief ) oversee the process, distributing man-
uscripts to board members. Their names appear on the masthead of the
journal—in print, online, or both—designating them as reviewing editors,
editorial board members, or an equivalent term. Second, scientists may be
asked to be ad hoc reviewers. In this case, they receive papers to review
from editors or editorial board members and are asked to evaluate them as
a courtesy. Usually, ad hoc reviewers are acknowledged on a regular basis in
the journal. Many scientific journals rely heavily on ad hoc reviewers. The
contribution made by ad hoc reviewers is an important part of professional
citizenship. For many journals, ad hoc reviewers comprise the workforce
that enables the process of peer review to function. Although editors—
especially those in high-level oversight positions—may be compensated by
journal publishers, ad hoc reviewers typically receive no remuneration for
their work.
All reviewers in general and ad hoc reviewers specifically provide a criti-
cal service. They prepare written evaluations that help editors decide on
106 Chapter 4
the acceptability of the submitted manuscripts. Equally important, their

comments often allow the authors to improve their manuscript if it is not
acceptable for publication in its current form. Reviewers may suggest im-
provements in writing style, presentation of data, or even further experi-
ments to be done.
Journals, professional societies, and related organizations publish guide-
lines or policies that speak to the process of peer review and the responsi-
bilities and ethical conduct of those involved in the peer review process. A
selection of such sources is provided at the end of this chapter. Here we’ll
use an amalgamation of these and similar resources to describe the flow of
a manuscript through a typical cycle of peer review. Then we’ll discuss the
duties and responsibilities of the peer reviewer and others in the peer re-
view process.
The workings of peer review

Typical peer review begins with submission of a manuscript to an editor or
to a central office of the publisher of the journal. In the latter case, office
staff assign the manuscript to an editor. Electronic submission of manu-
scripts is the rule rather than the exception, with the overwhelming major-
ity of scientific journals providing a computer interface to upload the
manuscript, supporting materials, and relevant correspondence or submis-
sion forms. Usually scientific journals have multiple editors who represent
the various subspecialties of the subject matter. The editor then reads the
paper to decide whom to ask to review it. Editors may select editorial
board members or ad hoc reviewers for this job. Typically a single paper is
assigned to two or three peer reviewers (also termed referees). Again, this
process and all remaining transactions occur electronically, using interac-
tive website interfaces, file transfers, or both. Some journals provide spe-
cial forms or online data fields on which to prepare manuscript reviews,
but these frequently consist of lots of blank space for the reviewers to write
comments. There may also be a separate form for comments that are in-
tended only for the eyes of the editor. The editor asks the reviewers to
complete their evaluations in a specific period of time, usually 2 weeks to a
month. When the completed reviews are returned to the editor, he or she
reads them. The editor then makes one of three decisions: (i) accept the
paper, (ii) reject the paper, or (iii) return the paper to the authors for revi-
sion. In all cases, the editor provides the authors with a communication
(e.g., e-mail) indicating the basis of his or her decision. Obviously, in the
case of outright acceptance, the text is brief. However, editors are usually
specific in their decision letters when explaining rejection or the need for
revision. Such letters reflect the editor’s own opinions of the paper, along
with the reviewers’ comments and recommendations. Along with the edi-
tor’s message to the authors go the verbatim copies of the reviewers’
comments. The parts of the review forms that indicate the reviewers’ rec-
ommendation (“accept,” “reject,” or “revise”) as well as any comments ex-
clusively made to the editor are not sent to the authors. Editors may use
comments sent to them separately by reviewers to help in composing their
decision letter.
For most scientific journals in the biomedical and natural sciences, the
comments of the reviewers are anonymous. However, some journals do
reveal the identity of reviewers to the authors. This can be done as a matter
of policy or by encouraging reviewers to sign their written reviews.
Authors consider the reviewers’ and editor’s comments in revising their
papers. They may make changes based on comments they agree with. Al-
ternatively, authors have the right to rebut any and all criticisms of the re-
viewers. The basis for handling each of the reviewers’ comments must be
explained to the editor in a letter that accompanies the revised manuscript.
It is then the editor’s job to reach a final decision on the paper and to notify
the authors.
Being a peer reviewer

Manuscripts for review usually arrive via e-mail attachment or are down-
loaded from a secure website of the publisher. Upon receipt, there are a
number of housekeeping chores that reviewers must do, and it is important
and courteous to attend to these quickly. First, the reviewer must scan the
paper and decide whether he or she is qualified to review it. The review
deadline must be evaluated: can the reviewer complete the review in the
time allotted by the editor? If the reviewer is uncomfortable with either of
these criteria, the manuscript should be sent back to be reassigned. Also,
reviewers should check that they have a complete version of the manu-
script. Are all the pages, figures, tables, and supplemental material, if any,
accessible to the reviewer? If anything is missing or in need of attention
(e.g., a low-resolution image that cannot be properly evaluated), the editor
or editorial office should be contacted to rectify the problem.
Reviewers must be comfortable with the job of impartially reviewing
the work. Their review of the paper must not constitute a conflict of inter-
est, real or perceived. Typically conflicts include papers from investigators
at the reviewer’s institution, trainees who have recently been in the review-
er’s lab, or collaborators of the reviewer at the reviewer’s own or other in-
stitutions. Commercial interests also create conflicts. For example, is the
paper authored by scientists at a company that pays the reviewer as a con-
sultant or has made a grant or gift to the reviewer’s research program?
Conflict-of-interest decisions of this type usually rest with the reviewer.
Most of the time, the information that points to the conflict is known only
to the reviewer, and the editor may never become aware of it. An extension
of such internal conflicts moves into the realm of conflicts of conscience
108 Chapter 4
(see chapter 7). Can a scientist who believes it is inappropriate to use cells
derived from human fetal tissues in research objectively review a paper
that reports the results of human embryonic stem cell experimentation?
The reviewer has to decide whether there is conflict or whether others
might perceive specific actions as conflict. A simple rule is “When in doubt,
don’t review the paper.” The reviewer may contact the editor to seek ad-
vice on matters of potential conflict. In general, any extensive rationaliza-
tion for overcoming what might be a perceived conflict is usually a signal
to both the reviewer and the editor that a real conflict may exist or may be
perceived by others. In such cases, reassignment of the manuscript to an-
other reviewer is necessary.
If a reviewer returns a manuscript for reassignment, it is a courtesy to
tell the editor the reason for doing so. It is also customary to suggest the
names of potential substitute reviewers. Such help is valuable, and editors
appreciate it.
Some of the guidance commonly found in peer reviewer guidelines
follows.
Philosophy of review
The peer reviewer’s job has two aims: (i) to help the editor make a good
decision on the acceptability of the paper and (ii) to help the authors com-
municate their work accurately and effectively. The peer reviewer does not
have to be an adversary to do either of these jobs. Especially in the latter
case, the reviewer should be an advocate for the authors. Indeed, guide-
lines sometimes urge reviewers to take a positive attitude toward the man-
uscript. Frequently, peer reviewer guidelines caution against the use of
derogatory or libelous comments and ad hominem remarks. Reviews that
are confrontational are distressing to authors and often make things diffi-
cult for all involved. Meaning sometimes gets lost in impolite and ill-
considered language, and this can make the editor’s job of evaluating the
reviewer’s comments confusing. It can distract and mislead authors as they
prepare their rebuttals. Authors may “miss the point” and in doing so fail
to improve their manuscript. Additionally, time is often wasted when au-
thors feel the need to respond in kind to offensive language in their rebut-
tal letters to editors.
Confidentiality
A manuscript sent to a reviewer is a privileged communication. It is confi-
dential information and should not be shared with colleagues except under
prescribed conditions. For example, if it is necessary for the reviewer to get
assistance from colleagues in performing the review, guidelines usually al-
low this only if permission from the editor is sought and received. Such
guidance is often explicitly stated in peer review policies provided by
journal publishers. Generally, the same holds true with regard to sharing
manuscripts with trainees. The opportunity to have a predoctoral or post-
doctoral trainee critically evaluate an unpublished manuscript may provide
a valuable learning experience. However, permission to allow a trainee to
do this should always be sought and received from the journal editor. Peer
review instructions published by some journals specifically address this, ac-
knowledging the value of the experience for the trainee but cautioning that
assigned reviewers should not share manuscripts with trainees without ed-
itorial permission. At least one scholarly organization, the Society for
Neuroscience, makes an exception for trainees, stating in its Guidelines for
Responsible Conduct Regarding Scientific Communication that
A reviewer may bring an immediate lab member with appropriate expertise
into the process for training purposes. In such situations, the reviewer is re-
sponsible for ensuring that the trainee fulfills all obligations for confidential-
ity, and the reviewer must report to the journal the identity of the trainee.
The reviewer remains fully responsible for the content and quality of the
review.
A customary policy is that a peer reviewer should never contact an au-

thor directly about the manuscript under review. This sounds like unnec-
essary advice because most journals use anonymous review. However, even
if journals allow disclosure of the reviewer’s identity to the authors, direct
contact between the two during the review process is usually forbidden.
The reviewer’s opinion about the merit and acceptability of a manuscript is
considered by the editor, who makes the final decision. By talking to au-
thors, reviewers may communicate misleading messages that can make the
editor’s job more difficult. Thus, reviewers who need clarification or addi-
tional information should contact the editor and let him or her obtain it
from the author.
Common criteria for evaluating merit

The manuscript should contain a clear statement of the problem being
studied, and it should be put in perspective. Reviewers should evaluate this
perspective in the context of appropriate literature citations. In other
words, are the authors giving appropriate credit to prior work in the field,
especially those contributions upon which the present report is built? The
originality of the work should be carefully weighed. The reviewer should
consider whether the manuscript reports a new discovery or if it extends or
confirms previous work.
Experimental techniques and research design should be appropriate to
the study. Did the authors use the right tools and techniques to test their
hypotheses? Description of methods is very important. This is the part of
scientific communication that permits verification of the work. The de-
scription of the materials and methods should provide enough detail so
110 Chapter 4
that other investigators can repeat the work. It is acceptable for some
methods to be mentioned briefly and then cited in the references. How-
ever, such citations should be the correct ones. Papers should not be used
as methods citations if they contain incomplete descriptions or if they refer
to an intermediary paper for the details of the method.
The reviewer should examine the presentation of data for clarity and
effectiveness, keeping in mind several questions. Is data presentation clut-
tered or confusing? Are figures and photographs unclear? What about the
organization of the data seen in tables and figures? Are there too many ta-
bles or figures? Can some be deleted? Would data given in tabular form be
better presented in figures? Should data in tables be combined or single-
panel figures redone as multipanel ones?
Interpretations of the data need to be sound and clearly worded. The
discussion of the work should be appropriate: arguments should be logi-
cally presented, and any speculation should be built on data in the paper or
the existing literature.
The writing in the manuscript should be clear, easy to follow, and gram-
matically correct. Many guidelines affirm that the peer reviewer’s job is not
to rewrite the manuscript. However, citing examples of writing deficien-
cies will help the authors in making global revisions. The reviewer should
also note whether the authors are adhering to correct scientific nomencla-
ture and abbreviations as specified by the journal.
The reviewer should evaluate the title and abstract after reading the
paper. Are they adequate and appropriate? With the widespread adoption
of electronic publication, the abstract has become the first line of scientific
communication. Thus, the abstract needs to clearly describe the essence of
the problem, how it was approached, and the outcome of the research.
Writing the review

The format for preparing a manuscript review varies from journal to jour-
nal. In some cases, there is a template of topics of questions about the
manuscript that must be addressed by the reviewer. In many cases, the re-
view instructions provide some guidance and then leave it to the reviewer
to present his or her review in narrative form. In such cases, it is typical for
a review to begin with a paragraph or two that summarize the major find-
ings and highlights of the paper. If there are overriding considerations, ei-
ther positive or negative, they are presented here. Shortcomings or flaws
that have influenced the reviewer’s assessment of the paper should be
stated in general terms.
Following this narrative, it is customary for the reviewer to list specific,
numbered comments. Numbering makes it easier for the authors to re-
spond to the critique and for the editor to make a final decision. Specific
comments should offer guidance to the authors on how to improve their
work. Problems should be identified and solutions suggested where

possible.
Finally, it is customary for the reviewer not to indicate in the narrative
or in the specific comments the ultimate recommendation for the paper.
Instead, this should be clearly transmitted to the editor. As mentioned ear-
lier, it is commonly done with a specific form or in a brief note. There is a
reason for this. Rarely do editors send a paper to just one reviewer; using
two or three experts is the norm. Reviewers can and do disagree about the
merits of the same paper. When this occurs, it is the editor’s job to sort out
the reviews and then write his or her final disposition in a decision letter to
the author. It is frustrating to the authors to read two reviews of the same
work, one explicitly recommending acceptance and the other explicitly
recommending rejection.
Debating peer review

The peer review process seems to be under regular scrutiny and debate.
Like most things driven by human judgment and behavior, it is often cited
as being imperfect. The fundamental nature of the process is a case in
point. Most journals still use the single-blind system. That is, the identity
of the reviewers remains anonymous throughout the process. Double-
blind systems, where the identity of the authors and the reviewers are
blinded to all but the editors, have been tried and are occasionally used.
The principal argument for this system is to reduce bias, but double-blind
peer review is often criticized on the grounds that it is difficult, if not im-
possible, to render a manuscript free of all information that would suggest
or identify the author or authors.
Inherent bias in peer review is sometimes offered as a weakness that
may limit the integrity and effectiveness of the process. Earlier in this
chapter we discussed examples of conflict of interest that could form the
basis for not accepting the assignment to review a manuscript. For ex-
ample, conflicts are created when the authors are collaborators or recent
trainees of the reviewer. But consider the case where an expert peer is
asked to review a paper reporting results that are in an area that is close to
or overlaps with her own research. The culture of confidentiality embraced
by the peer review system notwithstanding, this situation is rife with temp-
tation for the reviewer. There may be new information in the paper that
would benefit the reviewer, but it clearly should not be put to such use.
Contrast this with a timely review of the paper that recommends accep-
tance of the manuscript and, in doing so, precludes the reviewer from pub-
lishing and getting the credit for and recognition of priority of her work.
Another possible scenario—one that invokes harmful intent—involves the
reviewer delaying the review of the paper or delivering an unjustified harsh
review in order to gain an advantage in getting his work published in
112 Chapter 4
advance of the competing paper. Thus, the need for expert review to assure
the quality of published research findings is sometimes pitted against the
conflicts that may compromise its integrity. In this particular case, the re-
viewer is best advised not to accept the assignment to review the
manuscript.
Finally, let’s consider whether peer review is able to detect fraudulent
data, i.e., fabrication and falsification. This question is subject to ongoing
discussion in both scientific and public communities. Journal commentar-
ies and opinion pieces written by scientists and publishers focus on the
“limits of peer review” and whether “peer review can police fraud.” The
upshot of the discussion by scientists and publishers is that the process of
peer review generally is not designed to detect fabricated and falsified re-
sults. Certainly, as discussed above, the use of text-similarity detection
software can detect plagiarism, and the use of such programs is emerging
in the peer review process. The same argument can be made for the in-
creasingly used forensic methods for detecting inappropriately manipu-
lated digital images. These methods are capable of preemptively detecting
doctored images. However, it should be noted that even with this process
in place at one journal, a high-profile case emanated from the report of a
whistle-blower and not as the result of electronic monitoring of a photo-
graph for manipulation that resulted in deception.
The focus of the public media is more subjective and typically embraces
the expectation that peer review is able to detect fraud. For example, news-
print articles on publications that contain fabricated and falsified data have
invoked the “failure of the vaunted peer review” system as a contributing
cause in the publication of fraudulent results. Similarly, statements in arti-
cles on research misconduct claim that the peer review system in science is
designed to “root out” research fraud. Both of these assertions are
misguided.
So what are the realistic expectations of the peer review process when it
comes to papers that contain fabricated or falsified data? Media writers do
not offer the details of why the peer review process should be able to de-
tect bogus data in the first place. Instead, peer review of scientific publica-
tion is usually blamed in whole or in part when fraudulent published data
are uncovered. The reasons for the “failure” are not totally developed but
often include accusations of failure to uphold review standards or shortcuts
taken to publish high-impact research papers. The arguments from the
publishing and scientific communities are drawn from the day-to-day in-
volvement in the process and observations of its operation. Generally,
these arguments hold that detecting fabricated or falsified data that have
been created to deliberately deceive the peer reviewer and, ultimately, the
reader is practically impossible. Usually, perpetrators of fraudulent data
are careful enough in their fabrications and falsifications to generate data
sets that don’t raise suspicions or seem “too good to be true.” So recogni-
tion of such data as fraudulent at face value is not possible. Moreover, edi-
tors and peer reviewers typically do not receive original data outputs,
records, and related materials as part of the review process. This makes
detection of deliberately crafted fraudulent research data even less likely
during the review process.
In general, peer reviewers assume that research findings in manuscripts
are reported honestly and without intention to deceive the reader. The
whole process is built around trust in the authors’ conduct and reporting
of the research. The process expects that peer reviewers will judge the ap-
propriateness of methods selected to address the problem, the nature and
appropriateness of the data analysis, the plausibility of the interpretation of
the data, and whether the conclusions of the paper are consistent with the
data analysis and interpretation. In the absence of whistle-blowing or of
electronic detection of plagiarized material or manipulated digital images,
it is reasonable to posit that the best tool for detecting fraudulent research
results is what many call the “self-correcting” nature of science. Namely,
over time results that have been fabricated or falsified will not withstand
the scrutiny of additional research designed to repeat or build on them.
Publication’s Changing Landscape

Open Access
Digital technology began to have a significant impact on the publication of
scientific literature in the early 1990s. As mentioned above, the transac-
tions of peer review now are typically conducted electronically. Moreover,
the logistics of producing the final article have become electronic and on-
line journals now regularly accompany the print versions. The costs for
receiving the print journal and having access to the electronic version of
the journal are largely borne by subscribers, with the authors usually pay-
ing some of the costs of publication. A number of publishers make elec-
tronic versions of their journals available for public access from their
websites without charge after a defined period of time (e.g., a year). A re-
lated practice of many publishers is to also allow papers supported by vari-
ous research funders (e.g., the NIH) to be placed in public repositories and
made available at no charge within months following the original publica-
tion date. One such repository, PubMed Central, will be discussed below.
Publishers of some subscription journals that produce both print and on-
line versions offer a payment option that creates immediate, free access to
online publications. Specifically, the author is given the opportunity to pay
a fee in addition to standard publication charges. In return for the fee, the
publisher makes the online file of the author’s paper available to readers at
no cost as soon as it is posted to the journal’s website. Thus, authors
114 Chapter 4
electing to pay the fee have their publications placed in the public domain
immediately.
A second model for publishing research papers, Open Access (OA), also
began in the 1990s. In this model, papers are published electronically with-
out a corresponding print version. Instead of a subscription fee paid by
readers, the publication costs in the OA model are borne totally by the
author. Thus, OA publication is often referred to as an “author pays”
model. Peter Suber has written extensively about OA publication and de-
fines it simply: “open-access literature is digital, online, free of charge, and
free of most copyright and licensing restrictions.” Copyright, as mentioned
earlier and discussed in chapter 9, is that form of intellectual property law
that protects the expression of a tangible work product. Copyrightable
works include such things as writings, images and audiovisual products,
sound recordings, sculptures, choreographic works, and computer source
code. Copyrights protect the expression of ideas but not the ideas them-
selves. For example, the words in a journal article are protected by copy-
right exactly as they appear on the page. However, the ideas they contain
or may convey are not protected by copyright. As intellectual property,
copyrights are owned by their creators, but they may be licensed, sold, or
allowed to be used with permission of the creator.
Meetings of interested parties held in Budapest, Hungary (2002);
Bethesda, MD (2003); and Berlin, Germany (2003) gave rise to position
papers that defined OA, made recommendations about its development
and use, and provided a platform for its engagement and endorsement.
The Bethesda Statement on Open Access Publishing defines OA publica-
tion as follows.
An Open Access Publication is one that meets the following two conditions:
1. The author(s) and copyright holder(s) grant(s) to all users a free, irre-
vocable, worldwide, perpetual right of access to, and a license to copy,
use, distribute, transmit and display the work publicly and to make and
distribute derivative works, in any digital medium for any responsible
purpose, subject to proper attribution of authorship, as well as the
right to make small numbers of printed copies for their personal use.
2. A complete version of the work and all supplemental materials, includ-
ing a copy of the permission as stated above, in a suitable standard
electronic format is deposited immediately upon initial publication in
at least one online repository that is supported by an academic institu-
tion, scholarly society, government agency, or other well-established
organization that seeks to enable open access, unrestricted distribu-
tion, interoperability, and long-term archiving (for the biomedical sci-
ences, PubMed Central is such a repository).
Condition 1 of the Bethesda Statement is referred to as Gold OA and is

represented by OA journals that conduct peer review. Condition 2 is
termed Green OA and refers to literature that has already been peer
reviewed and has been deposited in repositories (e.g., PubMed Central)

where it is available to all users without charge.
An inventory of OA journals is maintained online at the Directory of
Open Access Journals. According to this site, the census of OA journals in
mid-2013 was approximately 9,600. By the end of the first decade of the
millennium, the OA journal count was increasing by more than 1,000 jour-
nals per year. The growth and impact of OA journals has been the subject
of various studies. In a 2011 study, significant findings included dramatic
growth of OA journals over a 15-year period compared with the number of
new subscription journals: 15 versus 3% per year. Data suggest that aware-
ness of the existence of OA journals has grown within the scientific com-
munity, as has the use of OA journals for publishing research results. OA
journals have the ability to publish large numbers of papers per year com-
pared with non-OA journals. Such numbers for some OA journals can eas-
ily exceed 1,000, and in 2012 one OA journal published more than 23,000
articles. Subscription journals publish a range of articles per year from sev-
eral dozen to upwards of 1,000 or even higher. Attitudes favoring OA pub-
lishing included free accessibility to readers along with the desire to reach
a wide readership.
Repositories
The repositories mentioned in the previous section are digital archives
into which journal articles are deposited, thus placing the paper into the
public domain. Most notable in this regard is PubMed Central, a reposi-
tory operated by the U.S. National Library of Medicine. In 2008, the NIH
began requiring that all publications reporting research supported by an
NIH grant must be deposited in electronic format on the PubMed Central
site within 12 months of the publication date. This requirement is in the
process of being expanded. In early 2013, the Office of Science and Tech-
nology Policy (an office of the executive branch of the U.S. government)
requested that all U.S. federal agencies “with over $100 million in annual
conduct of research and development expenditures” create plans to in-
crease public access to federally funded research results. There are approx-
imately 20 federal agencies that would fall into this category. Public access
to peer-reviewed publications must be addressed such that the public “can
read, download, and analyze in digital form final peer reviewed manu-
scripts or final published documents.” The plan must use a 12-month post-
publication embargo, similar to the NIH requirement, as a guideline for
making papers publicly available.
This Green OA policy is also employed by funding agencies outside of
the United States. Research Councils UK, the partnership of the seven
Research Councils of the United Kingdom, now requires that papers re-
porting research results obtained under grants from the Research Councils
116 Chapter 4
be made free to public access within 6 months of the publication date of

the paper. Repositories for depositing papers—selected at the authors’
discretion—include PubMed Central, Europe PubMed Central, and the
Economic and Social Research Council Research Catalog. Private research
funding agencies such as the Wellcome Trust (London, United Kingdom)
and the Howard Hughes Medical Institute (Chevy Chase, MD) have simi-
lar policies in place. There is strong sentiment by funding agencies world-
wide that scientific publications resulting from agency support should be
OA, and this is likely to result in increases in the use of Green OA. The
Action Plan towards Open Access to Publications published in 2013 by the
Global Research Council affirms this notion.
Preprint servers
In 1991, physicist Paul Ginsparg created a server-based archive for authors
to upload unreviewed manuscripts that would then be freely available in
the public domain. Ginsparg’s original vision in this venture was to provide
an electronic bulletin board intended to serve his colleagues working in
the field of theoretical high-energy physics. Preprints in this discipline had
historically been exchanged by postal mail service, and his rationale was to
“level the research playing field.” That is, his repository would replace this
limited distribution of photocopied manuscripts among selected colleagues
with a globally accessible electronic repository that would serve all levels
of the scientific community from students to senior scientists. He called
his repository arXiv (pronounced “archive,” with the X representing the
Greek letter chi), and within 2 years it had achieved traction as a global
resource for researchers. Among other things, it “became a place to stake
intellectual precedence claims, catalyzing further growth,” according to
Ginsparg. Some 20 years after its launch, arXiv is now hosted and operated
by Cornell University (Cornell University Library), where Ginsparg is a
faculty member. Preprints (called e-prints on the site) hosted on arXiv ex-
ceeded 850,000 in mid-2013 and included manuscripts in the disciplines of
physics, mathematics, computer science, quantitative biology, quantitative
finance, and statistics.
Ginsparg’s creation of arXiv launched a concept that has been repli-
cated extensively since 1991. Today, preprint servers are hosted by scien-
tific societies and other organizations, publishers, universities, specialty
groups, and even individuals. Some are underwritten by government spon-
sors. Preprint servers tend to be discipline specific to a greater or lesser
degree. All embrace the objectives of rapid information dissemination and
the free and open exchange of scientific information. Although some pre-
print servers reserve the right to reject submissions or to change the topic
classification suggested by the authors, arguments based on the lack of
peer review have been made against the concept. Criticisms have centered
on the reliability of the material being posted. Specific criticisms range

from lack of quality control with respect to the depth of experimental de-
tails to improper or omitted citations. Because preprint servers usually al-
low for revisions or updates of posted material, some argue that this creates
an opportunity for abuse. Posting of material on preprint servers typically
is in perpetuity, and some have objected to this.
Scientists posting their unreviewed manuscripts on preprint servers
should be aware of consequences that may come from their choice to do so.
First, a preprint may accidentally or unknowingly contain proprietary infor-
mation. Disclosing such information in the public domain may preclude the
ability to gain intellectual property protection of it (e.g., a patent). If there
was any reason to believe the manuscript contained proprietary informa-
tion, then the author would be well advised to file for a provisional patent
(see chapter 9) before posting it to a preprint server. Copyright ownership
may be an issue depending on the preprint server being used. For some pre-
print servers, posted papers are in the public domain and the host’s position
on copyright is silent. Other preprint servers hold the copyright by virtue of
the author providing a nonexclusive license. Yet others afford arrangements
to create public copyright licenses under the nonprofit organization Cre-
ative Commons. Last, and arguably most important, is that most publishers
of peer-reviewed journals require that authors may not submit manuscripts
that contain previously published material. Some peer-reviewed journals
consider material that has been placed on a preprint server to be an elec-
tronic publication, and as such, this action forfeits the authors’ rights to sub-
mit any or all of it for consideration. This is illustrated in the policy of the
journals of the American Chemical Society.
A preprint will be considered as an electronic publication and, according to
positions taken by most Editors of ACS journals, will not be considered for
publication. If a submitted paper is later found to have been posted on a
preprint server, it will be withdrawn from consideration by the journal.
Other journals make accommodations for manuscripts that have been

posted to preprint servers, as illustrated in Nature’s current policy.
Our policy on the posting of particular versions of the manuscript is as
follows:
1. You are welcome to post pre-submission versions or the original sub-
mitted version of the manuscript on a personal blog, a collaborative
wiki or a preprint server at any time (but not subsequent pre-accept
versions that evolve due to the editorial process).
2. The accepted version of the manuscript, following the review process,
may only be posted 6 months after the paper is published in a Nature
journal. A publication reference and URL to the published version on
the journal website must be provided on the first page of the
postprint.
118 Chapter 4
3. The published version—copyedited and in Nature journal format—

may not be posted on any website or preprint server.
For open access content published under a Creative Commons license, au-
thors can replace the submitted version with the final published version at
publication as long as a publication reference and URL to the published
version on the journal website are provided.
Clearly, the use of preprint servers has provided a novel dimension to

the concept of OA. They have gained acceptance and provide a useful
source of information to researchers across many disciplines. But the deci-
sion to upload an unpublished manuscript on a preprint server requires
forethought and planning so that doing so does not confound or preclude
the possibility of subsequent peer-reviewed publication or of protection of
proprietary information.
Postpublication review
In the early 2000s, a corporate endeavor was launched that allowed post-
publication peer review online. Originally called F1000—Faculty of 1000
Post-Publication Peer Review, it was composed initially of 1,000 selected
scientists who posted on the F1000 site their comments on peer-reviewed
publications in biomedical fields. In a little more than a decade, this enter-
prise has evolved into three separate services. F1000Prime is now a post-
publication service that publishes “Article Recommendations” made by
the F1000 Faculty. F1000Research is an OA journal covering the life sci-
ences. Articles are published immediately after a preliminary review and
are subject to peer review once posted on the F1000Research site. The
names of the peer reviewers and their comments are published online
with the article. F1000Posters is an OA repository for poster and slide
presentations. F1000Prime now consists of 5,000 scientists and clinical
researchers, assisted by another 5,000 associate faculty members. F1000
reviewers use a rating system of three levels: good, very good, and excep-
tional. Reviewed articles are catalogued and are searchable on the
F1000Prime site. Users of the F1000Prime service pay a fee. Subscribers
to F1000Prime may post comments on the Article Recommendations
made by Faculty. However, subscriber comments that are considered “de-
famatory or otherwise abusive” can be reported and may be removed by
F1000Prime.
Organizations, groups, and individuals also are contributing to the
growth of postpublication peer review using freestanding blogs, social me-
dia, and other online mechanisms. However, with these media, the com-
mentary does not always meet the etiquette prescribed by the policy
mentioned above, and individually sponsored blogs and social media typi-
cally do not have policies that deal with inappropriate remarks or mecha-
nisms in place for removing them. Not unexpectedly, such comments
occasionally appear. Arguably, the emergence of cultural norms that would

suppress if not eliminate such behavior can be expected over time.
Another area that has been the subject of discussion involves what, if
any, obligation authors have to respond to comments. This applies to all
forms of postpublication review, but especially to comments appearing on
independent blog sites or in the various forms of social media. To be sure,
there have been multiple examples of online criticisms that have faulted
methodology, interpretations, and conclusions. In the absence of relevant
cultural norms, authors’ comments have varied significantly. In one case,
the authors acknowledged a technical error, leading to a published “ex-
pression of editorial concern” by the journal’s editor. In contrast is another
well-known paper that claimed the discovery of a microorganism that was
able to replace the use of phosphorus with arsenic, an assertion that would
have a profound impact on the composition of DNA. Despite an intense
attack on the paper’s methodology, results, and conclusions, the authors
refused to engage their online critics, arguing that such comments should
be moderated in the peer-reviewed literature. The upshot was a series of
technical notes and published and unpublished papers that to date present
a compelling case against the findings and conclusions of the original
paper.
There is much left to play out on the field of postpublication review.
Despite some high-profile cases involving strong critiques and their se-
quelae, online commenting is far from commonplace. The critical nature
of some comments and the speed at which they appear postpublication
may be daunting to some authors in the absence of protocol that would
guide a response. In an article titled “Response Required,” the Nature
Publishing Group has taken the editorial position encouraging “post-
publication discussion on blogs and online commenting facilities as a com-
plement to—but not a substitute for—conventional peer review.” In their
article “The Paper Is Not Sacred,” Adam Marcus and Ivan Oransky argue
that the postpublication review process “boosts the long term credibility of
the scientific record.” They submit that the tangible record of online com-
ments and blog posts will accomplish this. What the postpublication re-
view process evolves into will ultimately depend on the engagement of the
relevant stakeholders along with a critical analysis that seeks to reveal its
true value to the scientific record.
Publication metrics
The advent and proliferation of digital journals has accelerated and ampli-
fied the use of metrics associated with scientific papers. The most estab-
lished and influential of these is the journal impact factor (IF). The impact
factor was conceived and developed several decades ago by Eugene Gar-
field, who initially published it under the banner of the Institute for
120 Chapter 4
Scientific Information. Today, the Institute is known as Thomson Reuters,

and journal IFs are published annually on Thomson Reuters Web of Sci-
ence, a repository for databases dealing with research data, research publi-
cations, and patents. The IF calculation is meant to express a journal’s
average citation frequency. The underlying assumption is that the more
that papers published in a journal are cited in other publications, the higher
the quality of the journal. The use of the IF metric has given rise to the
commonly used phrase “high-impact journal.” The IF is expressed as an
annual metric but is based on the average number of citations received per
paper appearing in the journal over the previous 2 years. For example, con-
sider a journal with an IF of 4 as published in the Thomson Reuters Jour-
nal Citation Reports 2012 Release. This would mean that the total of all
citations in 2012 made to papers published in the journal during 2010 and
2011 divided by the total number of journal papers during this biennium
would equal 4. Only citations in journals that are indexed by the Journal
Citation Reports are used in the IF calculation.
The use of the IF has been criticized because it is frequently misused as
an indicator to judge the quality of work of individual scientists and insti-
tutions. In fact, the IF metric was originally devised to help librarians make
subscription decisions based on journal quality. Some argue that using the
IF as a research quality proxy for individual scientists leads to the ques-
tionable conclusion that it’s not what you publish but where you publish.
Further arguments focus on the ill-advised selection of journals for publi-
cation based on their IF instead of factors like the appropriateness of the
journal’s readership and the expertise of the editor and editorial board.
The American Society for Cell Biology convened a group of scientists,
journal editors, publishers, scholarly societies, and funding agencies at its
annual meeting in 2012 to discuss journal IFs and their use. The outcome
of this meeting was the San Francisco Declaration on Research Assess-
ment released in mid-2013. The Declaration is subtitled “Putting Science
into the Assessment of Research,” and its 18 recommendations aim to “im-
prove the ways in which the output of scientific research is evaluated by
funding agencies, academic institutions, and other parties.” The first rec-
ommendation is overarching and calls for the elimination of journal IFs
and related metrics in the assessment of an “individual scientist’s contribu-
tions, or in hiring, promotion, or in funding decisions.” The Declaration
has more than 200 signatories, including individual scientists, editors, pub-
lishers, scientific societies, and funding agencies. However, there were a
number of high-profile publishers and groups that did not sign the Decla-
ration. The Declaration also was endorsed in journal editorials published
to coincide with its release. The recommendations provide a framework
that promotes new attitudes toward journal publication metrics, provides
new prescriptions for their use, and even suggests changes in publication
practices that would have an impact on how scientific research is reported.

Acceptance of the Declaration’s recommendations will have to involve a
variety of participants including researchers, publishers, institutions, fund-
ing agencies, and organizations that collect and provide metrics. This will
add complexity and time to whatever implementation will be achieved.
Unlike the IF, which was intended to measure journal quality, there is
another metric designed to measure the impact of a researcher’s publica-
tions. Developed by Jorge Hirsch, the h-index calculation—like the IF—is
based on citation frequency. The h-index measures both productivity and
impact. The h-index calculation begins with a researcher’s body of publica-
tions. Hirsch defines the h-index as “the number of papers with a citation
number higher or equal to h.” Thus, if at the time of calculation a re-
searcher has published 130 papers and 33 of those papers have been cited
33 or more times, then the h-index is 33. Since its inception in 2005, there
have been a number of variants of the h-index proposed, including ones
that give more weight to highly cited articles (Egghe’s g-index) or to more
recently published articles (contemporary h- index). Some researchers
present statistics, including their h-index, in the publication sections of
their curricula vitae. Other investigator statistics that sometimes get added
to curricula vitae include graphic representation of the researcher’s papers
published over time and citations of all of his or her papers on an annual
basis. Graphics for these can be easily prepared using the Thomson Reu-
ters Web of Science site.
It should be noted that some journals (both OA and subscription) now
include metrics associated with the online version of each paper they pub-
lish. Data that can be accessed at these sites include the number of cita-
tions in various databases, page views and downloads, mention in social
media, and coverage by the news media.
A final metric bears some discussion, namely the frequency at which
published manuscripts are retracted. Papers may be retracted in whole or
in part voluntarily by authors for reasons of errors in logic, errors in meth-
odology, irreproducibility, or other honest mistakes. Papers also may be
retracted by authors or by publishers as the result of confirmed or sus-
pected research misconduct: fabrication, falsification, or plagiarism. When
a paper is retracted, the citation and the online article (on PubMed Central
and the online journal) will indicate this status, meaning it should not be
considered valid. A partial retraction indicating that some but not all data
are invalid may be in order and used in lieu of a full retraction. Studies
show that the number of retracted articles in biomedical journals has risen
significantly since the beginning of the millennium. Using the PubMed
database, one study reported that total retractions (as indicated by a retrac-
tion alert associated with the citation) rose from 28 in 2001 to 407 in 2011.
However, estimates are that PubMed now adds a half- million new
122 Chapter 4
citations per year, making even the most recent number of retracted papers
a very small fraction of papers in the database.
In another study, Ferric C. Fang, R. Grant Steen, and Arturo Casadevall
reviewed approximately 2,000 biomedical and life sciences papers that had
been retracted as identified in the PubMed database. This resource refer-
ences more than 25 million biomedical research articles published since
the 1940s. Two important points were reported by these authors. First, the
earliest retraction of an article they found was in 1977 (originally pub-
lished in 1973). This suggests that retraction of publications in the bio-
medical literature is a relatively recent development. Second, and more
importantly, their analysis found that that 67% of the retractions were
connected to some form of research misconduct.
Unfortunately, retracted papers may still be incorrectly cited (i.e., cited
without acknowledging that they have been retracted). This could be the
result of oversight or could conceivably be the result of deliberate decep-
tion. Alternatively, confusion caused by retracted papers available on non-
publisher websites—but not noted as being retracted—may contribute to
incorrect or inappropriate citation.
Conclusion
Written communication is an essential part of scientific research. Science

benefits society only insofar as its findings are made public and applied. In-
deed, biomedical scientists have a moral obligation to share new knowledge
in order to advance and improve the health and well-being of humankind.
Scientific knowledge is accepted only when the published research results
that support it hold up under scrutiny and independent corroboration.
In the past, many of the decisions about authorship on scientific papers
were based on unwritten norms and standards. In recent years, written
guidelines for authorship have been promulgated by institutions, societies,
and publishers. These provide guidance to authors and can be especially
informative to the novice writer.
Providing peer review of scientific publications is an obligation that is
shared by scientists. While peer review must be scholarly and rigorous, it
must also be timely, respectful, and courteous. Above all, peer review must
be constructive. Peer review plays a vital role in the publication of research
findings, although the process is being increasingly challenged. Its work-
ings and effectiveness are likely to be the subjects of continuing debate
among scientists for years to come. Nonetheless, the process of peer re-
view is performed under both written and unwritten guidelines. Explicit
descriptions of the duties and responsibilities of peer reviewers are now
frequently published by scientific journals. They aim to foster consistency
and integrity in the process.
Since the early 1990s, the scientific literature has been increasingly
a ffected by computers and electronic publication. The peer review process
is dependent on electronic communication, as is the actual production of
the journal. Access to electronic versions of the published literature has
created an effective platform for communicating research findings, and the
concept of OA publication offers a new paradigm for both authors and
readers.
1. Should all coauthors share equally in the blame and punishment
when fabrication, falsification, or plagiarism is proved to have oc-
curred in a published paper?
2. What sanctions or punishment is appropriate for those who per
petrate fabrication, falsification, or plagiarism in scientific publica-
tions?
3. Should the scientific publication enterprise do more to be able to
detect falsified or fabricated data during the peer review process?
Why or why not?
4. The editors of Nature have taken the position in which they encour-
age “post-publication discussion on blogs and online commenting
facilities as a complement to—but not a substitute for—conventional
peer review.” (See the “Response Required” citation in the “Re-
sources” section below). Critically comment on Nature’s position and
provide your reasoning for supporting or rejecting it.
Case Studies
4.1 Dr. Colleen May is a participating neurologist in a clinical trial to

assess the efficacy and toxicity of a new anticonvulsant medication.
For the duration of the 2-year study, each neurologist is to meet with each
of his or her patients for an average of 30 minutes each month. In Dr.
May’s case, this amounts to an average of 20 hours per month. During each
visit, the physicians administer a variety of specialized tests, requiring
judgments dependent on their experience and training in neurology. At the
completion of the study, the results are to be unblinded and analyzed by
the project leaders. It is anticipated that at least two publications will be
prepared for the New England Journal of Medicine. Dr. May has just learned
that she will be listed in the acknowledgments but not as a coauthor of the
manuscript. Dr. May argues that she has provided nearly 500 hours of her
expert time, far more than needed to complete a publishable study in her
experimental laboratory. Does Dr. May have a case for authorship? Why
or why not?
124 Chapter 4
4.2 Dr. Ethyl Metzger has published five multiauthored papers during
her postdoctoral training. Ethyl shared first authorship on two of
these papers. The names of Ethyl and her co-first author were decided by
a coin toss as indicated in a footnote according to journal policy. In both
cases, Ethyl lost the coin toss and her name appears as the second author
in the byline. Her remaining three publications each have five authors in
their bylines, and Ethyl is third author on two and fourth author on one.
Ethyl is submitting application materials to several institutions to be con-
sidered for faculty positions. On her curriculum vitae she has changed the
order of the authors on her two shared first authorship papers so that her
name appears first instead of second. She is concerned that search com-
mittees reviewing applications may miss any notation indicating shared
first authorship, so she believes the most direct way to assert this is to
have her name first in the citation. Ethyl worries that if she doesn’t do
this there is a risk of her postdoctoral publication record appearing as
though she did not publish a single senior-authored paper. She mentions
this to you over lunch and asks if you have any concerns about her strat-
egy. What do you tell her? If you have concerns, what guidance or advice
do you have for her?
4.3 Aarti Shankar, a new M.D.-Ph.D. graduate, has a hypothesis about

a mechanism that would explain an unexpected phenotype dis-
played by a knockout mouse constructed by her doctoral mentor, Dr. Gina
Costello. With Dr. Costello’s permission and resources, Aarti experimen-
tally tests her hypothesis in the few remaining weeks before she leaves the
lab. Her results reproducibly demonstrate that the mouse is totally missing
a minor signaling protein called Xgro. This defect provides a compelling
explanation for the knockout phenotype. Aarti leaves for her residency
training buoyed by the hope of being an author on a major paper. In fol-
low-up work on the project, Raymond, another postdoc in the lab, is un-
able to repeat Aarti’s work. To Dr. Costello’s chagrin, not only are Aarti’s
data irreproducible but Raymond demonstrates that, to the contrary, the
mutant mouse produces 10-fold more Xgro than the wild-type mouse. It
takes another 4 months of experiments to rigorously collect confirmatory
data. In the process, Raymond also discovers that Aarti’s data were the re-
sult of her failure to properly conduct the signaling protein assay. Interest-
ingly, Raymond’s newly observed overproduction of Xgro provides an
attractive alternative explanation for the mutant phenotype. Upon com-
pleting the lab work and data analysis, Dr. Costello and Raymond write a
manuscript describing their findings on the mechanism underlying the
mouse phenotype. Aarti becomes aware of this and requests that she be a
coauthor on the paper because her seminal idea was key to the work even
though she did the assay incorrectly. Raymond is opposed to this, saying
that Aarti’s lab work has delayed submission of this important discovery for
publication. Dr. Costello seeks your advice on whether Aarti has a case for
authorship. What do you tell her? Why?
4.4 Bella Nassar is a tenure-track assistant professor of psychology

who has made good progress in building her professional portfo-
lio in anticipation of achieving promotion to associate professor with ten-
ure. With just a couple of years until she will be eligible to be considered,
she is concerned that she is weak in the area of external professional in-
volvement. The school guidelines expect involvement in external activi-
ties like service as a peer reviewer, editorial board work, service on
external expert panels, and the like. Bella has recently received an unso-
licited invitation to serve a 5-year term on the peer review board of an
online open-access journal in psychology. Following the invitation, she
gets a call from a high-level manager at the publisher’s office. The man-
ager urges her to accept the offer. He tells her that as a member of the
board she will be expected to submit at least three of her own papers to
the journal over the course of her term. To the extent possible, she is told
that these papers should cite relevant publications that have appeared in
the journal. The publisher tells her that these practices are “good for her
and good for the journal.” After the call, she has a phone conversation
with a current member of the journal’s peer review board. He tells her
that he has welcomed the opportunity to submit his papers to the journal
but has been pressured by the editor-in-chief to cite previous papers pub-
lished in the journal. He describes the pressure—which he calls “coercive
citation”—as a totally transparent effort to increase the journal’s impact
factor. Bella mulls this opportunity over and is inclined to accept, thus
strengthening her case for promotion and tenure. She doesn’t think there
will be any harm or downside associated with this assignment, even
though the practices of the journal strike her as unusual. She comes to
you seeking guidance. What’s your advice for her, and what’s your ulti-
mate take on whether she should accept the invitation to serve on the
journal’s peer review board? Why?
4.5 Demitri is a senior-level predoctoral student in the department of

biological chemistry. A member of his graduate advisory commit-
tee, Dr. Chris Sullivan, requires an additional experiment to be completed
before Demitri writes his dissertation. Demitri complies with this request,
but the results of the experiment itself do not yield any new or useful in-
formation. However, a positive control that Demitri conceived and de-
cided to include in the experiment lead him to some surprising results.
Ultimately, these findings enable him to prove that a small-molecule li-
gand in an important receptor binding event is not the native molecule but
126 Chapter 4
a significantly modified metabolite of it. This is a high-impact discovery,

and Demitri and his mentor write a manuscript about it. At his predefense
graduate advisory committee meeting, Demitri shares the manuscript de-
scribing this provocative finding and indicates that it is under review by a
prestigious journal. Later that day, Dr. Sullivan e-mails Demitri and his
mentor. In strong terms he expresses his dissatisfaction with not being in-
cluded as an author on the manuscript. His argument is straightforward: if
he had not required the experiment to be done, this discovery would never
have been made by Demitri. He argues that his insistence on Demitri do-
ing the experiment qualifies as a “significant idea” and that this phrase is
commonly mentioned in publication guidelines as a clear rationale for au-
thorship. He goes on to bitterly complain that the manuscript “adds insult
to injury” by not even including his name in the “Acknowledgments” sec-
tion. Demitri is intimidated by the e-mail and argues to his mentor that
Sullivan has made a compelling point and that they should add his name to
the author’s byline, telling the journal it was originally left off in error. As
Demitri’s mentor, what is your response to that suggestion? What is your
analysis of the situation, and what actions will you take as mentor to ad-
dress Dr. Sullivan’s challenge? Why?
4.6 Roger Tibault, a predoctoral student, is first author on a paper just

published online in a prestigious journal. Sharing the author’s byline
is Professor Wanda Whittaker, Roger’s mentor, and a postdoctoral trainee.
Roger receives an e-mail from a colleague who informs him that the paper
is being discussed on a blog. Roger immediately looks at the blog comments.
To his chagrin, the anonymous comments are attacking the paper with alle-
gations that a photographic image of a gel blot has been manipulated to
deliberately mislead the reader. One blog post displays the results of foren-
sic analyses of the image. The bloggers declare that their results demon-
strate that some of the lanes in the gel contain areas that have been “erased”
and that there is at least one example of a gel signal that has been “cut-and-
pasted” into the image. The experiments that resulted in this gel blot were
the team effort of Roger and the postdoc. Roger immediately brings the
blog allegations to Dr. Whittaker’s attention. He and the postdoc review the
data and the preparation of the image with her. They readily admit that the
gel blot image was edited to improve its clarity but say that nothing they did
was meant to be deceptive, nor did it change the data in the image. Dr.
Whittaker is convinced by their arguments. The three then discuss what, if
anything, they should do. Should they post a response on the blog defend-
ing their position? Should the editor of the journal be notified of the blog
posts and the Whittaker group’s conclusions? They also consider doing
nothing, since some have argued that authors are not obligated to respond
to the public comments of individuals outside of the peer review process.
Dr. Whittaker even suggests that they consider turning over all of the rele-
vant materials, including the raw data, to the institutional research integrity
officer. This could trigger an inquiry into the matter, but Whittaker feels
there has been no wrongdoing. So even if disclosure of the situation to the
research integrity officer results in an inquiry, she and her colleagues would
be exonerated. Do any of these possible strategies have merit? Why or why
not? What advice do you have for Dr. Whittaker?
4.7 Fred Taylor—a professor at Western State University (WSU)—

collected data on forest conditions and dynamics over a three-state
area in the western United States. The project required in-the-field data
gathering as well as telemetric data recording. All of the data were gath-
ered and used to create a large computer database under a contract funded
by the three states to WSU. Dr. Taylor was the principal investigator of the
project, and he and his trainees and technicians collected all of the data
over a 5-year period. The resultant large data set was analyzed, and Dr.
Taylor and his group wrote and published several peer-reviewed papers on
their findings. Dr. Taylor recently retired and moved to another state. The
data set was archived on a WSU server. Dr. Taylor was granted emeritus
faculty status upon his retirement; however, he continued teaching in envi-
ronmental science at Southwest University as an adjunct faculty member
and continued to stay active in his field by reading the literature. A year
into his retirement, Dr. Taylor reads a paper just published by a WSU ju-
nior faculty member and her predoctoral trainee that has used a new mod-
eling program to analyze parts of the large data set that he and his group
built. The paper reports novel and valuable insights into forest climatology
that were not possible with previously existing analytic algorithms. Al-
though Dr. Taylor was unaware of the new algorithm, he is furious that he
was not advised that the paper was being published, let alone being left off
the authors’ byline or not even mentioned in the “Acknowledgments” sec-
tion. The three-state contract to WSU is mentioned in the acknowledg-
ments as having supported the creation of the large data set, but the name
of the principal investigator—Dr. Taylor—was not listed. Dr. Taylor writes
to the WSU vice president for research demanding that his name be listed
as an author by requesting that the journal publish a “correction” to the
paper. He also threatens to file an allegation of plagiarism against the au-
thors because their use of the data set without his knowledge represented
an act of academic theft, or plagiarism. Comment on the implications of
authorship, data sharing, and data ownership that impinge on this situa-
tion. What advice for action would you give to the vice president? Does
Dr. Taylor’s threatened plagiarism allegation have any merit? Why or why
not? Are the junior faculty member and her trainee at fault for anything
they did or didn’t do?
128 Chapter 4
4.8 Dr. Roy Osaka, a well-funded scientist, leaves Medium University

to take a position at Large Medical Center University. Dr. Danielle
LeBlanc, the departmental chair, assigns another faculty member, Dr. Carl
Valdez, to Dr. Osaka’s former office and lab. A few months later, Dr. Valdez
comes across some of Dr. Osaka’s files in a cabinet drawer. In looking
through these materials, he discovers what looks to be a completed draft of
a manuscript written by Dr. Osaka. What attracts Dr. Valdez’s attention is
that the title page lists Osaka’s address as Large Medical Center Univer-
sity. No acknowledgment of Medium University is noted in the manu-
script. Dr. Valdez is puzzled by this but does not take any action. Several
months later, a paper authored by Dr. Osaka appears in a prestigious inter-
disciplinary journal. Dr. Valdez notes that the published paper is virtually
identical to the manuscript he discovered in Dr. Osaka’s former office. He
has a good appreciation of the science involved and believes that Osaka
could not have accomplished the work reported in the few months that he
has been at Large Medical Center University. What’s more, the acknowl-
edgments in the printed paper thank a technician whom Dr. Osaka super-
vised at Medium University. Dr. Valdez believes that Dr. Osaka is
attempting to demonstrate his research prowess by convincing his supervi-
sors at Large Medical Center University that his research program is up
and running at full throttle. In fact, however, it appears that the work was
performed at Medium University. Dr. Valdez brings the departmental
chair, Dr. LeBlanc, the manuscript and a copy of the published paper. He
suggests that Dr. Osaka has committed scientific misconduct by deliber-
ately falsifying information in the manuscript. Dr. LeBlanc comes to you,
the department’s resident expert in research ethics, and asks what she
should do. What’s your advice for her?
4.9 Suzanne Booth is recruited as a postdoctoral fellow in a laboratory

where research centers on the cell biology of a specific mammalian
cell type. Suzanne’s training has been in eukaryotic gene cloning and mo-
lecular genetics; no such technology is available in this laboratory. Suzanne
completely trains a senior-level graduate student working in the group.
Under Suzanne’s supervision, the student proceeds to build a complemen-
tary DNA (cDNA) library and isolates by molecular cloning a gene for a
membrane protein. Several months later, a manuscript describing this
work is prepared for submission. The principal investigator of the labora-
tory, Professor Jack Martin, and the student are listed as coauthors. Su-
zanne is listed in the “Acknowledgments” section of the paper. She is upset
with this disposition and confronts Dr. Martin. Dr. Martin says that he has
strict rules about authorship and that Suzanne’s contribution was a techni-
cal one that does not merit authorship. Dr. Martin quotes from several
different standards-of-conduct documents indicating that authorship must
be strictly based on intellectual and conceptual contributions to the work

being prepared for publication. Technical assistance, no matter how com-
plex or broad in scope, is not grounds for authorship. Does Suzanne have a
case for authorship? Why or why not?
4.10 Dave Clubman completes his Ph.D. program and leaves the labo-
ratory immediately to attend to personal matters. An important
manuscript based upon his dissertation exists only in a preliminary draft.
During the next year, Professor Holly Franks, his former advisor, attempts
to contact Dave to complete the manuscript. After some months, Dr.
Franks edits the manuscript, prepares the figures, and sends the updated
version to Dave. Dave acknowledges receipt of the manuscript but pro-
vides no comments and does not sign a memorandum acknowledging con-
sent to submit the manuscript. During this period, some results similar to
Dave’s are published by another laboratory. Dr. Franks and a postdoctoral
fellow extend the work and prepare a new manuscript with Dave as first
author and the postdoctoral fellow as an additional coauthor. The manu-
script is sent to Dave by certified mail, but he does not provide any com-
ments nor return a signed memorandum agreeing to submission for
publication. A third party hears that Dave blames Dr. Franks for the delay
and is trying to “give her a hard time.” Dave was supported by federal
funds, and his results were included in annual progress reports to the
granting agency. Can Dr. Franks submit the manuscript and publish it if it
is accepted by the journal? What should be the authorship on the paper?
Should any comments be included in the “Acknowledgments” section?
Resources
Print
Atlas R, Campbell P, Cozzarelli NR, Curfman G, Enquist L, Fink G, Flanagin
A, Fletcher J, George E, Hammes G, Heyman D, Inglesby T, Kaplan S,
Kennedy D, Krug J, Levinson R, Marcus E, Metzger H, Morse SS, O’Brien
A, Onderdonk A, Poste G, Renault B, Rich R, Rosengard A, Salzberg S,
Scanlan M, Shenk T, Tabor H, Varmus H, Wimmer E, Yamamoto K; Jour-
nal Editors and Authors Group. 2003. Statement on the consideration of
biodefence and biosecurity. Nature 421:771.
Carroll MW. 2013. Creative Commons and the openness of open access. N Engl J
Med 368:789–791.
Day RA, Gastel B. 2006. How To Write and Publish a Scientific Paper, 6th ed. Green-
wood Press, Westport, CT.
Fang FC, Steen RG, Casadevall A. 2012. Misconduct accounts for the majority
of retracted scientific publications. Proc Natl Acad Sci USA 109:17028–17033.
Frank M. 2013. Open but not free—publishing in the 21st century. N Engl J Med
368:787–789.
130 Chapter 4
Garner HR. 2011. Combating unethical publications with plagiarism detection

services. Urol Oncol 29:95–99.
Hames I. 2007. Peer Review and Manuscript Management in Scientific Journals:
Guidelines for Good Practice. Blackwell Publishing. Oxford, United Kingdom.
Haug C. 2013. The downside of open-access publishing. N Engl J Med 368:791–
793.
Kennedy D. 1997. Academic Duty. Harvard University Press, Cambridge, MA.
Mandavilli A. 2011. Peer review: trial by Twitter. Nature 469:286–287.
Marcus A, Oransky I. 2011. Science publishing: the paper is not sacred. Nature
480:449–450.
Merton RK. 1968. The Matthew effect in science: the reward and communication
systems of science are considered. Science 159:56–63.
Nature. 2010. Special issue: Science Metrics. 465:845, 860–862, 864–866, 870–872.
Nature. 2013. Special issue: The Future of Publishing. http://www.nature.com/
news/specials/scipublishing/index.html.
Nature Editors. 2010. Response required. Nature 468:867.
Resnick DB, Barner DD, Dinse GE. 2011. Dual-use review policies of bio
medical research journals. Biosecur Bioterror 9:49–54.
Science. 2013. Special issue: Communication in Science: Pressures and Predators.
342:13, 56–59, 66–71.
Sigma Xi. 2011. For the Record: American Scientist Essays on Scientific Publication.
Sigma Xi, Research Triangle Park, NC. http://www.sigmaxi.org/programs/
ethics/ForTheRecord.pdf.
A collection of essays on publication topics including authorship, peer review,
and electronic publication.
Steen RG, Casadevall A, Fang FC. 2013. Why has the number of scientific re-
tractions increased? PLoS One 8:e68397. doi:10.1371/journal.pone.0068397.
Suber P. 2012. Open Access. MIT Press, Cambridge, MA.
Wolpert AJ. 2013. For the sake of inquiry and knowledge—the inevitability of
open access. N Engl J Med 368:785–787.
Online
Selected instructions for authors or editorial policies
Journal of Bacteriology
http://jb.asm.org/site/misc/ifora.xhtml
Nature
http://www.nature.com/authors/gta.pdf
Phytopathology
http://apsjournals.apsnet.org/userimages/ContentEditor/1173286505152/phyto_au
thor_instructions.pdf
Proceedings of the National Academy of Sciences of the United States of America

http://www.pnas.org/site/misc/iforc.pdf
Proceedings of the National Academy of Sciences Prior Publication Policy

http://www.pnas.org/content/96/8/4215.full
Science
http://www.sciencemag.org/site/feature/contribinfo/index.xhtml
Metrics
San Francisco Declaration on Research Assessment (hosted by the Ameri-
can Society for Cell Biology)
http://am.ascb.org/dora/
Organizations and associations

Committee of Publication Ethics
http://publicationethics.org/
Council of Science Editors (including CSE’s White Paper on Promoting In-

tegrity in Scientific Journal Publications, 2012)
http://www.councilscienceeditors.org/
Ethics Collaborative Online Resource Environment (Ethics CORE) web-

site, a resource source for publications:
http://nationalethicscenter.org/resources/publications
International Committee of Medical Journal Editors website, where the

Recommendations for the Conduct, Reporting, Editing, and Publication
of Scholarly Work in Medical Journals may be accessed:
http://www.icmje.org/
The Office of Research Integrity website’s resources on publications and

authorship:
http://www.ori.hhs.gov/education/products/rcr_authorship.shtml
World Association of Medical Editors

http://www.wame.org/
132 Chapter 4
Open access
Action Plan towards Open Access to Publications, from the Global Re-
search Council:
http://www.dfg.de/download/pdf/dfg_magazin/internationales/130528_grc
_annual_meeting/grc_action_plan_open_access.pdf
Berlin Declaration on Open Access to Knowledge in the Sciences and

Humanities
http://openaccess.mpg.de/Berlin-Declaration
Bethesda Statement on Open Access Publishing

http://dash.harvard.edu/handle/1/4725199
Budapest Open Access Initiative Declaration

http://budapestopenaccessinitiative.org/
Directory of Open Access Journals

http://www.doaj.org/
Harvard Open Access Project website (Peter Suber, director):

http://cyber.law.harvard.edu/hoap/Main_Page
Howard Hughes Medical Institute open public access policy

http://www.hhmi.org/about/policies/open-access/
Scholarly Open Access: Critical Analysis of Scholarly Open-Access Pub-

lishing is a blog created and maintained by Jeffrey Beall:
http://scholarlyoa.com/
Wellcome Trust open-access policy

http://www.wellcome.ac.uk/About-u s/Policy/Policy-a nd-p osition-s tatements/
WTD002766.htm
Plagiarism detection software and use

CrossCheck
http://www.crossref.org/crosscheck/index.html
Deja Vu: a Database of Highly Similar Citations

http://dejavu.vbi.vt.edu/dejavu/
eTBLAST: a text-similarity based search engine

http://etest.vbi.vt.edu/etblast3/
iThenticate: online plagiarism detection software

http://www.ithenticate.com/
PubMed and related archives

PubMed, a biomedical literature citation database operated by the U.S.
National Library of Medicine, National Institutes of Health:
http://www.ncbi.nlm.nih.gov/pubmed
PubMed Central, a green, open-access, full-text archive of biomedical and

life sciences research publications operated by the U.S. National Library
of Medicine, National Institutes of Health:
http://www.ncbi.nlm.nih.gov/pmc/
PubMed Central International, a collaborative effort between PubMed

Central and organizations in other countries or areas (presently Europe
and Canada) aimed at creating digital archives of the scientific literature at
multiple global sites:
http://www.ncbi.nlm.nih.gov/pmc/about/pmci/
Europe PubMed Central, the website of the European PubMed Central

research literature archive:
http://europepmc.org/
For funding agencies that require or encourage archiving of research arti-

cles supported by agency grants in Europe PubMed Central:
http://europepmc.org/Funders/
PubMed Central Canada research literature archive; the Canadian Insti-

tutes of Health Research (CIHR) requires that its grant recipients archive
papers reporting their CIHR-supported research within 12 months of
publication:
http://pubmedcentralcanada.ca/pmcc/
Scientific societies’ guidance on authorship and publication

ethics
American Chemical Society
http://pubs.acs.org/page/policy/ethics/index.html
134 Chapter 4
American Psychological Association

http://www.apa.org/research/responsible/publication/index.aspx
Society for Neuroscience

http://www.sfn.org/member-center/professional-conduct/
guidelines-for-responsible-conduct-regarding-scientific-communication
Other online resources

ClinicalTrials.gov, a registry and results database of clinical studies of hu-
man participants:
http://clinicaltrials.gov/
National Institutes of Health Office of Biotechnology Activities website,

with links to the National Science Advisory Board for Biosecurity and
Dual Use Research of Concern pages:
http://oba.od.nih.gov/biosecurity/about_nsabb.html
Retraction Watch, an independent blog created and maintained by Adam

Marcus and Ivan Oransky that follows retractions of papers published in
the scientific literature:
http://retractionwatch.wordpress.com/
Thomson Reuters Web of Science

http://thomsonreuters.com/thomson-reuters-web-of-science/
chapter 5
Use of Humans in Biomedical

Experimentation
Paul S. Swerdlow and Francis L. Macrina
Overview • Are You Conducting Human Subjects Research? • The
Issue of Informed Consent • IRBs • The IRB and the Informed
Consent Issue • Research Exempt from the Federal Regulations
• The IRB and Expedited Review • Human Experimentation
Involving Special Populations • The Health Insurance Portability
and Accountability Act (HIPAA) • Fetal Tissue and Embryonic
Stem Cell Research • Conclusion • Discussion Questions • Case
Studies • The Declaration of Helsinki • Resources
Overview
T here are many important ethical issues in scientific endeavors, but

none has been better codified than experimentation involving human
beings as subjects. Much of early medicine undoubtedly involved experi-
mentation, most of which was not regulated. In fact, the rules for experi-
mentation with people were initially summarized in the Nuremberg
Principles that came out of the Nuremberg war criminal trials at the end
of World War II. These trials held accountable those involved in human
experimentation performed without the consent of the subjects. Although
largely of historical significance today, the Nuremberg Principles (also
called the Nuremberg Code) provided the foundation for future guideline
documents, most notably the Declaration of Helsinki (discussed below).
The 10 Nuremberg Principles included statements about protection of
human subjects; experimental design based on previous animal studies;
careful risk-to-benefit analysis in the context of the importance of the
problem being studied; performance of experiments only by scientifically
qualified persons; subject-initiated withdrawal from the research at any
stage; and investigator-initiated cessation of the experiment in the face of
possible injury, disability, or death.
doi:10.1128/9781555818487.ch5
135
136 Chapter 5
Unfortunately, a significant number of ethically questionable studies

have been performed, both before and after promulgation of the Nurem-
berg Principles. A particularly egregious example was the syphilis study
conducted at the Tuskegee Institute with funding from the U.S. Public
Health Service (PHS). The aim of the 1932 study was to determine the
course of untreated syphilis in African Americans, a disease that was widely
believed to be a distinct entity from that in whites. The arsenic-and
mercury-based therapy then in use was quite toxic but generally believed
to be beneficial. No patient consent was obtained in this study, wherein
spinal taps were disguised as “free treatment.” Even the scientific basis of
the study was flawed, as most of the 412 infected men had received some
initial treatment as an inducement to participate in the study. It was later
decided that, because their treatment had been inadequate, follow-up as an
untreated cohort was warranted. The study clearly documented a 20% de-
crease in life span for the infected men as compared with the control group
of 204 uninfected men.
In the 1940s, when penicillin was found to be effective therapy, the
study was nonetheless continued. Authorities reasoned that this was the
last chance to study untreated syphilis because of soon-to-be-widespread
antibiotic use. Patients were not informed about the potential new therapy,
although their infections could have been cured by penicillin. As late as
1969, a review panel allowed the study to continue. The Macon County
Medical Society, which included African American physicians, promised to
assist in the study and to refer all patients before using antibiotics for any
reason. In 1972, the study was finally reported in the public press. In 1973,
more than 20 years after penicillin entered widespread use, the govern-
ment finally took steps to ensure treatment of the few surviving infected
patients. In May 1997, President Bill Clinton apologized for the Tuskegee
study on behalf of the American people, saying that “the United States
government did something that was wrong—deeply, profoundly, morally
wrong.” Now, more than 4 decades after the closure of this study, and with
numerous additional safeguards in place, many people remain reluctant to
trust clinical research studies.
Early in the present millennium it came to light that a similar study
was conducted in Guatemala by National Institutes of Health (NIH) re-
searchers in collaboration with some Guatemalan agencies. Documents
show that from 1946 to 1948, prostitutes, prisoners, and soldiers were
intentionally infected with syphilis and other venereal diseases for the
purpose of studying the effects of penicillin on prevention and treatment.
None of the research subjects provided informed consent. While it ap-
pears that some penicillin was given to those infected, documentation
does not show evidence of treatment completion for the overwhelming
Use of Humans in Biomedical Experimentation 137
majority of those involved. Documentation about the study was discov-

ered in 2005 by Susan Mokotoff Reverby when she was researching the
Tuskegee study. The U.S. government officially apologized to the Guate-
malan government in 2010.
In 1964, the World Medical Association (WMA) sponsored a confer-
ence in Helsinki, Finland, to formalize guiding principles for the ethical
use of humans in biomedical experimentation. The Declaration of
Helsinki, prepared at this conference, has prevailed as the international
standard for biomedical research involving human subjects. Since then,
the Declaration of Helsinki has been amended and reaffirmed as a guid-
ing force in experimentation with human subjects nine times, most re-
cently in 2013. The text of the current version of the Declaration of
Helsinki is reprinted at the end of this chapter. Two years after the
WMA Helsinki conference, the U.S. PHS issued a memo identifying the
first U.S. requirement for institutional review boards (IRBs). The memo
called for independent review of PHS-funded research to evaluate the
rights and welfare of subjects to be involved, the appropriateness of
the informed consent process, and the risks and potential benefits of the
research.
In 1979, the National Commission for the Protection of Human Sub-
jects of Biomedical and Behavioral Research wrote the Belmont Report
in an attempt to summarize the basic ethical principles of human subjects
research. The three principles of the Belmont Report are generally ac-
cepted by today’s IRBs as the basis for ethical review. The first Belmont
Report principle, Respect for Persons, speaks to the notion of autonomy,
specifically that individuals must be treated as autonomous agents capa-
ble of making independent decisions. Individuals who are unable to make
independent decisions due to diminished capacity should be afforded
greater protections. The principle of Respect for Persons is exemplified
in the informed consent process, whereby individuals are to be fully in-
formed, in understandable language, about all aspects of research studies
to enable informed decision making. The second principle, Beneficence,
addresses the ethical concept of “do no harm.” In practice, this equates to
minimizing risks and maximizing benefits. Weighing the risks versus
benefits is one of the primary decisions IRBs make in their deliberations.
The third principle, Justice, indicates that the benefits and burdens of
research should be equally distributed. In other words, research subject
selection should ensure that no particular population is being unduly
burdened, nor are some excluded from the potential benefits that bio-
medical research might bring to bear. The federal regulations guiding
IRB criteria for approval of research are directly associated with the Bel-
mont Report principles.
138 Chapter 5
Are You Conducting Human

Subjects Research?
Before discussing the major areas of human subjects research procedures
and regulations, we shall address those activities that officially meet the
definition of research involving a human subject. The legal requirements
that govern human subjects experimentation are broad and may cover re-
search based only on private identifiable information about living individ-
uals, as well as on materials being used or activities that create an interface
between a human subject and the researcher. The website of the Office
for Human Research Protections (OHRP) of the Department of Health
and Human Services (HHS) provides decision charts that graphically
clarify whether a research activity is subject to federal regulations govern-
ing human subjects experimentation. The key points from the OHRP
website may be summarized as follows.
The definition of human subjects research comprises two components
addressed in the federal law (45 CFR 46.103) that governs such activities.
Research means a systematic investigation, including research development,
testing and evaluation, designed to develop or contribute to generalizable
knowledge. Activities that meet this definition constitute research for pur-
poses of this policy, whether or not they are conducted or supported under a
program which is considered research for other purposes. For example,
some demonstration and service programs may include research activities.
Human subject means a living individual about whom an investigator
(whether professional or student) conducting research obtains:
(1) data through intervention or interaction with the individual, or
(2) identifiable private information.
Intervention includes both physical procedures by which data are gathered
(for example, venipuncture) and manipulations of the subject or the subject’s
environment that are performed for research purposes. Interaction includes
communication or interpersonal contact between investigator and subject
(e.g., engaging in an interview or completion of a survey). Private information
includes information about behavior that occurs in a context in which an indi-
vidual can reasonably expect that no observation or recording is taking place,
and information which has been provided for specific purposes by an indi-
vidual and which the individual can reasonably expect will not be made public
(for example, a medical record). Private information must be individually
identifiable (i.e., the identity of the subject is or may readily be ascertained by
the investigator or associated with the information) in order for obtaining the
information to constitute research involving human subjects.
Human subjects research includes all studies where there is an interven-

tion or interaction with a living person that would not be happening outside
of the conduct of the experimentation. Even if this is not the case, the activ-
ities may still be subject to regulations if identifiable data or information
gathered during the research— or collected outside of the study in
question—may be linked to the human subjects. Federal regulations also

apply to human subjects who are used to test devices, materials, or products
that have been developed through research. The use of existing human sub-
ject data or specimens may be subject to federal regulations regardless of
whether they were generated as part of the study in question. In general, the
use of any materials or data of human origin needs to be evaluated to deter-
mine whether the use meets the definition of research with a human subject
and associated regulatory obligations apply. Tissues, blood, organs, excreta,
secretions, hair, nail clippings, and materials derived from these sources
(e.g., DNA) generally define the activity as human subjects experimentation
subject to regulatory compliance whenever the materials have associated
identifiers or a code that would allow for reidentification. Investigators
should consult with the office of their IRB for advice and guidance on
whether the definition of human subjects research has been met.
A simplified decision tree designed to introduce the reader to the
decision-making process in approaching human subjects research is pre-
sented in Fig. 5.1.
The Issue of Informed Consent
Key among the principles of experimentation on human subjects is the con-

cept of obtaining informed consent from research subjects. While the in-
formed consent document is generally considered the primary component
of informed consent, consent should be thought of as an ongoing process
rather than the one-time signing of a document. There are several essential
components of the consent process needed in order for valid consent to be
obtained. First, the person must be “competent to consent”—to understand
consequences and to make decisions. The decisions do not have to meet any
particular criteria for “good” decisions—he or she may enter a study for the
“wrong” reason or make a decision someone else thinks is “bad.” In other
words, the individual must simply be able to understand the consequences
of various decisions and have the capacity to make such a decision. In prac-
tice, many people who are clearly competent routinely make bad decisions
regarding relationships, employment, medical care, and many other matters.
The standard of competence for medical research is no different. When in-
dividuals who might benefit from participation in research are not compe-
tent to consent for themselves, the regulations make certain provisions for
an IRB to determine that consent by a legally authorized representative of
the potential research subject is appropriate.
Consent must also be voluntary, that is, free from coercion. Coercion to
participate in studies, however, can be very subtle and at the same time pow-
erful. Coercion can come from many sources, including the patient’s family,
the researcher, the physician, the institution, and even the health care system
140 Chapter 5
Are you doing research? Research is a systematic investigation designed to create or

contribute to generalizable knowledge, e.g., through
presentations or publications.
NO: YES
IRB review
and
approval not
needed
Does your research involve “Human being” means a living individual about whom any
interaction or intervention investigator (professional or trainee) obtains information,
with a living human being, including specimens, or any other data by any means; private information
obtaining private information about means that which would allow identification of the individual.
a living human individual?
NO: YES
IRB review
and
approval
not needed
Your research must be submitted for review by your institutional

review board (IRB). This review may involve consideration by a
fully constituted IRB panel, or it may involve specific
consideration under one or more of six categories deemed
exempt by federal law. The determination that a protocol may be
reviewed under an exempt category must be made by the IRB, not
the investigator.
Figure 5.1 A simple decision tree for determining whether IRB review and ap-
proval are needed for your proposed work. doi:10.1128/9781555818487.ch5.f5.1
itself. While most researchers and institutions avoid coercing study partici-
pants, subtle coercion may not be apparent to those conducting the research,
let alone the potential subjects for the research. Some of these elements are
difficult to control. Family coercion to participate in some form of therapy is
often strong, even when no clear benefit exists. This is often seen in cancer
chemotherapy, where even though prolongation of survival may be minimal
and treatment fraught with side effects, familial pressure to take treatment
can nevertheless be intense. This is usually related to standard therapy, but
the same factors may pertain in research situations. Studies of genetic pedi-
grees for inherited conditions are much more likely to be revealing if more
family members participate. Family pressure can be extreme in these situa-
tions and even extend to those who do not wish to know if they carry a
certain gene (such as that for Huntington’s disease, a terminal condition that
results from genetically programmed degeneration of brain cells).
Different aspects of coercion can become part of the health care system,
as illustrated in the following two examples. First, people without insurance
may join studies to receive basic care that would otherwise be unavailable.
While this has often been a problem in underdeveloped countries, it has also
been a problem in the United States. Under some health insurance plans, in
an effort to decrease costs, physicians have not been allowed to present cer-
tain standard medical alternatives to their patients. Thus, patients in such
situations may face subtle coercion to join a study because all medical op-
tions presented seem inadequate. The second example derives from situa-
tions where only marginally effective standard therapies exist and therapeutic
research is felt by many to be a patient’s best option. Such research compares
the most promising new therapy with the best current (but usually far from
ideal) therapy. In aggressive attempts to control costs, health insurance plans
are limiting a patient’s freedom to embark on therapeutic clinical trials by
calling such trials “experimental.” Nearly all health care policies specifically
exclude experimental expenses. Such denials occur even when the costs of
the study are no greater than those for the standard therapy. An ethical di-
lemma arises when all potential therapies for the disease in question are ex-
perimental. The result may be that even those willing to enroll in large
peer-reviewed clinical trials may not be allowed to participate. Recent regu-
lations do require insurers to pay for patient care costs associated with spe-
cific types of therapeutic trials. However, the burden often falls to the
research subject to work with insurance carriers directly to determine what
costs will be covered, which presents a significant disincentive to participate.
Coercion by the basic researcher (one not licensed to treat patients), phy-
sician, or institution must also be controlled. Researchers are often reim-
bursed in clinical studies on a per-patient basis. The per-patient fee covers
the experimental costs and often a portion of the researcher’s salary and
even the departmental budget. There is thus great incentive to enroll as
many patients as possible. While the basic researcher usually has little to use
to coerce people into participating (other than reimbursement for the ac-
tivity), a physician-researcher has much more power. To a large and ever-
increasing extent, the physician controls the patient’s access to the U.S.
health care system and is often entrusted to make medical decisions for the
patient. Many patients refuse to even question their physicians about these
decisions, in part because they trust them, since they possess requisite spe-
cialized knowledge, and in part because of paternalistic (or maternalistic)
attitudes held by many physicians. Under such circumstances, it is easy for
patients to feel that if they decline to participate in a study, they may lose a
precious doctor-patient relationship and even access to the health care sys-
tem. Such issues must be addressed through consent forms and patient
142 Chapter 5
education, or coercion may occur. This is especially likely if the physician is

a participant in or will benefit from the research (e.g., the department em-
ploying the physician conducts the research). It is also important to regard
the circumstances of the study and how the study will be employed in spe-
cial populations where coercion is more likely (see below).
Consent must also be informed. The participant must have adequate
information to make a valid decision. The participant has the right to know
what she will be asked to do for participation, as well as be informed about
the risks of the study, including risks that are even beyond what would
normally be discussed for medical informed consent. When routinely in-
forming a patient about potential risks of a procedure or course of treat-
ment, the physician makes an effort to reveal all realistic risks that are
likely to affect the decision making of the patient. However, known risks of
extremely small magnitude are often not mentioned. They are confusing
and may adversely affect decision making to the detriment of the patient.
For example, risks significantly lower than dying in a car accident on the
way to the doctor’s office are often not disclosed. With a study, however,
particularly one that is not of therapeutic intent, all known risks should be
disclosed for truly informed consent.
Merely presenting the information is not sufficient. Informed consent
requires comprehension of the study procedures and risks by the partici-
pant. The investigator should verify that the person really understands the
various options and risks and potential benefits of the study. For this rea-
son, many institutions encourage the participant to have a relative or friend
witness the signature on the consent form. This provides the person with
an ally who hears the same information, can ask additional questions, and
is likely to be less emotionally involved.
Who must ensure that the above obligations are fulfilled? While the
principal investigator is ultimately responsible for the conduct of a study, it
is the obligation of all who are involved in the conduct of the research to
ensure that informed consent is obtained. This duty is not restricted to
those who obtain the informed consent or to those involved solely with the
clinical parts of the study. It can be delegated to parts of the group but
should not be delegated lightly; that is, all involved are responsible to see
that it is done correctly. It is essential for all involved to read the consent
form and then to ensure that the study, its risks, and its benefits are fairly
and understandably presented.
IRBs
Institutions receiving federal support in the United States are required to

have a Federalwide Assurance, naming at least one IRB to approve and
oversee research on human subjects. This document is kept on file with the
OHRP. The OHRP is the arm of the HHS charged with the oversight of
human research that is federally funded in the United States. The Federal-
wide Assurance commits an institution to adhering to the HHS regula-
tions governing human subjects research. Institutions may choose to apply
the regulations to all research or limit the assurance to only federally
funded research.
Committees similar to the IRB are found in other countries, but their
rules and composition vary. Rules pertaining to the formation of U.S. IRB
committees are relatively simple. The committee must include at least five
members, and the membership list must be filed with the U.S. Secretary of
Health and Human Services and the Food and Drug Administration (FDA)
if the institution conducts FDA-regulated research. All five members can-
not have the same profession, and there must be at least one member with
primary concerns in nonscientific areas (often a lawyer, ethicist, or mem-
ber of the clergy). There must also be at least one member not affiliated
with the institution or with family so affiliated. The nonaffiliated member
may also be the nonscientific member. Most academic institutions have
larger committees than required to ensure adequate expertise for the re-
view of research.
Approval of projects requires a simple majority vote. At least one non-
scientific member of the committee must vote but does not have to vote
for approval. No member is allowed to participate in the review of a project
in which he or she has a personal interest. The committee may invite ex-
perts to appear, but such experts may not vote. Proposals must be rere-
viewed at least yearly, and there must be written procedures that prescribe
the operations of the committee. An institution’s selection on the Federal-
wide Assurance to apply the regulations to all or to only federally funded
research determines whether all or only some serious or continuing non-
compliance in research or with the IRB review process must be reported to
the OHRP.
The committee is charged with specific criteria with which to review
proposals. First, the risks to subjects must be minimized consistent with
the aims of the research. Ideally, proposed procedures would be those al-
ready being performed for diagnostic or therapeutic purposes. For re-
search to be ethically valid, it must first be technically valid. Even a study
with minimal risk requires that valid scientific results are to be obtained, or
it cannot be justified. This is most often a problem with small clinical stud-
ies in which statistically valid data may be difficult to obtain. Common
reasons for such small studies include:
• Study of a rare disease or disorder. These are often called “orphan dis-
eases.” Traditionally, pharmaceutical companies have had little inter-
est in pursuing clinical trials of drugs to treat orphan diseases because
144 Chapter 5
the small potential market often cannot justify the development

costs. However, the FDA conducts an orphan drug program that
provides incentives to pharmaceutical sponsors, and this continues to
spark interest in their study and the development of new drugs and
biologicals for orphan diseases.
• Pilot studies of new therapies. It is often difficult to get funding for large
and therefore expensive clinical studies. Pilot studies test the feasibil-
ity of new treatments but are generally not sufficient to establish ef-
ficacy. They provide the information needed to properly design and
obtain funding for the larger study.
These types of studies must have clearly defined endpoints so the IRB
can determine their risk-to-benefit ratio. Valid endpoints can include de-
termination of treatment toxicity, patient compliance, or drug pharmaco-
kinetics. Attempting to determine efficacy of treatments with too few
patients, however, will likely create problems at the IRB. Statisticians, in
particular, will instantly realize that the chances of determining efficacy
with a small population are nil unless dramatic changes are found in easily
measured outcomes. A good statistical analysis is often essential for proper
study design and can save time and unnecessary effort with the IRB, with
granting agencies, and subsequently with data analysis.
Most important to the IRB review, the risks to subjects must be reason-
able in relation to anticipated benefits. Study benefits include benefits to
the research subject as well as the importance of the knowledge that may
reasonably be expected to result. In assessing the risk-to-benefit ratio of
the project, only the risks and benefits of the research should be consid-
ered. Risks of procedures that would still be performed if not included in
the study should not be considered. Similarly, a beneficial procedure per-
formed as part of a study cannot be considered a benefit if the same proce-
dure would be performed without the study.
For clinical studies in which two different treatments are being com-
pared, there must be a valid null hypothesis that the two arms are equiva-
lent. This is the concept of equipoise, that neither of the two treatments is
known to be better. The researcher should be able to honestly say that
there are no convincing data indicating that one arm is better. If one arm is
known to be better, the point of the study is moot and the research is no
longer ethical. This includes placebo-controlled studies, in which the test
treatment is compared with no treatment at all. Such studies may be rea-
sonable if the efficacy of the treatment being tested is not known and there
is no known efficacious therapy.
The committee is prohibited from considering long-range effects on
public policy that may result from the research. For example, in reviewing a
study of an expensive therapy for dissolution of gallstones, the committee

should not take into account the bankrupting of the health care system that
might result if the procedure were eventually used on all gallstone patients.
The research must make adequate provision for monitoring data to en-
sure the safety of subjects. The FDA also requires such information for all
new agents. The research must also include adequate plans to protect pri-
vacy and confidentiality. Records containing identifying information
should be maintained in locked locations with access restricted to those
who have a need to use the information and who are trained in medical
confidentiality or privacy. It is especially important not to discuss such in-
formation in public places such as hallways, elevators, or lunch rooms
where comments might be overheard. It is often a good idea to create a
second database lacking identifying information for ease of use and
convenience.
Selection of subjects must be equitable. For example, it is not appro-
priate to restrict a study to people with health insurance in the hopes that
such patients will eventually financially support the hospital should they
return to have other medical problems treated. There is also a national ef-
fort to ensure that minority populations and women are not excluded from
studies, as has been done in the past. One reason often used to exclude
women from studies was the issue of pregnancy. A new drug will likely not
have been tested in human pregnancy and will pose an unknown risk to
such pregnancies. It was often felt simpler not to include women so as not
to have to worry about pregnancy. Currently, most studies will allow
women using medically approved birth control to participate. Further-
more, if the research will be of potential medical benefit to the woman,
pregnancy will not necessarily exclude her from the research.
Finally, in addition to IRB oversight, a separate data and safety moni-
toring board (DSMB) may be used during studies involving human
subjects, especially clinical trials. DSMBs are oversight bodies that may
be established at the request of a principal investigator or the IRB or
may be required by the sponsor of the study. Typically DSMBs are cre-
ated to track research that involves high risk to subjects with the overar-
ching purpose being to ensure subject safety and welfare. DSMBs may
serve a variety of other purposes including identifying unacceptably slow
accrual rates, identifying protocol violations and suggesting remediation,
and identifying unexpected rates of ineligibility or subject dropout that
may compromise the credibility and validity of the study results. DSMBs
are composed of physicians, scientists, biostatisticians, and others with
expertise relevant to the study. These individuals must be free of conflicts
of interest. A DSMB examines data at regular points in the study and is
empowered to unblind data if it deems such action necessary. DSMBs
146 Chapter 5
may recommend stopping a study for cause, including undue risk to par-
ticipants or clear evidence that the data support a conclusion that argues
against continuing the research.
The IRB and the Informed Consent Issue
Informed consent is one of the basic tenets of protecting the rights and
welfare of research subjects. The concept of informed consent stems di-
rectly from the Belmont principle of Respect for Persons. IRBs must en-
sure that informed consent is sought from each prospective subject or his
or her legally authorized representative, unless adequate justification is
made to waive the consent process. If the IRB approves the process, those
unable to consent but who have an appropriate legal representative or
guardian may participate if the representative gives informed consent. All
consents must be properly documented unless the IRB waives the need for
signature. The informed consent document must contain specific infor-
mation such as the purpose of the research, the research procedures, and
risks and benefits of participation.
Special provisions must be made for studies in which some or all of the
subjects are likely to be vulnerable to coercion or undue influence. The
regulations afford specific protections to pregnant women and fetuses,
children, and prisoners. Other vulnerable populations considered by the
IRB include people with acute or severe physical or mental illness and
those who are economically or educationally disadvantaged. One such
safeguard could be to have a patient representative to ensure that when
studies are complicated and involve acute medical situations or include
people with limited education, subjects completely understand all implica-
tions. Consent forms must be read to those who cannot read (or read well)
and should be written so they are easy to understand. It often helps to have
the consent form reviewed by those used to dealing with the educationally
disadvantaged.
There is an increasing trend for consent forms to be approved by cen-
tral authorities for large projects involving substantial numbers of people.
While this may seem intrusive, such efforts have so far yielded high-quality
consent forms by employing people with expertise in the creation of such
forms and who are skilled in presenting complex topics in lay language.
While a written informed consent document continues to be the norm,
study sites are increasingly integrating technology, such as video, into the
process in an effort to simplify consent information and to enhance com-
prehension and retention.
What should be included in an informed consent? Consent forms ful-
fill several roles in human research. They are designed to describe the
study in detail, including risks and benefits. They can, however, also be a
contract and include compensation for participation in the study. Consent

forms must describe the compensation for participation in the study.
Consent forms must explain the participants’ rights, including the right to
withdraw from the study at any time. They must also reassure participants
that they will not forfeit any other rights because of refusal to participate
or withdrawal from the study. The form should specify what happens if a
participant becomes pregnant and whether birth control is required to
participate. The consent form also provides the participant with the
phone number of the investigator, as well as that of the IRB should a par-
ticipant with concerns not wish to speak with the investigator. Each insti-
tution has its own format, but uniformity of protocol and consent formats
aids in the review process.
One challenging issue in the informed consent process is that of stored
DNA samples. Such samples contain the full genome of the donor, in-
cluding information (real and potential) on predisposition to genetic dis-
eases and other potential health or employment problems. Release of this
information could be tremendously damaging for a participant. He or she
could be denied insurance (e.g., life or disability) or even employment
based on the information. The protection of this information must be
considered by the IRB and explained in the consent form. If such samples
are to be stored for future use, the types of use must be specified. If a new
use is found in the future, a new consent might be required from the do-
nors for this use. Such consents are difficult to obtain, especially given
our mobile society. One alternative is to make the samples anonymous by
stripping off any identifiable information so the samples cannot be
tracked back to the donor. The difficulty here is that no further informa-
tion about the samples is then available.
Research Exempt from

the Federal Regulations
As noted previously, certain types of minimal-risk research are exempt
from human subjects regulations, including the need for IRB approval
and informed consent requirements. Minimal risk is generally consid-
ered risk that is no greater in magnitude or severity than risks normally
encountered by average healthy individuals (as opposed to risks that may
typically be encountered by the target population of the research, such as
cancer patients). The regulations have designated six categories of re-
search that may be considered exempt. These include research on educa-
tion instructional strategies, the efficacy or the comparison of
instructional techniques or curricula, or classroom management meth-
ods. Research involving the use of educational tests (cognitive, diagnos-
tic, aptitude, or achievement), surveys, interviews, or observations of
148 Chapter 5
public behavior is also exempt if the information collected is either re-

corded in a deidentified manner or would not place the subjects at risk of
harm (e.g., criminal or civil liability, loss of employability, or social stig-
matization). The use of secondary data or specimens that are previously
collected (e.g., is retrospective) may be exempt when no identifying in-
formation is recorded for the research. In medical settings, examples of
the most common exempt research are studies based on medical chart
reviews or the use of previously collected specimens, such as pathology
samples. Research that is requested by a public agency to evaluate the
effectiveness of programs or services may also be considered exempt. Fi-
nally, research on taste or food quality may be exempt as long as food
ingredients remain below federally allowable levels.
Some of the exemption categories include exclusions for certain study
populations (e.g., children and prisoners); thus, the categories should be
reviewed carefully to ensure that proposed research does not require IRB
review. While a project may well be exempt from regulations, the decision
of whether or not it is exempt is not generally made by the individual in-
vestigator. Institutional policy typically dictates who has the authority to
determine whether project is exempt; often this authority is delegated to
the office of the IRB.
The IRB and Expedited Review
Many committees have procedures for expedited review for specific types
of research involving no more than minimal risk. Expedited review may be
conducted by one or more IRB committee members rather than by the
full, convened IRB. As with exempt research, study conduct must be lim-
ited to certain types of procedures to qualify for expedited review. These
include procedures listed below, adapted from the Code of Federal Regu-
lations (45 CFR 46).
Prospective collection of:
• Biological specimens for research purposes by noninvasive means

such as (i) hair and nail clippings in a nondisfiguring manner; (ii)
deciduous teeth at time of exfoliation; (iii) permanent or deciduous
teeth if routine patient care indicates a need for extraction; (iv) ex-
creta and external secretions (including sweat); (v) uncannulated
saliva collected either in an unstimulated fashion or stimulated by
chewing gum base or wax or by applying a dilute citric solution to
the tongue; (vi) placenta removed at delivery; (vii) amniotic fluid
obtained at the time of rupture of the membrane prior to or during
labor; (viii) supra-and subgingival dental plaque and calculus,
provided the collection procedure is not more invasive than routine

prophylactic scaling of the teeth and the process is accomplished in
accordance with accepted prophylactic techniques; (ix) mucosal
and skin cells collected by buccal scraping or swab, skin swab, or
mouth washings; and (x) sputum collected after saline mist
nebulization.
• Blood samples by finger stick, heel stick, ear stick, or venipuncture
collected no more than twice weekly (i) from healthy, nonpregnant
adults who weigh at least 110 pounds in amounts not to exceed 550
ml in an 8-week period or (ii) from other adults and children, consid-
ering the age, weight, and health of the subjects, the collection pro-
cedure, the amount of blood to be collected, and the frequency with
which it will be collected, but the amount drawn may not exceed the
lesser of 50 ml or 3 ml per kg in an 8-week period.
• Research involving materials (data, documents, records, or speci-
mens) that have been collected or will be collected solely for non
research purposes (such as medical treatment or diagnosis). In
expedited research, as opposed to exempt research, data may be col-
lected prospectively and identifiers may be retained.
• Data obtained through noninvasive procedures (not involving gen-
eral anesthesia or sedation) routinely employed in clinical practice,
excluding procedures involving X rays or microwaves. Any medical
devices must be already approved for marketing and not currently
being tested for safety and effectiveness. Examples: (i) physical sen-
sors that are applied either to the surface of the body or at a distance
and do not involve input of significant amounts of energy into the
subject or an invasion of the subject’s privacy; (ii) weighing or testing
sensory acuity; (iii) magnetic resonance imaging; (iv) electrocardiog-
raphy, electroencephalography, thermography, detection of naturally
occurring radioactivity, electroretinography, ultrasound, diagnostic
infrared imaging, Doppler blood flow, and echocardiography; and (v)
moderate exercise, muscular strength testing, body composition as-
sessment, and flexibility testing where appropriate given the age,
weight, and health of the individual.
• Data from voice, video, digital, or image recordings made for re-
search purposes.
• Data on individual or group characteristics or behavior (such as re-
search on perception, cognition, motivation, identity, language, com-
munication, cultural beliefs or practices, and social behavior) or
research employing survey, interview, oral history, focus group, pro-
gram evaluation, human factors evaluation, or quality assurance
methodologies.
150 Chapter 5
Human Experimentation
Involving Special Populations
Incompetent patients
It is often assumed that those with mental illness or those who are not
able to provide informed consent must be excluded from all studies. This
is not the case. Consent must be provided by the legally responsible per-
son, and the study must be designed in such a way that adequate safe-
guards exist for the participants. It would seem unfair to deprive these
people of the right to participate in potentially therapeutic studies or to
prevent information from being gained to help people with mental disor-
ders. Clearly, the IRB and the researchers must ensure that individual
rights are respected. They must also take into account that participating
in arduous programs without being able to understand the reason for the
treatments makes such programs much more difficult to endure. This
type of research (certain chemotherapy trials, for example) may therefore
be inappropriate for certain populations. Psychiatric patients may be es-
pecially vulnerable emotionally. Particular attention must be paid to
avoid covert (and likely unintentional) coercion. Furthermore, it has been
suggested that research personnel should use the medical definitions of
informed consent for certain studies in this patient population rather
than the more comprehensive information usually required, in an effort
to reduce patient anxiety. Thus, the IRB has special responsibilities for
protocols involving these patients.
Prisoners
Prisoners constitute an excellent example of a population that requires ad-
ditional safeguards for consent for scientific study. The nature of incarcer-
ation affords numerous potential coercions, and thus federal regulations
specifically offer additional safeguards for this population. Only certain
types of federally sponsored research can be performed on prisoners.
These include:
• Studies of possible causes, effects, and processes of incarceration or
criminal behavior that present no more than minimal risk or incon-
venience to the prisoner.
• Studies of prisons as institutional structures or of prisoners as incar-
cerated persons.
• Research on conditions affecting prisoners as a class, such as vaccine
studies on hepatitis due to the increased incidence of hepatitis in
prisons or social or psychological problems such as alcoholism or
drug addiction. The Secretary of Health and Human Services must
consult with experts in penology, medicine, and ethics and give no-
tice in the Federal Register of intent to approve such research.
• Research on both innovative and accepted practices that have the

intent to improve the health or well-being of the subject. If control
groups will be used in the protocol, the Secretary must again consult
with experts and give notice as above.
There are very specific requirements for the IRB when reviewing re-
search involving prisoners, including the requirement that a prisoner or a
prisoner representative must be a member of the IRB. A prisoner represen-
tative must have the appropriate background and experience to serve as a
true representative of the prisoners. Another requirement is that a majority
of the IRB (exclusive of prisoner members) must have no association with
the prisons involved. There is no requirement that the prisoner or prisoner
representative must vote for a given proposal for it to be enacted.
The IRB must further determine that any advantages gained by the
prisoner by participating are not of such magnitude that the prisoner’s
ability to weigh the risks of participation is impaired. These would include
advantages in living conditions, medical care, food quality, amenities, po-
tential earnings, and outside contacts. The risks involved must also be risks
that would be accepted by nonprisoner volunteers. Study information
must be presented in a manner the population can understand.
Selection of subjects in prison must be fair to all prisoners and cannot
be arbitrarily used or influenced by prisoners or prison authorities. Studies
must not be used as a reward or method to control the inmate population.
Participation in scientific or medical studies cannot be taken into account
by parole boards in determining eligibility for parole. The prisoner must
be specifically informed that parole considerations will not be affected. Al-
lowing participation to affect parole would be an example of undue influ-
ence or coercion to participate.
Where follow-up is required, arrangements must be made for the vari-
ous lengths of sentence of the prisoners. The researchers should also con-
sider the likelihood of noncompliance after the sentence is over. The
potential import of these arrangements is illustrated by the case of a
35-year-old prisoner who developed testicular cancer while incarcerated.
The prisoner was placed on a standard, noninvestigational therapy with his
consent. With aggressive chemotherapy, testicular cancer is largely cur-
able. After the first course of chemotherapy resulted in a good response,
the court, at the county’s request, paroled the prisoner. The reason for pa-
role was not made clear to the medical staff, but it was suspected that ei-
ther it was a compassionate parole (which seemed strange for a largely
curable, as opposed to terminal, cancer) or the county did not wish to pay
the costly medical bills for the therapy. The prisoner, who had tolerated
the chemotherapy well, left the hospital against medical advice in the mid-
dle of a treatment, saying he had “things to do.” He never returned for the
152 Chapter 5
needed therapy and was lost to follow-up. While it was clearly his right to
leave, it is also likely that the cancer recurred. Recurrent cancer has a di-
minished prognosis and if left untreated is usually fatal. If the prisoner had
been on a study, it is certain he would not have continued with it. In this
particular case, some of the medical staff thought that the county, by parol-
ing the prisoner, had converted his sentence to a death sentence (albeit
with the prisoner’s unintentional collaboration).
Children
The regulations include special protections for the involvement of chil-
dren in research. The definition of a child varies from state to state, with
most indicating the age of majority to be 18. IRBs and investigators must
be aware of the legal age of majority for the location in which research
will occur. For minors, parents or guardians must give consent. When
research involves significant risk, both parents must consent when avail-
able, unless only one parent has legal responsibility or custody. In addi-
tion to parental consent, the assent or agreement of the child is required
when the IRB deems that he or she is capable. In making this determina-
tion, the IRB must consider the age, maturity, and psychological state of
the children involved. This can be done for all children involved in a given
protocol or individually. If the IRB determines that the capacity of the
child is too limited or if the research may offer benefits important to the
health or well-being of the child, assent is not required.
It has been pointed out that certain behaviors commonly accepted in
society put children at much greater risk than do most research studies.
Gideon Koren, Daphna Birenbaum Carmeli, Yoram Carmeli, and Robert
Haslam calculated the risk of a babysitter having to deal with a severe
medical emergency in Canada. They calculated that each year at least 900
Canadian babysitters would have to deal with an acute asthmatic attack in
one of their charges and that 26 would likely have a child who experiences
sudden infant death syndrome while under their care. These situations
would place the babysitters, often between the ages of 10 and 15, at risk of
emotional trauma far greater than would most research studies. The work
of Koren et al. suggests that if a child is deemed mature enough to super-
vise younger children in potentially extremely dangerous situations, he or
she should be able to consent to most research studies.
Children who are wards of the state or any other agency can be in-
cluded in research only if the research is either related to their status as
wards or conducted in institutions in which the majority of children in-
volved are not wards. In such cases, the IRB shall require appointment of
an advocate—not associated with the research, the investigator, or the
guardian organization—who agrees to act in the best interests of the child
for the duration of the child’s participation in the research.
Additional restrictions are imposed for research with greater than mini-
mal risk. However, when there is greater than minimal risk but also the pos-
sibility of direct benefit to the child, the IRB must determine that the risk is
justified by the anticipated benefits. The risk-to-benefit ratio must also be at
least as good as that of all alternative approaches. When there is no prospect
of direct benefit but the research is likely to yield important knowledge
about a disorder, the risk must represent a minor increase over minimal
risks. The interventions must be comparable to those inherent in the actual
or expected medical, dental, social, or educational situations. The informa-
tion to be obtained must be of vital import for the understanding or amelio-
ration of the subject’s disorder or condition. To bypass these restrictions,
there must be a reasonable opportunity to achieve further understanding,
prevention, or alleviation of a serious problem affecting the health or wel-
fare of children. Nevertheless, the Secretary of Health and Human Services
must consult with a panel of experts and ensure that such a condition exists
and that the research will be ethically conducted.
These restrictions may seem excessive and may indeed slow research in
some areas. It must be remembered, however, that for children who are not
old enough to consent, the parents and the IRB remain their sole advocates.
There is even some indication that parents who volunteer their children for
studies may be psychologically different from those who do not, making the
issue of study regulation and control even more important.
More recently, efforts have been made to ensure that children are incor-
porated into studies of most new medications. This is part of an effort to
include all underrepresented groups in research studies to ensure wide-
spread applicability of the results. Efforts to include women and minorities
are also under way. Many medications routinely used in pediatrics have not
been studied in children but are merely used after approval for adults. By
requiring pediatric studies (i.e., in persons less than 21 years old) for most
medications, it is hoped that this situation can be reversed.
The Health Insurance Portability and

Accountability Act (HIPAA)
The HIPAA was passed in 1996 to improve the efficiency of electronic in-
formation processing during health care. At the same time, the law im-
posed strict new regulations for handling health care information. The
HIPAA regulates both the privacy (who can access what information) and
the security of the information (mechanisms for prevention of inappropri-
ate, accidental, or intentional disclosure or loss). In response to this law,
HHS issued regulations in 2003, titled “Standards for Privacy of Individu-
ally Identifiable Health Information,” which is generally called the Privacy
Rule. The Privacy Rule applies to individually identifiable health
154 Chapter 5
information created or maintained by a covered entity. Covered entities

are health plans, health care clearinghouses, and health care providers that
transmit health information electronically in connection with HIPAA
transactions, such as claims or eligibility inquiries. In practice, all health
plans, clearinghouses, and providers will be covered entities since all fed-
eral and insurer health transactions are currently becoming electronic. Re-
searchers are not covered entities, unless they are also health care providers
or are employed by covered entities.
Elements of the HIPAA that need to be considered during the conduct
of human subjects research are as follows.
• Protected health information (PHI) is any information gathered by a
health care provider that contains data that could directly or indi-
rectly identify the patient. This includes common items such as
name, address (standard mail or e-mail), phone or fax number, date
of birth, or social security number, as well as items such as vehicle or
device serial number (such as on a heart valve or pacemaker), names
of relatives or employers, photos, medical scans or X rays, voice re-
cordings, fingerprints, or DNA sequences.
• The Privacy Rule limits the use of information to purposes necessary
for treatment, payment, or health operations and prohibits disclosure
or use of the information for other reasons without permission from
patients. As a result, when investigators plan to use PHI through the
course of research, they need to be attentive to the regulatory path-
ways that allow for such access.
• Similar to obtaining informed consent from research subjects, the
standard for acquiring subject permission to use PHI in research is
an Authorization. This Authorization may be a stand-alone docu-
ment or it may be combined with the informed consent.
A valid HIPAA Authorization is an individual’s signed permission that
allows a covered entity to use or disclose the individual’s PHI for the pur-
pose(s) and to the recipient(s) stated in the Authorization. The Privacy
Rule requires that Authorizations include explicit information (required
elements) and pertain only to a specific research study, not to future, un-
specified projects.
When researchers want to review PHI in medical records to determine
study feasibility or to gather patient contact information for purposes of
study recruitment, covered entities may permit researchers to do so under
a Review Preparatory to Research pathway. The researcher may only ex-
amine but not remove any PHI from the covered entity. To allow a Review
Preparatory to Research, the covered entity must receive from the re-
searcher representations that (i) review of PHI is necessary to prepare the
research protocol or for other similar preparatory purposes, (ii) no PHI
will be removed from the covered entity during the review, and (iii) the use
is necessary for research purposes.
There are three basic ways that research can be done without individual
authorization under the Privacy Rule: (i) doing research with deidentified
data sets, (ii) utilizing a limited data set, or (iii) obtaining a waiver from an
IRB or privacy board.
Deidentified information is not considered PHI and as such is not gov-
erned by the Privacy Rule, and no Authorization or waiver is necessary for
its use or disclosure. The most common method of deidentifying health
information is to remove all identifiers of the individual and of the individ-
ual’s relatives, employers, and household members. An exhaustive list of 18
possible identifiers is defined in the Privacy Rule.
The Privacy Rule allows for the use of a limited data set for research
purposes without obtaining patient authorization. Such a data set may
contain a limited number of identifiers, including geographic address
(above the street level) and dates. A limited data set is often a useful path-
way for researchers conducting retrospective chart review research.
As with informed consent, a researcher may seek to waive the require-
ment to obtain Authorization when there is minimal risk to subject privacy
and when it is not feasible to conduct the research without Authorization.
The waiver must be granted by a privacy board, which is often an IRB but
may be a separate compliance body within an institution. Many IRBs have
accepted a dual role and also serve as a privacy board, reviewing access to
PHI as part of their overall review of privacy protections.
Clinical research will not generally qualify for a waiver of Authorization
if a clinical research participant will be asked to sign an informed consent
before entering the study. In such circumstances it is relatively easy to have
a second HIPAA consent or to incorporate HIPAA language into the over-
all consent. Waiver of Authorization is more common in research that in-
volves, for example, retrospective medical chart reviews.
It should be stressed that the regulations of the Privacy Rule and those
regulating human research from HHS and the FDA are independent and
the rules of each must be followed completely. The HHS and FDA Protec-
tion of Human Subjects Regulations are concerned with the risks associ-
ated with participation in research. These may include, but are not limited
to, the risks associated with investigational products and experimental or
research procedures and the confidentiality risks associated with the re-
search. The Privacy Rule is concerned with the risk to the subject’s privacy
associated with the use and disclosure of the subject’s PHI.
The FDA regulations apply only to research over which the FDA has
jurisdiction, primarily research involving investigational products. The
HHS Protection of Human Subjects Regulations apply only to research
that is conducted or supported by HHS or under an applicable
156 Chapter 5
OHRP-approved assurance where a research institution has agreed volun-

tarily to follow the HHS protection regulations for all human subjects re-
search regardless of the source of support. The Privacy Rule applies to a
covered entity’s use or disclosure of PHI, including for any research pur-
poses, regardless of funding or type of research.
Fetal Tissue and Embryonic

Stem Cell Research
There has been a good deal of controversy surrounding the use of human
fetal and embryonic tissue in research, specifically in transplantation re-
search. As early as 1974, a national Commission for the Protection of Hu-
man Subjects established a moratorium on human fetal research until it set
up appropriate regulations. Its findings are now part of HHS regulations.
It was not until February 1993 that this moratorium on funding of human
fetal research ended. The use of human embryonic stem cells (hESCs) in
research is presently governed by the NIH Guidelines for Human Stem
Cell Research, which were put in force by a U.S. presidential executive
order in 2009. These guidelines describe the eligibility of hESCs for re-
search under NIH funding and mention the need for IRB review in certain
cases. The NIH maintains an online registry of hESC lines that are eligi-
ble for use in research supported by NIH funding. There is also a list of
hESC lines under review for consideration as additions to the list of ap-
proved cell lines.
In the harvesting of fetal cells, including embryonic stem cells, for re-
search, it is believed important to separate the abortion from the research.
This includes issues such as the decision to terminate a pregnancy, the
timing of the abortion, and which abortion procedures to use. Payments
and other inducements to participate in research on fetal tissues are pro-
hibited. Directed donations are prohibited, including the use of related
fetal tissue transplants. Anonymity between donor and recipient must be
maintained. The donor will not know who will receive the tissue, nor will
the recipient or transplant team know the donor.
Consent of the pregnant woman is required and is sufficient unless the
father objects (except in cases of incest or rape). The decision and consent
to abort must precede discussion of the possible use of fetal tissue and any
request for such consent that might be required for such use. Recipients of
such tissues, researchers, and health care participants must also be properly
informed about the source of the tissue in question.
The guidelines may well undergo continued revision. Some suggest
that the person performing the abortion or any physician supplying fetal
tissue not be allowed to be a coauthor or receive support from the study.
Others believe that the consent of the mother alone is not appropriate and
that an external consent should be sought.
Research directed toward the fetus in utero can be approved by an IRB if

(i) the purpose of the research is to meet the health needs of the fetus and the
research is conducted in a way that will minimize risk or (ii) the research
poses no more than minimal risk and the purpose is to obtain important
biomedical knowledge that is unobtainable by other means. Risk-to-benefit
ratios need to be carefully considered under the first category, especially as
medical and surgical intervention in utero becomes more prevalent.
Research directed toward the fetus ex utero depends on viability. If the
fetus is judged viable, it is then an infant and is covered by standard pediatric
regulations and policies. If it is nonviable (i.e., cannot possibly survive to the
point of sustaining life independently despite medical care), then research
cannot either artificially maintain vital functions or hasten their failure. Re-
searchers must maintain the dignity of the dying human and avoid unseemly
intrusions in the process of dying for research purposes. Research with dead
fetal material, cells, and placenta is regulated by the states.
Use of fetal tissue or stem cells for transplantation, particularly for the
treatment of Parkinson’s disease and juvenile diabetes, has been particu-
larly controversial. Interim guidelines require adherence to all fetal re-
search conditions listed above; in addition, there must be sufficient
evidence from animal experimentation to justify the human risk.
The increased inclusion of women in research studies raises the issue of
pregnancy. In research directed primarily toward the health of the mother,
her needs generally take precedence over those of the fetus. For example, if
a new therapeutic agent is considered necessary to improve a pregnant
woman’s condition, her consent alone is sufficient even if the treatment
poses greater than minimal risk to the fetus. The study must, however, try to
minimize the risk to the fetus consistent with achieving the research objec-
tive. When there is no health benefit to the mother, research on nonpreg-
nant participants must be used as a guide to the level of risk to the fetus. If
there is greater than minimal risk, the research cannot currently proceed, as
it requires review by the Ethics Advisory Board before going to the Secre-
tary of Health and Human Services, who could approve the research.
Surprisingly, there are no regulations for studies on lactating women,
enhancing conception or contraception, or abortion techniques. However,
many of the above considerations will apply to IRB deliberations of such
research.
Conclusion
In contrast to most areas of biomedical research, human subjects experi-

mentation is governed stringently by policies and regulations that have
their underpinnings in federal law. Although this history of formal regula-
tion dates back over 50 years, the regulatory network that applies to human
subjects experimentation increasingly spans research efforts worldwide.
158 Chapter 5
Biomedical researchers thus have both ethical and legal obligations. Re-
search using human subjects demands careful planning that will pass rigor-
ous peer review before the performance of any experimentation. Scientists
wishing to do human subjects research must be conversant with the appli-
cable policies and regulations.
Controversy still abounds about the best way to ensure appropriate and
efficient monitoring of human research. For example, there remain diffi-
cult questions such as whether IRBs could be biased in favor of research
projects that aid their organization and whether national IRBs could do a
better job ensuring uniformity and increasing efficiency for protocols run
at multiple sites. Federal regulations requiring conflict-of-interest policies
and oversight have been updated, and now institutions must collect finan-
cial disclosures from investigators so that institutional committees are able
to evaluate and manage potential bias based on financial incentives. The
outcomes of such deliberations are to be shared with IRBs so that the ade-
quacy of how a conflict of interest is managed can be evaluated in light of
human research participant protections. IRBs have the authority to require
additional protections to help minimize potential bias. Frequently, IRBs
will require that financial relationships be disclosed during the informed
consent process. Additionally, IRB members must recuse themselves from
the review of any research where they have a real or perceived conflict of
interest, financial or otherwise.
Other topic areas discussed in this book also have strong implications
for human subjects research. Record keeping (chapter 10) plays heavily
into clinical research with humans in terms of maintenance, form, storage,
retention, and confidentiality of results. Conflicts of interest (chapter 7)
must be frequently dealt with in clinical research. For example, investiga-
tors need to disclose industrial support or commercial affiliations at vari-
ous stages in the project, e.g., to IRBs, patients, editors, and reviewers.
Finally, issues relating to collaborative research (chapter 8) and authorship
(chapter 4) are common in human subjects experimentation owing to the
frequent interdisciplinary nature of this research.
1. Would you volunteer to enroll in a clinical trial as a healthy volun-

teer? Why or why not?
2. Is it ethical to oversimplify an informed consent document so that in
reality it no longer is scientifically accurate? Is it legal to do this?
3. What are some examples of coercion that might come up in recruit-
ing human subjects into human trials?
4. Under what conditions should a human subjects research study be
immediately stopped?
Case Studies
5.1 Professor Sandra Gottleib approached local Veterans of Foreign

Wars and American Legion posts and inquired whether any vet-
erans of recent international conflicts would be interested in volunteer-
ing to participate in a veterans’ oral history project. Her plan was to have
her Oral History 101 students collect veterans’ oral histories for the Na-
tional Library of Congress Veterans’ History Project. Dr. Gottleib un-
derstood that federal agencies like the Library of Congress do not
consider oral history activities as contributing to generalizable knowl-
edge, so she did not seek IRB approval for this project. Fifty veterans
agreed to participate. Using the Library of Congress’s release forms and
following all the Library of Congress guidelines for gathering these vet-
erans’ oral histories, Dr. Gottleib’s class conducted interviews and for-
warded the transcripts along with all of the original release paperwork to
the Library of Congress’s permanent holdings of this collection. Two
years later, Dr. Gottleib decides to write an article featuring a large num-
ber of quotes from the interviews. She uses the quotes to define a pattern
of attitudes among the veterans about armed conflicts. Dr. Gottleib has
sought and received permission from each of the veterans she quoted in
her manuscript. What are the IRB review implications of her intentions?
Must she seek IRB approval at this stage in her project? Explain your
position and the rationale for it.
5.2 Dr. Claudio Hernandez is studying antibiotic resistance in bacte-

ria. One of his goals is to evaluate the epidemiology of penicillin
resistance in streptococci. His colleague Dr. Kari Nakamura is chief of
infectious diseases at the same institution. Claudio approaches Kari and
asks her for help in obtaining fresh clinical isolates of streptococcal bacte-
ria. Kari is more than happy to help, and she tells Claudio she will keep
track of patients who have difficult-to-treat infections caused by strepto-
cocci. Kari will periodically send to Claudio the names of inpatients who
have such streptococcal infections so that he can visit the clinical microbi-
ology laboratory and obtain pure culture isolates of these bacteria. Kari
cautions Claudio that once the bacteria are secured they should be coded
so that the patients’ names are no longer associated with the clinical spec-
imens. Claudio agrees to this. Should Claudio be thinking about submit-
ting a human subjects protocol to cover this research? Explain your
position.
5.3 Ronald Weinstein, an associate professor of physiology at Univer-

sity Medical Center (UMC), is a member of UMC’s IRB. He suf-
fers from a type of dermatitis that is uncomfortable, but his condition is
160 Chapter 5
not obvious to his colleagues. He has been told by his physician that he
probably has a syndrome known as “chronic dermal condition” (CDC),
the cause of which is unknown and for which there is no effective treat-
ment. To confirm this unusual disease, a skin biopsy must be done. Dr.
Weinstein has not yet had a biopsy. In his latest package of assignments
for IRB review, Dr. Weinstein receives a protocol that proposes to study
CDC. To qualify for the study, a participant must have a confirmed diag-
nosis of CDC, and a skin biopsy will be performed on all who sign up to
be considered for enrollment. The study has two components: an evalua-
tion of factors that may be related to the causation of CDC and the mon-
itoring of the response of CDC to a combination of experimental drugs
that has shown promise in other clinical trials. Dr. Weinstein is impressed
with the study and submits a favorable review. Further, he decides to pur-
sue enrolling in the study. He reasons that at least he can get a definitive
answer about his CDC diagnosis by submitting to a skin biopsy. At most,
if he has CDC, he may benefit from the experimental therapy. He comes
to you, chair of UMC’s IRB, to let you know his intentions. What will
you tell him?
5.4 A proposal currently under consideration by your IRB involves the

administration of fluorescently labeled, mouse-derived monoclo-
nal antibodies to patients. These immunologic reagents would be used to
test their ability to localize and diagnose tumors. The committee discusses
the informed consent form proposed for use in these experiments. Specifi-
cally, one member of the committee argues that the consent form fails to
reveal that participation in this study could preclude the future use of anti-
tumor, mouse- derived monoclonal antibody therapy in these patients.
This argument is based on the possibility that such patients could mount
an anti-mouse antibody response. Considerable disagreement among the
committee members erupts as a result of this issue. Where do you stand?
Why?
5.5 Dr. Pearl Kachina is a medical school faculty nutritionist who is

conducting a survey on the consumption of “fast food” by high
school juniors and seniors. The study population will come from nine
high schools that are part of a city school district. Dr. Kachina has filed a
human-use protocol with her medical school’s IRB. The protocol is given
expedited review and falls under PHS exempt category 5 (research in-
volving survey procedures). With her IRB approval in hand, Dr. Kachina
is ready to start her research when the superintendent of the school dis-
trict, Gordon Ashe, calls her. Mr. Ashe wants his district to help Dr.
Kachina as much as possible in her research. He suggests that Dr. Kachina
include a statement at the beginning of her survey stating that the study
has the full support of the city school district. Mr. Ashe wants to advertise
his cooperativeness to his peer school districts. Moreover, he tells Dr.
Kachina that this statement will read like a “seal of approval,” maximizing
participation in the study. Dr. Kachina knows that if she modifies her
survey she will have to have it reviewed again by the IRB, thus delaying
the start of her research. She makes a counterproposal to Mr. Ashe, ask-
ing him to prepare a one-page announcement that delivers the school
district’s message of support for the project. Dr. Kachina suggests that
this be printed on bright yellow paper and that it be stapled to the survey
instrument when it is distributed to the students. Mr. Ashe finds this pro-
posal acceptable and prepares the announcement. Comment on the eth-
ics and the legality of what has happened. Is this study still in IRB
compliance? Why or why not?
5.6 Dr. James Orlando heads a new IRB-approved study to test a

novel drug to control blood sugar levels in type 2 diabetics. To
qualify, patient volunteers must meet several clinical criteria and must be
taking sulfonylurea as their prescribed diabetes medication. Following a
4-week “washout” period in which the patients cease taking sulfonylurea,
the subjects are randomized into two groups and are given a 20-week
course of an experimental compound or a placebo. Patients will be paid
$1,800 for completing the study. A partial payment, to be determined by
Dr. Orlando, is stipulated for anyone who does not finish the study, re-
gardless of whether they withdraw voluntarily or must be taken off the
study for medical reasons. The informed consent document states that
blood sugar level will be monitored by the research team on a weekly
basis. Anyone whose blood sugar level exceeds 240 mg/dl (normal range
is 80 to 120 mg/dl) will be taken off the drug or placebo and treated with
standard therapy (e.g., sulfonylurea). The study accrues patients at a brisk
rate. Several of the enrolled subjects are from a local “diabetes support
group,” and they are zealous in their pursuit of knowledge and in their
own health care. About 2 weeks into the washout period, Dr. Orlando
receives an e-mail from one of these subjects. She mentions that she uses
an accurate device to check her blood sugar and has found her numbers
steadily increasing since she went off the sulfonylurea. She says her day
14 reading was at 185 mg/dl and “on its way to 240 mg/dl.” She wants to
be released from the study, put back on sulfonylurea, and appropriately
compensated. Fearing other requests from support group members in
the study, Dr. Orlando is worried that a collapse in enrollment will jeop-
ardize the study. He asks Becky Baker, his research coordinator, to write
to everyone enrolled in the study and assuage their anxiety about any rise
162 Chapter 5
in blood sugar levels. Ms. Baker composes a carefully worded, compel-

ling letter to all current study participants. In the letter Ms. Baker re-
states the partial payment contingency. Are Dr. Orlando and Ms. Baker
acting ethically? What, if any, IRB review or intervention is needed, in
your view?
5.7 Anju Raina is a clinical research nurse involved in a phase 3 drug

trial of a novel chemotherapy combination given to pediatric pa-
tients with acute lymphocytic leukemia. One of the subjects in the trial is
10-year-old Willow Morgan. Initially, Willow was a particularly challeng-
ing patient, exhibiting excessive anxiety during chemotherapy sessions that
often led to disruptive behavior on the outpatient unit. Anju worked very
closely with Willow and her parents over the course of several treatments.
Eventually, Anju’s patience, understanding, and highly professional efforts
were credited for bringing about a major turnaround in Willow’s behavior.
Within a few weeks after the conclusion of the experimental therapy, Wil-
low was declared to be in clinical remission, to the joy of her family. Sev-
eral weeks later, during a routine follow-up visit, Willow’s father tells Anju
he wants to express his gratitude for her compassionate care of his daugh-
ter. Anju unwraps a small gift box that he gives to her. It contains a set of
keys and a map. He explains that these are the keys and map to the Morgan
family beach house. He simply says: “It’s yours for the last 2 weeks of the
summer!” Anju is overwhelmed, but gracious in her thanks for this gesture.
She and her family have not had a vacation in 4 years. After sleeping on
these events, Anju comes to you, her supervisor, and asks you if accepting
the gift was appropriate. She wants to know what she ought to do. What do
you tell her?
5.8 You have been attending a meeting on eukaryotic growth factors

and have just finished listening to Dr. Sidney Wolanski give his
keynote address. His overview involved some clinical studies, and he
showed slides of patients undergoing procedures as part of an institution-
ally approved clinical trial. In all instances the faces of the patients were
clearly visible. On two other slides there were clinical materials depicted,
and these were labeled with the patient’s name. One tissue sample was
clearly labeled with a tag that read “Mrs. MacDonald.” After the lecture
you leave to make a phone call. As you return to the lecture, you are inter-
cepted by Professor Susan Jeris, a colleague you know casually from an-
other institution. Susan confides in you that one of the slides shown by Dr.
Wolanski was a picture of her stepmother, Shirley MacDonald. She is agi-
tated and claims that Dr. Wolanski’s use of the picture and disclosure of
her stepmother’s name are a violation of her stepmother’s privacy and in
violation of accepted standards of clinical research. She claims that Dr.

Wolanski’s presentation is an egregious violation of human subjects re-
search practices and thinks he should be punished. She asks you what she
should do about this situation. What advice and guidance will your provide
to Dr. Jeris?
5.9 The frequencies of hospital-acquired infections in both the med-

ical intensive care unit (MICU) and the surgical intensive care
unit (SICU) of a university medical center have reached alarming pro-
portions. In response to this crisis, a research team implements a clinical
study designed to reduce the frequency of occurrences of hospital-
acquired infections in the MICU. This study involves a series of aggres-
sive strategies, which include (i) the use of experimental antibacterial
towelettes for hand cleansing, (ii) controlled use of antibiotics to counter
the emergence of antibiotic-resistant bacteria, and (iii) daily environ-
mental monitoring for potential pathogenic bacteria. The researchers
seek and receive IRB approval for this work, and every patient in the
MICU is enrolled. Of course, MICU patients are required to sign in-
formed consent forms approved by the IRB. Over the next 4 months a
dramatic decrease in hospital-acquired infections is seen in the MICU.
During the same period, the infections in the SICU remain at high lev-
els, and one patient in this unit dies from an infection caused by a multi-
ply antibiotic- resistant bacterium. In preparing their results for
presentation at a national meeting, the research team compares the fre-
quency, type, and seriousness of infections between the MICU and the
SICU. Comment on the ethical implications of this study. Should the
SICU patients have been included in the protocol and required to sign
informed consent forms? Why or why not?
5.10 Professor Angela Duarte is the course director of a physiology lab

taught to medical students. One of the laboratory exercises in-
volves students drawing blood from one another (under supervision) and
using the serum to perform a variety of chemical and cellular analyses.
The lab exercise is carried out successfully. At its conclusion, Professor
Duarte announces to the class of 100 students that she would like to re-
tain their leftover blood sera. She informs them that some of the sera will
be used individually while some will be pooled. In all cases, these sera will
be used to gather baseline control data for a number of research projects.
She asks if anyone wants to refuse having his or her serum used for re-
search but receives no objections. Are Professor Duarte’s actions appro-
priate? Is an IRB-approved protocol needed? Do the students need to
give informed consent?
164 Chapter 5
The Declaration of Helsinki
World Medical Association Declaration of Helsinki—Ethical

Principles for Medical Research Involving Human Subjects†
Adopted by the 18th WMA General Assembly, Helsinki, Finland,
June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa,
October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, October 2002 (Note of
Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of
Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Declara-
tion of Helsinki as a statement of ethical principles for medical re-
search involving human subjects, including research on identifiable
human material and data.
The Declaration is intended to be read as a whole and each of its
constituent paragraphs should be applied with consideration of all
other relevant paragraphs.
2. Consistent with the mandate of the WMA, the Declaration is ad-
dressed primarily to physicians. The WMA encourages others who
are involved in medical research involving human subjects to adopt
these principles.
General Principles
3. The Declaration of Geneva of the WMA binds the physician with
the words, “The health of my patient will be my first consideration,”
and the International Code of Medical Ethics declares that, “A
physician shall act in the patient’s best interest when providing med-
ical care.”
†
Disclaimer: © 2013 World Medical Association, Inc. All rights reserved. All intel-
lectual property rights in the Declaration of Helsinki are vested in the World Medi-
cal Association. Reprinted with permission of the World Medical Association.
4. It is the duty of the physician to promote and safeguard the health,

well-being and rights of patients, including those who are involved
in medical research. The physician’s knowledge and conscience are
dedicated to the fulfillment of this duty.
5. Medical progress is based on research that ultimately must include
studies involving human subjects.
6. The primary purpose of medical research involving human subjects
is to understand the causes, development and effects of diseases and
improve preventive, diagnostic and therapeutic interventions
(methods, procedures and treatments). Even the best proven inter-
ventions must be evaluated continually through research for their
safety, effectiveness, efficiency, accessibility and quality.
7. Medical research is subject to ethical standards that promote and
ensure respect for all human subjects and protect their health and
rights.
8. While the primary purpose of medical research is to generate new
knowledge, this goal can never take precedence over the rights and
interests of individual research subjects.
9. It is the duty of physicians who are involved in medical research to
protect the life, health, dignity, integrity, right to self-determination,
privacy, and confidentiality of personal information of research
subjects. The responsibility for the protection of research subjects
must always rest with the physician or other health care profession-
als and never with the research subjects, even though they have
given consent.
10. Physicians must consider the ethical, legal and regulatory norms
and standards for research involving human subjects in their own
countries as well as applicable international norms and standards.
No national or international ethical, legal or regulatory require-
ment should reduce or eliminate any of the protections for research
subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that minimises
possible harm to the environment.
12. Medical research involving human subjects must be conducted
only by individuals with the appropriate ethics and scientific educa-
tion, training and qualifications. Research on patients or healthy
volunteers requires the supervision of a competent and appropri-
ately qualified physician or other health care professional.
13. Groups that are underrepresented in medical research should be
provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care should
involve their patients in research only to the extent that this is jus-
tified by its potential preventive, diagnostic or therapeutic value
166 Chapter 5
and if the physician has good reason to believe that participation in

the research study will not adversely affect the health of the pa-
tients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be ensured.
Risks, Burdens and Benefits

16. In medical practice and in medical research, most interventions in-
volve risks and burdens.
Medical research involving human subjects may only be con-
ducted if the importance of the objective outweighs the risks and
burdens to the research subjects.
17. All medical research involving human subjects must be preceded by
careful assessment of predictable risks and burdens to the individu-
als and groups involved in the research in comparison with foresee-
able benefits to them and to other individuals or groups affected by
the condition under investigation.
Measures to minimise the risks must be implemented. The risks
must be continuously monitored, assessed and documented by the
researcher.
18. Physicians may not be involved in a research study involving hu-
man subjects unless they are confident that the risks have been ad-
equately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physicians
must assess whether to continue, modify or immediately stop the
study.
Vulnerable Groups and Individuals

19. Some groups and individuals are particularly vulnerable and may
have an increased likelihood of being wronged or of incurring addi-
tional harm.
All vulnerable groups and individuals should receive specifically
considered protection.
20. Medical research with a vulnerable group is only justified if the re-
search is responsive to the health needs or priorities of this group
and the research cannot be carried out in a non-vulnerable group.
In addition, this group should stand to benefit from the knowledge,
practices or interventions that result from the research.
Scientific Requirements and Research Protocols

21. Medical research involving human subjects must conform to gener-
ally accepted scientific principles, be based on a thorough knowledge
of the scientific literature, other relevant sources of information, and

adequate laboratory and, as appropriate, animal experimentation.
The welfare of animals used for research must be respected.
22. The design and performance of each research study involving hu-
man subjects must be clearly described and justified in a research
protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include in-
formation regarding funding, sponsors, institutional affiliations,
potential conflicts of interest, incentives for subjects and infor-
mation regarding provisions for treating and/or compensating
subjects who are harmed as a consequence of participation in the
research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees

23. The research protocol must be submitted for consideration, com-
ment, guidance and approval to the concerned research ethics com-
mittee before the study begins. This committee must be transparent
in its functioning, must be independent of the researcher, the spon-
sor and any other undue influence and must be duly qualified. It
must take into consideration the laws and regulations of the coun-
try or countries in which the research is to be performed as well as
applicable international norms and standards but these must not be
allowed to reduce or eliminate any of the protections for research
subjects set forth in this Declaration.
The committee must have the right to monitor ongoing studies.
The researcher must provide monitoring information to the com-
mittee, especially information about any serious adverse events. No
amendment to the protocol may be made without consideration
and approval by the committee. After the end of the study, the re-
searchers must submit a final report to the committee containing a
summary of the study’s findings and conclusions.
Privacy and Confidentiality

24. Every precaution must be taken to protect the privacy of research
subjects and the confidentiality of their personal information.
Informed Consent
25. Participation by individuals capable of giving informed consent as
subjects in medical research must be voluntary. Although it may be
168 Chapter 5
appropriate to consult family members or community leaders, no

individual capable of giving informed consent may be enrolled in a
research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving in-
formed consent, each potential subject must be adequately in-
formed of the aims, methods, sources of funding, any possible
conflicts of interest, institutional affiliations of the researcher, the
anticipated benefits and potential risks of the study and the discom-
fort it may entail, post-study provisions and any other relevant as-
pects of the study. The potential subject must be informed of the
right to refuse to participate in the study or to withdraw consent to
participate at any time without reprisal. Special attention should be
given to the specific information needs of individual potential sub-
jects as well as to the methods used to deliver the information.
After ensuring that the potential subject has understood the in-
formation, the physician or another appropriately qualified indi-
vidual must then seek the potential subject’s freely-given informed
consent, preferably in writing. If the consent cannot be expressed in
writing, the non-written consent must be formally documented and
witnessed.
All medical research subjects should be given the option of be-
ing informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the potential
subject is in a dependent relationship with the physician or may
consent under duress. In such situations the informed consent must
be sought by an appropriately qualified individual who is com-
pletely independent of this relationship.
28. For a potential research subject who is incapable of giving informed
consent, the physician must seek informed consent from the legally
authorised representative. These individuals must not be included
in a research study that has no likelihood of benefit for them unless
it is intended to promote the health of the group represented by
the potential subject, the research cannot instead be performed
with persons capable of providing informed consent, and the re-
search entails only minimal risk and minimal burden.
29. When a potential research subject who is deemed incapable of giv-
ing informed consent is able to give assent to decisions about par-
ticipation in research, the physician must seek that assent in
addition to the consent of the legally authorised representative.
The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally incapable
of giving consent, for example, unconscious patients, may be done
only if the physical or mental condition that prevents giving in-

formed consent is a necessary characteristic of the research group. In
such circumstances the physician must seek informed consent from
the legally authorised representative. If no such representative is
available and if the research cannot be delayed, the study may pro-
ceed without informed consent provided that the specific reasons for
involving subjects with a condition that renders them unable to give
informed consent have been stated in the research protocol and the
study has been approved by a research ethics committee. Consent to
remain in the research must be obtained as soon as possible from the
subject or a legally authorised representative.
31. The physician must fully inform the patient which aspects of their
care are related to the research. The refusal of a patient to partici-
pate in a study or the patient’s decision to withdraw from the study
must never adversely affect the patient-physician relationship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or simi-
lar repositories, physicians must seek informed consent for its col-
lection, storage and/or reuse. There may be exceptional situations
where consent would be impossible or impracticable to obtain for
such research. In such situations the research may be done only af-
ter consideration and approval of a research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new intervention
must be tested against those of the best proven intervention(s), ex-
cept in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary to
determine the efficacy or safety of an intervention and the patients
who receive any intervention less effective than the best proven
one, placebo, or no intervention will not be subject to additional
risks of serious or irreversible harm as a result of not receiving the
best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. In advance of a clinical trial, sponsors, researchers and host country
governments should make provisions for post-trial access for all
participants who still need an intervention identified as beneficial
170 Chapter 5
in the trial. This information must also be disclosed to participants

during the informed consent process.
Research Registration and Publication and Dissemination of Results

35. Every research study involving human subjects must be registered
in a publicly accessible database before recruitment of the first
subject.
36. Researchers, authors, sponsors, editors and publishers all have ethi-
cal obligations with regard to the publication and dissemination of
the results of research. Researchers have a duty to make publicly
available the results of their research on human subjects and are ac-
countable for the completeness and accuracy of their reports. All
parties should adhere to accepted guidelines for ethical reporting.
Negative and inconclusive as well as positive results must be pub-
lished or otherwise made publicly available. Sources of funding, in-
stitutional affiliations and conflicts of interest must be declared in
the publication. Reports of research not in accordance with the prin-
ciples of this Declaration should not be accepted for publication.
Unproven Interventions in Clinical Practice

37. In the treatment of an individual patient, where proven interventions
do not exist or other known interventions have been ineffective, the
physician, after seeking expert advice, with informed consent from
the patient or a legally authorised representative, may use an un-
proven intervention if in the physician’s judgement it offers hope of
saving life, re-establishing health or alleviating suffering. This inter-
vention should subsequently be made the object of research, de-
signed to evaluate its safety and efficacy. In all cases, new information
must be recorded and, where appropriate, made publicly available.
Resources
Print
Altman LK. 1998. Who Goes First? The Story of Self-Experimentation in Medicine.
University of California Press, Berkeley, CA.
Bankert E, Amdur R. 2005. Institutional Review Board Management and Function,
2nd ed. Jones and Bartlett, Boston, MA.
Beecher HK. 1966. Ethics and clinical research. N Engl J Med 274:1354–1360.
Fulford KW, Howse K. 1993. Ethics of research with psychiatric patients: princi-
ples, problems and the primary responsibilities of researchers. J Med Ethics
19:85–91.
Harth SC, Johnstone RR, Thong YH. 1992. The psychological profile of parents
who volunteer their children for clinical research: a controlled study. J Med
Ethics 18:86–93.
Jones JH. 1993. Bad Blood: the Tuskegee Syphilis Experiment. The Free Press, New
York, NY.
Kahn JP, Mastroianni AC, Sugarman J (ed). 1998. Beyond Consent: Seeking Justice
in Research. Oxford University Press, New York, NY.
Koren G, Carmeli DB, Carmeli YS, Haslam R. 1993. Maturity of children to
consent to medical research: the babysitter test. J Med Ethics 19:142–147.
Presidential Commission for the Study of Bioethical Issues. 2012. A Study
Guide to “Ethically Impossible” STD Research in Guatemala from 1946 to 1948.
Presidential Commission for the Study of Bioethical Issues, Washington, DC.
http://bioethics.gov/sites/default/files/Study%20Guide.pdf.
Reverby SM. 2009. Examining Tuskegee: the Infamous Syphilis Study and Its Legacy.
University of North Carolina Press, Chapel Hill, NC.
Sugarman J, Mastroianni AC, Kahn JP (ed). 1998. Ethics of Research with Human
Subjects: Selected Policies and Resources. University Publishing Group, Frederick,
MD.
Online
The general reference used in preparation of this chapter was the Code of
Federal Regulations, Title 45 Part 46, Protection of Human Subjects. This
is available online at the website of the U.S. Public Health Service Office
for Human Research Protections (OHRP):
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html
Human Subjects Regulations Decision Charts (OHRP):

http://www.hhs.gov/ohrp/policy/checklists/decisioncharts.html
The Belmont Report may be accessed online at

http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html
The Nuremberg Code may be accessed online at

http://history.nih.gov/research/downloads/nuremberg.pdf
The World Medical Association Declaration of Helsinki may be accessed

online at
http://www.wma.net/en/30publications/10policies/b3/
The National Cancer Institute (NCI) of the National Institutes of Health

(NIH) has created online resources containing recommendations for writ-
ing informed consent documents. The NCI’s stated need in publishing
recommendations is based on its observation that “many informed consent
documents have become too long and complex, and do not provide a sound
basis for informed decision-making.” The website contains recommenda-
tions aimed at clarifying and simplifying informed consent documents.
172 Chapter 5
These recommendations are accompanied by model templates and a num-

ber of useful appendix materials including definition of terms, federal reg-
ulations, checklists to facilitate writing easy-
to-
read informed consent
documents, communication tips, and a bibliography. The NCI website
may be accessed at
http://www.cancer.gov/clinicaltrials/conducting/
simplification-of-informed-consent-docs/page2
IRB: Ethics and Human Research provides a wealth of practical and useful
information for those interested in human research. This periodical is
published by the Hastings Center (Hastings-on-Hudson, NY) and is avail-
able in most university and medical center libraries. The current table of
contents of this publication may be found online at
http://www.thehastingscenter.org/
A powerful bibliography of books, audiovisual materials, and journal arti-

cles relevant to ethical issues in human subjects experimentation may be
found online at
http://www.nlm.nih.gov/archive//20061214/pubs/cbm/hum_exp.html
The impact of the Health Insurance Portability and Accountability Act

(HIPAA) on research is reviewed online at
http://privacyruleandresearch.nih.gov
NIH Guidelines for Human Stem Cell Research:

http://stemcells.nih.gov/policy/pages/2009guidelines.aspx
Registry listing human embryonic stem cell lines eligible for NIH
funding:
http://grants.nih.gov/stem_cells/registry/current.htm
Part II of U.S. Public Law 103-43 deals with Research on Transplantation

of Fetal Tissue and may be accessed at
http://www.hhs.gov/ohrp/policy/publiclaw103-43.htm.html
Appendix material
Appendix IV of this book contains the text of a human subject protocol as
well as examples of informed consent forms.
chapter 6
Use of Animals in Biomedical

Experimentation
Introduction • Ethical Challenges to the Use of Animals in Research
• Practical Matters: Constraints on the Behavior of Scientists • A
Continuum of Realities • Conclusion • Discussion Questions • Case
Studies • Resources
Introduction
A consensus challenged
Animal experimentation has been an important, long-standing research
tool. At the dawn of the 19th century, scientific medicine was beginning to
challenge medical traditions more than 1,000 years old. Physiological re-
search involving animals was one of the key technologies that spurred this
transition and led to an understanding of bodily functions and the physical
basis of disease. However, the new approach was resisted by traditionalists
who employed as one of their foremost criticisms the cruel nature of ani-
mal research. Present-day scientists should not delude themselves: early
animal experiments could be exceedingly brutal. Fully conscious dogs were
nailed to boards by their four paws, before being cut open, so that the beat-
ing of a heart might be observed. While the advent of anesthesia in the
mid-1800s addressed some concerns, it by no means ended the debate over
the fundamental morality of animal research. Numerous groups formed in
the late 1800s to challenge the existing social order with regard to animals.
These “antivivisectionists” were the antecedents of the contemporary “an-
imal rights” movement.
In 1975, Peter Singer, an Australian philosopher, first published the
book Animal Liberation, which many believe was the seminal event in the
rebirth of modern antivivisectionism. Since that time, animal rights activ-
ists have assiduously set about achieving their ultimate goal—the abolition
of the use of animals for biomedical research, for food and clothing, and
doi:10.1128/9781555818487.ch6
173
174 Chapter 6
for entertainment. The most extreme activists even question the morality
of pet ownership. The animal rights movement is viewed by many scien-
tists as a threat to scientific progress and, ultimately, to the health and well-
being of humankind. But the majority of scientists have not actively
participated in the debate by responding to the charges of the animal rights
activists at the local level, preferring instead to allow a defense to be
mounted by national scientific organizations. This is arguably a serious
mistake. The animal rights organizations have been quite successful in car-
rying their message to the general public. While the majority of the popu-
lation still expresses support for the use of animals in biomedical research,
the efforts of animal rights activists have clearly eroded this support, espe-
cially among young people. Additionally, the animal rights movement has
sought to link its agenda with that of other popular causes, such as envi-
ronmentalism, saying in essence, “If you care about our environment, you
must support animal rights.”
It is important that individual scientists take the time to become better
educated about the moral and political controversies that surround the use
of animals in biomedical research. Scientists often have a tendency to dis-
miss the animal rights philosophy as irrational. Yet the movement’s leading
philosophers, people like Peter Singer and Tom Regan, are respected schol-
ars who have presented eloquently argued, and intensely rational, cases for
their belief in animal rights. Inadequately prepared scientists can embarrass
themselves and the larger scientific community when trying to debate some
of the articulate, well-prepared leaders of the animal rights community. One
will not catch these individuals in trivial moral blunders—they do not eat
meat, wear leather shoes, or frequent the circus. Many of them struggle to
live an ethically consistent (and difficult to maintain) lifestyle because of the
moral status that they ascribe to animals. The fact that scientists are often
unfamiliar with the ethical theories of the leading animal rights philosophers
is bound to reduce their effectiveness in any public debate of the issues.
Scientists occasionally have a tendency to dismiss all animal rights ac-
tivists as the members of a “lunatic fringe.” This view is untenable. The
vast majority of people in attendance at animal rights meetings are not lu-
natics, but rather people just like our neighbors. It is important to realize
that most of the people at such meetings are not fervent animal rights ac-
tivists. They continue to eat meat, value the benefits of medical research,
and own pets, no matter what their leadership might have to say about
these practices. These people are, however, extremely concerned about
how the animals used in biomedical research are being treated. And unfor-
tunately, their major source of information is often the animal rights
groups themselves. Because of this, they are often inherently distrustful of
the scientific establishment. It is not likely that any impersonal scientific
Use of Animals in Biomedical Experimentation 175
organization is going to be able to quiet their fears without the help of

large numbers of individual scientists explaining to their own neighbors
exactly how they do biomedical research.
“Rights” for animals?

While most scientists would probably not claim that animals have rights, it
is important to realize that we nevertheless act as though animals do have
something like rights. It is worth spending a moment to consider why most
working scientists support the use of animals in biomedical research and
are also concerned that such research be conducted humanely. Likewise,
while fairly large percentages of the general public (especially young peo-
ple) express support for the concept of animal rights, they simultaneously
eat animals and support the use of animals in biomedical research. There-
fore, while it is apparent that nearly all of us perceive animals to be objects
of moral concern, the exact nature and extent of our moral obligations are
not entirely clear.
If asked to describe the difference between a test tube and a mouse,
you would not have any problem in doing so. Precisely how you choose
to reply might well depend on whether you have been trained in biology,
chemistry, genetics, etc. However, it seems likely that your initial answer
would focus on the most compelling distinction between the test tube
and the mouse—the fact that the mouse is a living creature. Now let’s
suppose that someone enters your laboratory with a hammer and smashes
one of your test tubes. Clearly, it would be wrong for them to do so.
They would have intentionally, and senselessly, destroyed your property.
To be sure, in these days of disposable culture tubes, the actual loss to
you would be a small one. But now let us change the scenario and sup-
pose that instead of destroying one of your test tubes, the person enters
your laboratory to smash one of your mice. This act, too, would be
wrong. But is it wrong for precisely the same reasons as the previous de-
struction of the test tube? The person has once again destroyed your
property, and it is also true that the mouse is undoubtedly worth more in
purely monetary terms. But is this the full measure of the difference be-
tween these acts? Few of us would equate the senseless destruction of a
whole shelf pack of test tubes (to equalize the monetary value) with that
of a single laboratory mouse.
It is important to understand that ownership of property is not the key
issue. What if instead of using the hammer to smash your mouse, the per-
son in question used it to smash one of his own? How many would feel
significantly better about the event? So what is the fundamental difference
in the destruction of these two objects? Is it only the fact that the mouse is
alive while the test tube is not? Then let’s suppose that it is not a test tube
176 Chapter 6
that is about to be destroyed, but rather a tissue culture flask full of living
animal cells. Clearly, the senseless destruction of a mouse is more trou-
bling than that of a flask of cells. Therefore, it is not the mere fact that the
mouse is alive that we are responding to—it must be something else.
Moral judgments
At some level, many scientists are abolitionists. That is, if we were able to
acquire the information needed to adequately answer compelling research
questions without the use of animals, who among us would not gladly do
so? Nevertheless, one of the best methods we have developed to advance
biomedical knowledge involves the use of animals, which, unlike the test
tube, have interests. They have interests in obtaining sufficient food, in
remaining free from pain, in reproducing themselves, and perhaps in living
a normal life span. Experiments can frustrate the interests of laboratory
animals, and most scientists recognize this both in their concern for the
humane treatment of animals and in their belief that research should be
directed at important problems. The fact that animals have interests does
not necessarily mean that we should never use them in biomedical experi-
ments; however, it does mean that any such use should be preceded by a
moral judgment. Do the benefits derived from the biomedical research
that is being considered offset the associated moral costs?
Animal rights groups are challenging the existing societal consensus on
many questions involving animals. Their actions will undoubtedly have an
influence on public policy decisions that will be made whether or not sci-
entists choose to participate in the ongoing debate over the issues.
Ethical Challenges to the Use

of Animals in Research
Peter Singer and Tom Regan remain as the two most influential animal
rights philosophers. Singer is on the faculty at Princeton, and Regan, an
emeritus professor at North Carolina State University, continues to be in-
volved in a variety of ways. Each has argued that society should radically
restructure the moral status it grants to animals from his own ethical per-
spective, utilitarianism (Singer) or deontology (Regan). While chapter 2
provided an introduction to the utilitarian and deontological approaches
to ethical decision making, we will now briefly consider how these well-
known opponents of animal research apply them.
Singer’s utilitarianism and animal “rights”

Peter Singer’s book Animal Liberation, published in 1975, is credited with
the modern revival of the animal rights movements. There is a small irony
in this because Singer, like utilitarianism’s founder Jeremy Bentham before
him, does not believe in the philosophical concept of rights. Although

Singer uses the term “rights,” he considers it to have no philosophical
meaning but instead to be a “convenient political shorthand.” Singer
echoes an assertion made by Bentham that the key moral question related
to animals is not whether they can reason but whether they suffer. For
Singer, sentience—the ability to feel pleasure or pain—is the key charac-
teristic required for admittance into the moral universe. Singer concludes
that many animals can suffer from physical pain, deprivation, loneliness,
etc., while fully acknowledging that humans can suffer in ways that animals
cannot (e.g., the fear of a future catastrophe). Singer, again drawing from
Bentham, proposes that a principle of equality requires that we give equal
consideration to the suffering of individuals, regardless of their species.
Failure to do so amounts to “speciesism,” an offense that Singer finds anal-
ogous to racism or sexism. It is important to realize that Singer is not
claiming that there are no relevant moral differences between humans and
animals. Human children have an interest in learning to read. Therefore, it
would be immoral for us to raise a child and intentionally prevent him or
her from acquiring this skill. Clearly, such disapprobation is meaningless
for animals, which have no interest (or capability) in reading. Nevertheless,
Singer argues that both animals and humans have an equal interest in be-
ing free from torment. Because of this, he maintains that it is just as wrong
to torture an animal as it is to torture a human being. But once again, this
does not mean that Singer believes that all lives are of equal moral worth.
He plainly states that if one is required to decide between the life of a hu-
man being and the life of an animal, then one should choose to save the life
of the human. Singer can envision circumstances that might alter this deci-
sion. If the life of a normal animal is placed in the balance with that of a
severely impaired human, the normal decision might be reversed and the
life of the animal saved.
Thus, Singer does not say it is never appropriate to use animals in scien-
tific research. As a utilitarian, he must support such use if the benefits ob-
tained outweigh the harm done. But Singer places an enormous barrier in
the way of such research, one he believes will forbid essentially all of it.
Since pain in animals and humans is viewed as exacting an equivalent
moral cost, no animal experiment should be conducted unless it would also
be permitted on a human.
We have seen that experimenters reveal a bias in favor of their own species
whenever they carry out experiments on nonhumans for purposes that they
would not think justified them in using human beings, even brain damaged
ones. This principle gives us a guide toward an answer to our question. Since
a speciesist bias, like a racist bias, is unjustifiable, an experiment cannot be
justifiable unless the experiment is so important that the use of a brain-
damaged human would also be justifiable.
178 Chapter 6
It is clear that Singer does not believe that very much animal research
would be able to overcome this obstacle. It is also clear that he does not
believe this loss to be a serious one. He believes that “animal experimenta-
tion has made at best a very small contribution to our increased lifespan.”
For Singer the benefits of animal research (or of meat eating) are not
worth the moral costs.
In his writings, the late R. G. Frey, a fellow utilitarian, criticized Singer’s
philosophy. Frey defended the use of animals in medical research using
essentially the same utilitarian ethic as does Singer. In some of their writ-
ings it is difficult to understand where Frey and Singer differ in method,
even though they differ radically in their conclusions. Frey, too, believed
that animal research must pass a test similar to the one described by Singer.
Frey believed that it would be wrong to perform an experiment on an ani-
mal if we were not willing to perform it on a human with an even lower
quality of life (e.g., an orphaned infant born without a brain). However,
Frey recognized the benefits that flow from animal research and seemed
intent on preserving them. Therefore, while he maintained that we should
be willing to perform such human experiments, he also recognized reasons
why we might choose not to. The side effects of such human research (e.g.,
societal uproar, outraged relatives) may outweigh the benefits derived and
thereby cause us to refrain from conducting them in the first place.
Singer’s claim that speciesism is analogous to racism has also been criti-
cized. Peter Carruthers, a British philosopher and supporter of animal re-
search, believes that species membership is a morally relevant characteristic,
as do Stephen Post and Carl Cohen. Animal rights philosopher Mary Midg-
ley, who is clearly willing to demand limitations on the use of animals in re-
search, also rejects the speciesism-racism analogy. She argues that “race in
humans is not a significant grouping at all, but species in animals certainly is.
It is never true that, in order to know how to treat a human being, you must
first find out what race he belongs to. . . . But with an animal, to know the
species is absolutely essential.” For Midgley, there are morally significant
bonds between species members just as there are between the members of a
family. However, these species bonds are not absolute, and it is important to
realize that we also form significant bonds with members of other species.
Regan’s deontology and animal rights

In his book The Case for Animal Rights, Tom Regan embraces the philo-
sophical concept of rights, in contrast to Singer’s position. Regan describes
“the rights view” as a type of deontological theory distinct from that artic-
ulated by Kant.
According to this theory, certain individuals have moral rights (e.g., the right
to life) and they have these rights independently of considerations about the
value of the consequences that would flow from recognizing that they have
them. For the rights view in other words, rights are more basic than utility
and independent of it, so that the principle reason why, say, murder is wrong,
if and when it is, lies in the violation of the victim’s moral right to life, and
not in considerations about who will or will not receive pleasure or pain or
have their preferences satisfied or frustrated, as a result of the deed. Those
who subscribe to the rights view need not hold that all moral rights are abso-
lute in the sense that they can never be overridden by other moral consider-
ations. For example, one could hold that when the only realistic way to
respect the rights of the many is to override the moral rights of the few, then
overriding these rights is justified.
In his rejection of utilitarian ethics, Regan charges that the consequen-

tialist philosophies make a mistake in viewing individuals as little more than
receptacles to be filled with pleasure or displeasure. Regan’s analogy is that
of a cup filled with a sweet liquid, a bitter liquid, or some combination of the
two. He maintains that utilitarians ignore the value of the cup (the indi-
vidual) and only concentrate on the liquid within it (pleasure or displeasure).
Regan argues that individuals themselves possess a property that he calls
“inherent value.” Inherent value, according to Regan, is not dependent on
the race, sex, religion, or birthplace of an individual. Further, it does not
depend on the intelligence, talents, skills, or importance of a person. Regan
declares: “The genius and the retarded child, the prince and the pauper, the
brain surgeon and the fruit vendor, Mother Teresa and the most unscrupu-
lous used car salesman—all have inherent value, all possess it equally, and all
have an equal right to be treated with respect, to be treated in ways that do
not reduce them to the status of things, as if they existed as resources for
others.” Regan also claims that it would be blatant speciesism to insist that
only humans have inherent value. He argues that many animals also possess
it. But how does he decide which animals possess inherent value and which
animals do not? Regan’s test for the possession of inherent value is some-
thing he terms the “subject of a life criterion.” This does not require that
beings merely be alive but also that they “have beliefs and desires; percep-
tion, memory, and a sense of the future, including their own future, an emo-
tional life together with feeling of pleasure and pain; preference-and
welfare-interests; the ability to initiate action in pursuit of their desires and
goals; a psychophysical identity over time; and an individual welfare in the
sense that their experiential life fares well or ill for them.” At the time he
wrote The Case for Animal Rights, Regan seemed to think that all mammals
over the age of 1 year possess inherent value. In subsequent statements, he
seems to believe that this range should be expanded considerably.
The claim that animals have inherent value seems to agree with our sense
of moral intuition, and up to this point you may have found little to argue
with. However, Regan’s insistence that inherent value is a “categorical con-
cept” is likely to prove more controversial. By this, Regan means that hu-
mans cannot be said to possess any more inherent value than any other
180 Chapter 6
animal. Either animals are in the category of beings that possess inherent
value or they are not. “One either has it, or one does not. There are no in-
betweens. Moreover, all those who have it, have it equally. It does not come
in degrees.” When pressed to delineate the exact point of demarcation be-
tween those beings said to possess inherent value and those who do not,
Regan deflects the question as essentially moot. “Whether it belongs to
others—to rocks and rivers, trees and glaciers, for example—we do not
know and may never know. But neither do we need to know, if we are to
make the case for animal rights. We do not need to know, for example, how
many people are eligible to vote in the next presidential election before we
can know whether I am.” But Regan’s position does not imply that he be-
lieves that there are no moral differences between animals and humans. If
there are five individuals (four humans and a dog) who seek sanctuary in a
lifeboat that can hold only four of them, what should be done? Regan be-
lieves that it is the dog that should be thrown overboard to die. He argues
that while the inherent value of each of these beings is equivalent, the harm
that would be done to them through their deaths is not. Humans have a
much greater range of possibilities open to them in their lives than do dogs.
Humans can experience joys and satisfactions that no dog will ever experi-
ence. Because of this, death forecloses far more potential opportunities for
satisfaction in the human than it will in the dog. Regan argues that it would
be allowable to throw even 1 million dogs overboard to save the humans
because each dog’s death, when considered one at a time, is less harmful
than the death of a human considered one at a time.
One might imagine, from such a position, that Regan would be disposed
to permit animal research that could save the lives of humans. However,
Regan’s position is, if anything, more severe than Singer’s on the question of
animal research. Regan states that his ethic requires the immediate abolition
of all such research. Why isn’t medical research seen as analogous to the
lifeboat ethics described above? In the lifeboat example, all (including the
dog) would have perished if one individual were not sacrificed. A decision
had to be made as to whether a human or a dog had to die so that the others
could live. Regan does not see that choice as analogous to using animals in
research on human disease. The animals are not in the lifeboat, because they
are not sick. No decision has to be made to sacrifice one or the other. In
Kantian terms, one can imagine that Regan believes that medical research
uses animals merely as a means and not also as an end.
While Regan is quite comfortable with his abolitionist position, it
should be noted that he, like Singer, does not seem to view the loss of the
ability to use animals in research as having grave consequences for medical
advances. Regan writes, “Like Galileo’s contemporaries, who would not
look through the telescope because they had already convinced themselves
of what they would see and thus saw no need to look, those scientists who
have convinced themselves that there can’t be viable scientific alternatives

to the use of whole animals in research (or toxicity tests, etc.) are captives
of mental habits that true science abhors.”
Regan’s views have been extensively criticized. Frey, who was a cautious
supporter of animal research, questioned the claim that animals have moral
rights. As a utilitarian, Frey doubted the existence of moral rights in the
first place, but his criticism extended beyond his philosophical viewpoint.
Frey noted that the concept of moral rights is especially popular in the
United States and that, in this country, the position in contentious social
issues is often stated using rights language (women’s rights, gay rights,
children’s rights). Often the opposing sides in a debate will each make ap-
peals using rights language—the “right to life” versus “a woman’s right to
choose.” Frey argued that, in the United States, for a group “to fail to cast
its wants in terms of rights . . . is to disadvantage itself in this debate.” In
contrast, he observed that debates over the moral treatment of animals
have proceeded in Britain and Australia with relatively little mention of
rights.
Carl Cohen has argued that animals are not the kind of creatures capa-
ble of possessing rights. He states that rights can only be accorded to “be-
ings who actually do, or can, make moral claims against one another.”
Peter Carruthers criticizes Regan on a much more fundamental level. He
claims that Regan has not adequately provided groundwork for his moral
theory. Where are the rights he argues for supposed to have come from?
What exactly is the inherent value that Regan claims is possessed by (at
least) all mammals of 1 year of age or older? How do we detect inherent
value; that is, how are we to determine which life forms have it and which
do not? Carruthers accuses Regan of altogether failing to provide the kind
of “governing conception” necessary to explain his moral theory.
Practical Matters: Constraints on the

Behavior of Scientists
Overview
We have seen that there is no unanimity among those philosophers critical
of the use of animals in biomedical research. Likewise, there is no unanim-
ity among the philosophers who support such use. Frey, Carruthers, Co-
hen, and Michael Leahy all argue from their own philosophical perspectives.
So while these readings can provide us with useful frameworks for think-
ing about ethical problems, those hoping for a simple consensus view on
why it is morally permissible to experiment on animals will be just as dis-
appointed as those hoping for a consensus supporting the opposite view.
But we do not require a confluence of philosophical opinion to recognize
that the use of animals in research entails a moral responsibility.
182 Chapter 6
Legislation
Scientists no longer have the luxury, or burden, of being the sole arbiters
of the acceptability of their own experiments. In the early days of animal
research, there was little to restrict scientists’ use of animals other than
their own individual consciences. Scientists work under a number of
restrictions—legal, institutional, and moral—that constrain how animals
may be used in experiments.
Table 6.1 presents a brief history of legislation and regulations pertain-
ing to animal care and use. In 1963, the National Institutes of Health
(NIH) published the first edition of its Guide for the Care and Use of Labora-
tory Animals. At first, compliance with the recommendations set out in the
guide was voluntary. The movement to pass restrictive legislation on ani-
mal use gained momentum in early 1966 when an article in Life magazine
caused public outrage by chronicling the despicable conditions under
which many animal dealers maintained their dogs. In August 1966, Con-
gress passed the Laboratory Animal Welfare Act. A major goal of this leg-
islation was to require the registration of research facilities and dog dealers
with the U.S. Department of Agriculture. A clear intent of the bill was to
minimize the number of instances of people’s cats and dogs being stolen
and sold to research institutions. These institutions were now required to
buy their cats and dogs from licensed dealers. This legislation was amended
in 1970, 1976, and 1985 and is now referred to as the Animal Welfare Act
(AWA). The legislation mandated humane care and treatment for dogs,
cats, rabbits, hamsters, guinea pigs, and nonhuman primates. However, it
provided no protection for rats and mice, the two species that account for
the vast majority of all animals used in research.
Table 6.1 Brief U.S. legislative and regulatory history

1960 Animal Welfare Institute initiatives lead to proposed federal legislation that would require individual
animal researchers to be licensed. No legislation enacted.
1963 NIH publishes first voluntary Guide for the Care and Use of Laboratory Animals (the Guide). The
Guide was revised in 1965, 1968, 1972, 1978, 1985, and 1996.
1966 Congress enacts the Laboratory Animal Welfare Act in response to public outcry over a Life magazine
article. Amended and strengthened in 1970, 1976, and 1985. The legislation is now called the Animal
Welfare Act.
1985 Health Research Extension Act of 1985 requires the NIH to establish guidelines for the use of animals
in biomedical and behavioral research. First animal law covering the U.S. PHS.
1986 NIH Office of Protection from Research Risks publishes the Public Health Service Policy on the
Humane Care and Use of Laboratory Animals. PHS laboratories and any institutions wishing to
receive PHS funding must agree to comply with the PHS policy and the Guide.
2010 Publication of the 8th edition of the Guide for the Care and Use of Laboratory Animals by the U.S.
National Academy of Sciences indicates the broad acceptance of the Guide within the U.S. and
international animal research communities.
It was not until 1985 that Congress passed the Health Research Exten-
sion Act of 1985 (Public Law 99-158). This was the first law concerning
animals under which the U.S. Public Health Service (PHS) was required
to operate. This law, in effect, caused the heretofore voluntary Public Health
Service Policy on the Humane Care and Use of Laboratory Animals (1986) to
become mandatory for both PHS research labs and any nongovernmental
institutions that received funding from any PHS agency. The PHS policy
includes a number of key elements, one of which is an assurance obtained
from research institutions stating that they are committed to following the
PHS policy and the Guide for the Care and Use of Laboratory Animals.
The Guide for the Care and Use of Laboratory Animals, often referred to
simply as the Guide, is an important document for scientists and animal
care personnel. While previous versions of the Guide were supported solely
by the NIH and published by the Government Printing Office, the 1996
edition received support from the NIH, the U.S. Department of Agricul-
ture, and the U.S. Department of Veterans Affairs. The 8th edition, pub-
lished in 2010, was revised by an ad hoc committee of the Institute of
Laboratory Animal Research of the National Research Council and pub-
lished by the National Academies Press. (The National Research Council
is the operational arm of the nongovernmental National Academy of Sci-
ences.) The broader financial support of this new edition, as well as its
publication by the National Academies Press, gives some indication as to
how widely the Guide is used by the animal research community.
The Guide includes details on how animal research should be carried out
within an institution, including recommendations for animal program over-
sight, animal housing and environment, facilities management, and veteri-
nary care. Although the AWA itself does not address standards in regard to
rats and mice, the Guide does include these species. Additionally, the newest
edition of the Guide recognizes the increasing use of aquatic animals by in-
cluding recommendations for environment and housing of these species.
This edition emphasizes the notion of a comprehensive animal care and use
program based on a partnership between the Institutional Animal Care and
Use Committee (IACUC), the attending veterinarian, occupational health
and safety personnel, and investigators, all working collaboratively to ensure
animal welfare and safe working conditions for researchers. The AWA re-
quires that each research institution identify an attending veterinarian and
an IACUC, the two primary administrative components responsible for an-
imal welfare in research. The attending veterinarian is responsible for over-
seeing all aspects of animal care including husbandry and veterinary care.
The IACUC is responsible for evaluating the care, treatment, housing, and
use of animals, including approval of research protocols.
The Guide details a number of institutional policies that should be put
into place concerning issues such as the qualifications and training of the
184 Chapter 6
professional animal care staff and the establishment of an occupational

health program to protect personnel who come into contact with the ani-
mals. The Guide also addresses issues surrounding the animal facilities and
housing requirements for laboratory animals. Minimum space recommen-
dations are given in detail for a number of different species. (For example,
it is suggested that a 20-gram mouse be allotted at least 12 square inches of
floor space in a cage that is at least 5 inches high.) Further, it is recom-
mended that attention be given to the particular social requirements of the
animal species in question. Communal animals should be housed in groups
whenever appropriate, while taking into account population density, famil-
iarity of individuals, social rank, etc. For highly social animals (such as dogs
and nonhuman primates), it is suggested that group composition be held as
stable as possible. It is also suggested that the environment of the animals
be enriched to prevent boredom, especially when animals are to be held
for a long period of time.
The physical environment under which the animals are maintained is
also addressed in the Guide. Temperature and humidity ranges are given
for a number of species, as well as suggestions for ventilating the animals’
rooms (10 to 15 room air changes per hour). Levels of illumination are
suggested because light that is within the comfortable range for humans
can actually be so bright that it damages the retinas of albino mice. In ad-
dition, the Guide discusses noise levels and requirements for bedding, wa-
ter, sanitation, waste disposal, and vermin control. Veterinary care issues
such as quarantine, separation by species, and disease control are discussed,
as are anesthesia, surgical and postsurgical care, and recommended means
of euthanasia. The Guide also addresses many aspects of the actual physical
plant in which animals are housed and experimented upon. Recommenda-
tions are given for corridor sizes, animal room door sizes, ceiling heights,
placement of floor drains, the surface material from which the walls should
be constructed, and suggested locations of storage areas for food and
bedding.
IACUCs
Both the AWA and the PHS policy mandate the establishment of an
IACUC, which oversees the animal care and use program for each institu-
tion. The AWA and the PHS policy differ somewhat in their minimal re-
quirements for the committee. The AWA requires a committee of at least
three people. The members of the committee are to possess “sufficient
ability to assess animal care, treatment, and practices in experimental re-
search . . . and shall represent society’s concerns regarding the welfare of
animal subjects.” At least one of the committee members is to be a doctor
of veterinary medicine (DVM) and one member is not to be affiliated with
the institution in any way (other than as a member of the IACUC). The
nonaffiliated member is supposed to represent the interests of the general

community in the proper care and treatment of animals. The nonaffiliated
member cannot be an immediate family member of a person affiliated with
the institution.
The PHS policy requires a committee of at least five people. One of the
members must be a DVM with training or experience in laboratory animal
science and medicine. This individual must have direct or delegated au-
thority and responsibility for the research activities involving animals at
the institution. The committee must also include one practicing scientist
with experience in animal research, one individual whose primary con-
cerns are in a nonscientific area (e.g., clergy member, lawyer, or ethicist),
and one individual who is not affiliated with the institution in any way
(other than as an IACUC member).
The Guide does not specify a minimum number of members for an
IACUC (and so is compatible with the policies of institutions operating
under the AWA or the PHS policy) but suggests that the number should be
determined by the size of the institution and the extent of the program.
The Guide uses slightly different wording to describe the requirements for
the members of the committee. This difference is most significant in the
requirements for the nonaffiliated or public member. As in the other poli-
cies, the public member is not to be affiliated with the institution or to be
a member of the immediate family of a person affiliated with the institu-
tion. Again, the public member is to “represent the general community
interests in the proper care and use of animals.” However, the Guide adds
the requirement that the public member not be a user of laboratory ani-
mals. This requirement prevents an animal research scientist from one in-
stitution from serving as the public member on the IACUC of another
institution.
IACUCs are often larger than the minimum size required and may have
10 or more members. The IACUC is charged with evaluating the institu-
tion’s animal care and use program and animal facilities every 6 months
and preparing a report on its findings. The IACUC also evaluates and
makes recommendations regarding all aspects of an institution’s animal
program, including training of the personnel. The IACUC has the author-
ity to suspend any activity that involves animals should it determine that it
is not being conducted in accordance with the AWA or, if applicable, the
Guide. Table 6.2 presents a comparison of the AWA, PHS policy, and the
Guide in their requirements for IACUCs.
Most scientists will interact directly with the IACUC when they submit
a research protocol for approval. An approved protocol is required before
any experiments involving animals, even pilot projects, are conducted. The
NIH will not fund a grant that has not had its animal research protocol
reviewed and approved. Graduate students, postdoctoral students, and
186 Chapter 6
Table 6.2 Comparison of the AWA, PHS policy, and the Guide in their requirements for IACUC
Requirement AWA PHS policy The Guide
IACUC mandated Yes Yes Yes
Minimum number 3 5 Not specified
of members (but minimum of 3 because
of special requirements)
Special requirements • 1 DVM • 1 DVM • 1 DVM
for members • 1 nonaffiliated • 1 practicing scientist • 1 practicing scientist
• 1 nonscientist • 1 nonaffiliated,
• 1 nonaffiliated non-animal researcher
Applies to rodent use No Yes, through reference Yes
to the Guide
technicians who work with animals must be operating under an approved

protocol submitted by the laboratory’s principal investigator. It is impor
tant that persons working under an approved animal protocol be familiar
with that protocol to prevent accidental deviations from existing tech-
niques that might require new approval before being adopted.
When preparing a protocol for submission, the investigator should
use clear language and avoid the use of unnecessary jargon. The nonaffil-
iated public member of the IACUC should be able to understand what
types of procedures are being proposed and why the research is import-
ant. The investigator should be careful to address the same topics that
the IACUC will consider in its review. Most institutions have a form that
will act as a guide for the process. The submission should discuss the
rationale of the experiments, and the selection of the species should be
justified. Alternatives to the use of animals (cell cultures, computer mod-
els, etc.) that were considered should be discussed. The investigator
should explain why the use of these alternatives was rejected for the pro-
posed study. Any steps that were taken to make the proposed experi-
ments less invasive, or to make use of a species lower on the phylogenetic
tree, should be explained for the committee. The investigator should jus-
tify the number of animals requested for the series of experiments
planned. Whenever possible, this justification should include a statistical
analysis to demonstrate that appropriate numbers of animals (neither
too many nor too few) will be used. Recent research by Junhee Seok et al.
demonstrates why ongoing assessment of alternatives is critically im-
portant. In an analysis of genomic models of mice versus humans, the
authors determined that mice may demonstrate similar bodily functions
to humans with immune diseases but that, in fact, their genomic re-
sponses differ. Seok et al. argue that the genomic differences account for
the failure of numerous clinical trials of agents to block immune re-
sponse in sepsis or burn victims that were based on preclinical mouse
studies. Studies such as this will prompt closer examination of animal

models and alternatives that may provide better molecular matches to
complex human systems.
Along with a detailed explanation of the experimental procedures to be
performed on the animals, the use of appropriate anesthetics, analgesics, or
sedatives should be described. Description of the drugs used for these pur-
poses, as well as the dosages and frequency of administration, should be
detailed enough that the committee can determine that they are appro-
priate for the species and experimental procedures involved. An assessment
of pain and distress anticipated can be useful for the committee. (Proce-
dures that are painful in humans must be considered to be painful in ani-
mals unless evidence to the contrary is supplied.) The investigator must
also describe the criteria and process that will be used to remove animals
from a study, or euthanize them, if painful or stressful outcomes may be
anticipated. Postprocedure care of the animals should be described, as well
as the method of euthanasia or ultimate disposition.
The investigator should assure the IACUC that the experiments pro-
posed do not unnecessarily duplicate previous work by providing evidence
of having completed a recent and rigorous search of the literature. The
training and experience of the laboratory personnel in the specific proce-
dures proposed should be discussed. The safety of the work environment
and any precautions taken to protect laboratory personnel should be
described.
Protocol review by the IACUC

When reviewing an investigator’s research protocol, the IACUC must de-
termine whether the proposed experiments are being conducted in accor-
dance with the AWA and, if applicable, the Guide for the Care and Use of
Laboratory Animals. Additionally, the IACUC evaluates the proposed re-
search according to the U.S. Government Principles for the Utilization
and Care of Vertebrate Animals Used in Testing, Research, and Training,
which were incorporated into the PHS policy in 1986. The scientist must
justify any departures from these guidelines to the satisfaction of the com-
mittee. The committee must ensure that protocols are designed to avoid or
minimize discomfort, distress, and pain to animals consistent with sound
research design. Any procedure that is judged to cause more than a “mo-
mentary or slight pain or distress” should be performed with the appro-
priate sedation, analgesia, or anesthesia unless the investigator can convince
the committee that withholding such treatment is justified for scientific
reasons. Animals that would suffer severe or chronic pain and distress that
cannot be relieved must be euthanized. The committee must also ensure
that the laboratory animals covered by a particular protocol will be housed
under conditions that are appropriate for the species and will contribute to
188 Chapter 6
“their health and comfort.” A veterinarian, or other scientist trained and

experienced in the care of the species being used, must direct the housing,
feeding, and nonmedical care of the animals. A qualified veterinarian must
provide medical care for the animals. Any means of euthanasia employed
must be consistent with the recommendations of the American Veterinary
Medical Association Panel on Euthanasia unless the investigator is able to
justify any deviation on scientific grounds to the satisfaction of the
IACUC.
The Guide describes a number of issues that should be given careful
consideration by IACUCs, all based on the goal of minimizing pain and
distress in animals. For example, some protocols may require that extra
attention be paid to identifying humane endpoints—when pain or distress
is relieved or eliminated, such as studies involving tumor models or trauma.
Additionally, IACUCs should establish a policy discouraging the use of
prolonged physical restraint of animals and require valid justification for
such experimental procedures. Similarly, the use of multiple survival surgi-
cal procedures on a single animal, particularly if considered major surgery,
should be limited to protocols where valid scientific justification prevails.
The newest edition of the Guide includes reference to the use of
pharmaceutical-grade drugs to prevent unwanted toxicities or side effects
that could impact animal welfare and experimental endpoints. The use of
non-pharmaceutical-grade drugs in animal research requires justification
such as experimental necessity or unavailability of alternatives.
Generally speaking, IACUC protocol review leads the committee to
identification of those proposals that are the most problematic. But the
IACUC is not restricted to simply accepting or rejecting the investigator’s
protocol. Often, the IACUC will suggest alterations to a protocol that
would make it acceptable. The committee may suggest a different anes-
thetic, or perhaps an alternative dose or schedule of treatment. The
IACUC can draw upon the expertise of its various members in order to
work with the investigator to see that both scientific and animal welfare
concerns are met. Occasionally, investigators feel that the suggestions of
the IACUC are intrusions into their scientific experimental design. This is
unfortunate, but it is nonetheless the responsibility of the committee to
ensure that all animal welfare concerns are satisfied. An investigator’s at-
tempt to justify a particular technique by using the argument that “this is
the way that we have always done it” is not a sufficient rationale for an
IACUC to approve a protocol that might otherwise be questionable. Like-
wise, it is not a sufficient rationale to claim that similar (or identical) tech-
niques have been approved for use at other institutions. Each IACUC is
responsible for making decisions on the protocols that come before it, and
differences of opinion from one institution to another as to the acceptabil-
ity of a specific technique are bound to occur.
Another important element of the AWA and the PHS policy is the re-
quirement that the institution provide training for those staff members in-
volved in the care and/or research use of animals. This training is to include
a discussion of humane methods of animal care and experimentation, tech-
niques available to minimize the use of animals and animal distress, the
proper use of anesthetics and analgesics, methods by which deficient animal
care procedures may be reported, and how to use available services to learn
more about appropriate animal care and alternatives to animal techniques.
The National Research Council has prepared a book to assist in the devel-
opment of such institutional programs, Education and Training in the Care
and Use of Laboratory Animals: A Guide for Developing Institutional Programs
(1991). In addition, several online training options exist.
The AWA has been amended several times in recent years. Most often
this has happened through congressional legislation, but periodically it has
occurred through judicial action as some animal welfare or animal rights
organizations have attempted to alter the scope and specifics of the act.
Because the AWA covers both research and nonresearch activities involv-
ing animals, not all of the updates are relevant to institutions utilizing re-
search animals. Most recently, in December 2012, a final rule was passed
requiring U.S. Department of Agriculture-registered facilities to maintain
an emergency response plan and train animal care staff on how to imple-
ment the plan. This requirement was implemented following several natu-
ral disasters that resulted in significant losses of animals at research and
other registered animal facilities.
Given the current legal climate, it is impossible for a textbook to pre
sent a current assessment of the laws regulating the care and use of labora-
tory animals. The AWA has been amended in the past, and it is certain to
be modified again in the future, whether by legislation or lawsuit. For cur-
rent information, scientists will have to depend on the division of animal
care within their own research institutions. Without doubt, the relation-
ship between animal care professionals and scientists will continue to grow
in importance.
Beyond legislation
While laws define the minimum requirements scientists must follow in
their care and use of animals, most scientists will want to strive for levels of
care that exceed these minimums. The scientist’s primary ally in this goal is
the institution’s division of animal care or equivalent body. The veterinari-
ans and animal care professionals employed by this department serve as a
powerful resource to scientists. Using their knowledge can lead to both
better animal care and better science.
In most instances, it will be these professionals who provide the training
that is now mandated by law for those who are going to use animals in
190 Chapter 6
their research. New graduate students should be sure that they attend
these training sessions as early as possible. Traditionally, the training in
animal procedures for new graduate students has taken place within the
laboratory of their chosen advisor. However, animal care professionals are
better able to provide a comprehensive training experience than ad hoc
methods that may be in place in laboratories. In addition to this formal
training experience, students should realize that their institution’s animal
care professionals could also be an invaluable resource when they are seek-
ing to learn a new procedure or technique. In addition to being able to
advise students as to what the law requires when, for example, performing
rodent surgery, they will also be able to advise them on the appropriate
surgical techniques, use of anesthetics, and postoperative care. This advice
can ensure both that the animal does not suffer any unnecessary pain or
distress and that the students obtain the best data possible from their ex-
perimental efforts.
Although it is the legal responsibility of the faculty advisor (principal
investigator) to submit protocols to the IACUC, students would be well
advised to look at the protocols under which they are conducting their re-
search. Laboratory techniques often drift over time as personnel and expe-
rience change. Graduate students are likely to be in a better position than
their advisors to see this happening and realize that it is time to submit an
amended protocol to the IACUC. Additionally, scientists are required to
consider the use of nonanimal alternative techniques before resorting to
the use of animals for any procedure likely to cause pain or distress. Senior
graduate and postdoctoral students are often on the cutting edge of tech-
nology and thus in an excellent position to make suggestions to their advi-
sor for improving laboratory procedures.
In 1959, William Russell and Rex Burch enumerated three principles
that should act as a guide for the humane use of animals in research.
These are commonly referred to as the 3 R’s: replacement, reduction, and
refinement.
• Replacement refers to the attempt to substitute insentient materials or,
if this is not possible, a lower species that might be less susceptible to
pain and distress than a higher species. Why sacrifice the life of a
monkey for an experiment in which a dog would suffice? Why use a
dog where a mouse would do? Why use a mouse if the research ques-
tion could be answered using a cell culture?
The issue of replacement as it pertains to the involvement of
chimpanzees in research has garnered recent attention. In 2011, at
the request of the NIH, the Institute of Medicine and the National
Research Council completed an evaluation of the scientific necessity
of using chimpanzees in NIH-supported research. The committee
concluded that most biomedical research can effectively be con-

ducted utilizing other animal and nonanimal models, with several
exceptions including testing for a preventative hepatitis C vaccine,
short-term monoclonal antibody research while new testing meth-
ods are refined, and some comparative genomics and behavioral re-
search. The report outlined criteria that should be utilized to assess
the necessity of utilizing chimpanzees in specific research studies.
• Reduction refers to the attempt to use the minimum number of ani-
mal lives necessary to answer the research question. To design an
experiment in which the n of a treatment group is 25 in a situation
where statistical significance could be achieved with an n of 8 is both
economically wasteful and morally troubling. However, it is equally
troubling to see an experimental design in which too few animals are
used. If the group size is too small to permit any reasonable chance of
demonstrating a statistically significant difference, then the entire
experiment is a wasted effort. There are techniques available to assist
in the estimation of the appropriate numbers of animals to be used in
an experiment. Additionally, one can seek the advice of a professional
statistician before conducting a series of experiments, both to pre-
vent the waste of animal lives and to ensure a more rigorous scien-
tific study.
• Refinement refers to the attempt to reduce the incidence or severity
of pain and distress experienced by laboratory animals. Use of anes-
thetics and analgesics that are appropriate for the species as well as
appropriate doses and intervals of administration are all important.
Additionally, use of trained personnel to perform experimental or
surgical manipulations and effective postoperative procedures will
improve both animal welfare and scientific validity. (Who would
want pain introduced as an uncontrolled variable into their experi-
mental design?)
Finally, it should be recognized that animal care professionals play
something of a dual role within the institution. As we have discussed, they
can serve as an invaluable resource to the research scientist. However, they
also must ensure the welfare of the animals under their care. This role
could potentially put them at odds with the research scientist. The animal
care staff is also there to protect the animals from any researcher who re-
fuses to observe the rules. This dual role can be stressful; they are at the
same time advocates for both scientific research and animal welfare.
We should recognize that while the work we do is important and mor-
ally justified in the minds of most people, our system is not perfect and
there are ways in which we can contribute to improved animal care. Each
of us should be on the lookout for animals that are suffering, either from
192 Chapter 6
neglect or from abuse at the hands of a careless or poorly trained scientist.

In some instances, the situation might be resolved by talking to the person
involved. In other situations, a report might have to be made (formally or
anonymously) to the head veterinarian of the animal care staff.
It is also beneficial to realize that there are moral inconsistencies in the
way we relate to animals. Harold Herzog has written provocatively on this
matter. He wonders why it is that we have strict rules for how we may use
and euthanize laboratory mice and yet we are allowed to catch and kill es-
caped mice in inhumane “sticky traps.” After once being accused (unjustly)
by an animal activist of obtaining kittens from a local animal pound in or-
der to feed his son’s boa constrictor, Herzog began to think about the eth-
ics of pet food. Is it more moral to raise a rat to feed to a boa than it is to
use a kitten that is about to die anyway? For that matter, is it any more
moral to keep a kitten (an obligate carnivore) than it is a boa?
A Continuum of Realities
Social attitudes and activism

Political and social realities are such that there is no chance that scientists
will be left to decide by themselves how laboratory animal welfare may be
improved. Recent history has seen the rise of a number of well-funded ani-
mal rights groups that can and do press for legislative and judicial mandates
to alter the existing procedures. While some of these initiatives originate
from a genuine concern to improve the treatment of laboratory animals,
others seek to harass animal researchers until such time when the groups
believe that they will amass the political might to see this research abolished.
While scientists often like to believe that the animal rights movement con-
sists of a lunatic fringe, such an assertion is not true and carries with it great
danger. On the one hand, in America and worldwide there are groups that
are overtly aggressive and militant in their actions, advocating for and carry-
ing out both disruptive and destructive activities aimed at impeding the use
of animals in research. However, the statements and actions of groups or
individuals who fall into this category represent a small fraction of organiza-
tions whose missions center on animal rights. For groups in this category,
there is no evidence that their membership comprises anything other than
highly concerned citizens. It is important that we set aside the easy and of-
ten erroneous explanations of the animal rights phenomenon and seriously
consider who is involved in the movement and attempt to understand their
reasons for doing so. We also need to keep in mind the distinction between
those organizations that are concerned primarily with the humane treat-
ment of animals (animal welfare) and those that press for radical alterations
in the predominant world view (animal rights). It is not always possible to
identify with certainty a particular organization as being one or the other. It

is not unusual for both sentiments to coexist within an organization. Not
surprisingly, the more radical beliefs sometimes lead to internal inconsisten-
cies between the leaders of the movement and the rank-and-file member-
ship over issues such as the morality of pet ownership.
In 1992, Wesley Jamison and William Lunch published the results of a
survey of animal rights activists attending a march in Washington, DC.
Demographic data collected in this study found typical followers of the
animal rights movement to be young, highly educated women. Nearly
79% of those interviewed reported some college education, 47% a bache-
lor’s degree, and nearly 19% a graduate or professional degree. Of those
surveyed, 74% had contacted their elected representatives about animal
rights and 38% had made political donations to candidates supportive of
such rights, suggesting a highly motivated and politically sophisticated ac-
tivist group. The fact that nearly 14% of the activists reported having in-
comes in excess of $70,000 per year and more than 30% in excess of
$50,000 per year helps to explain why the animal rights movement is so
well funded. Many respondents displayed profound doubts about scientific
enterprise. Fifty-two percent of the animal rights activists surveyed felt
that science does “more harm than good.” This opinion sets them dramat-
ically apart from the general public, only 5% of whom express this belief.
Further, it is a mistake to believe that this skepticism is limited to the
benefits derived from scientific research or to the character of the scien-
tists performing such work. Gary Francione, professor of law at Rutgers
University and former legal advisor to People for the Ethical Treatment of
Animals (PETA), has expressed mistrust of the scientific process itself.
Science no longer enjoys a position as epistemologically superior to other

forms of knowledge. Despite the seductive simplicity of the traditional em-
piricist point of view—that science represents “objective” truth, the assump-
tions supporting this traditional view have been challenged effectively in
recent years. Philosophers and sociologists of science have argued persua-
sively that factual assertions are completely contingent on theoretical as-
sumptions, and that observation itself is subject to interpretation. . . .
This recognition erodes the pedestal upon which science has presided for
many years. More and more people in the animal rights movement, the en-
vironmental movement, and the alternative health care movement recognize
that science is as value-based as any other activity. Indeed, there is increasing
criticism of the fundamental premises of Western medicine.
Francione has also challenged the “general view” that scientific inquiry
is protected under the First Amendment to the United States Constitu-
tion. Francione’s view is that the First Amendment provides very little pro-
tection for the conduct of scientific research although, somewhat
194 Chapter 6
paradoxically, the dissemination of the research results themselves is pro-

tected. Francione has said: “For example, under this analysis, the govern-
ment could . . . prohibit all research involving genetic engineering as long
as the purpose of the prohibition is not to suppress the dissemination of
the information derived from such research.”
While it is not clear that Francione would be in favor of prohibiting all
genetic engineering research, there is little doubt that he opposes all use of
animals in scientific research. Francione gives us some insight as to why he
appears to be so opposed to the concept of constitutional protections for
research when he says:
It may be the case, however, that the federal government will, at some point,
try to impose on all experimentation a risk/benefit regulatory structure. . . .
Moreover, it is likely that even though experimenters find themselves with
the federal (or other) funds to do an experiment, state and local governments
may seek to restrict or even to prohibit such experimentation.
We may be seeing in such statements a strategy for political action from

a movement that has been unable to convince a majority of society as to
the legitimacy of its views. Although during the recent past the animal
rights activists have succeeded in causing increasing numbers of the public
to question both the validity and humanity of animal research, they have at
the same time failed to build anything approaching a consensus for animal
rights as they conceive of them. Thus, it seems possible that in the future
they may try to achieve, through targeted political actions in state and lo-
cal arenas, what they have been unable to win through philosophical and
political debate at the national level. Further, given the political savvy of
the movement, this would not appear to be an idle threat. While there is
no possibility, in the foreseeable future, of the movement’s securing a legal
prohibition of animal research at the national level, things seem less cer-
tain at the level of local government. Imagine the impact of a local ordi-
nance proscribing animal research within the city limits of a community
such as Berkeley, CA, or Cambridge, MA. The ordinance may not even be
phrased in the philosophical terms of animal rights, but rather may appear
to be primarily concerned with the alleged environmental impact or health
risks to citizens that may be associated with animal research.
Increasingly, animal rights activist organizations are seeking to target
individual localities, institutions, and researchers by attempting to gather
and disseminate information about animal research programs at state or
federally supported institutions via the Freedom of Information Act. Not
only do these requests place a burden on institutions, they behoove re-
searchers and institutional administrative units, such as the IACUC and
veterinary care programs, to be extremely diligent in how research and
animal husbandry activities are documented.
Animal research enterprise security

There is a troubling side of anti-animal research activism that has reared
its head with concerning regularity over the decades. It has occurred glob-
ally and has involved attacks on researchers with intent to inflict harm and
property destruction. Some individuals and militant animal rights groups
have openly embraced and used violence as a tactic to discourage the use of
animals in research (Fig. 6.1). Others have publicly implied that taking a
human life to save the lives of many animals provides a justification for the
use of violence. In the United States, violent crimes aimed at any animal-
use enterprise prompted the 2006 passage of the Animal Enterprise Ter-
rorism Act. This law makes acts of violence directed against animal
enterprises and individuals who are associated with them an act of terror-
ism. Included among the animal enterprises covered by this law are bio-
medical facilities and researchers. Legislation addressing acts of violence
against animal-use enterprises was enacted in Great Britain in 2005.
Increasingly, universities and research institutions have developed
guidelines and policies for the prevention of and management of crises
that could result from acts of violence against researchers or property. So
have scientific societies, and the Guidelines for Crisis Management:
Figure 6.1 Images depicting the impact of anti-animal use activism. (Left) In
North America, the automobile of a university scientist who uses animals in re-
search is firebombed. Courtesy of J. David Dentsch. Used with permission. (Right)
In Europe, construction of a laboratory dedicated to animal research was sus-
pended for over a year due to threats against construction workers and staff by
animal rights protesters. Ultimately, security measures including a barrier wall
were used to establish an exclusion zone around the site to allow construction to be
safely completed. Courtesy of R. Wayne Barbee.
doi:10.1128/9781555818487.ch6.f6.1
196 Chapter 6
Responsible Use of Animals and Humans in Research, published by the Society

for Neuroscience, is an excellent example of the scope and detail of guid-
ance that can be offered to researchers to prevent and deal with criminal
acts, including violence, aimed at an institution’s animal research enter-
prise. Guidelines like those of the Society for Neuroscience provide a good
model for institutions to create crisis management policies that suit their
specific needs. If your institution has an animal enterprise crisis manage-
ment policy, all researchers, including trainees, should be familiar with it
and adhere to its guidance.
Finally, natural disasters can pose serious threats to research animal en-
terprises. Although this has been long recognized, it was dramatically
demonstrated in 2012 when Hurricane Sandy wreaked havoc and destruc-
tion on buildings containing vivaria in the New York City area. The 8th
edition of the Guide for the Care and Use of Laboratory Animals calls for an
institutional disaster plan that addresses the research animal enterprise. This
is especially important for institutions in areas that are at high risk of natural
disaster: those prone to hurricanes, tornados, extreme temperatures, or
earthquakes. Researchers who use animals should be familiar with such doc-
uments and must participate in relevant institutional training. Protecting
the animal enterprise is part of using animals responsibly in research.
Conclusion
Written in the late 1940s, the Nuremberg Code listed 10 principles that
strongly influenced the ethical and legal foundation of biomedical research
using human subjects (see chapter 5). The use of animals in research was
validated in the third principle of the Code, which states: “The experiment
should be so designed and based on the results of animal experimentation
and a knowledge of the natural history of the disease or other problem
under study that the anticipated results will justify the performance of the
experiment.” Since that time, the use of animals in biomedical and behav-
ioral research has played a crucial role in understanding biological systems
and in translating basic research discoveries into products that benefit hu-
mans and animals alike. The use of animals in research is governed by laws
that must be carefully followed. Institutional processes that approve and
authorize animal use are derived from federal law in the United States and
other countries. Principal investigators are ethically bound to ensure that
all trainees and staff who work with animals are properly educated and
monitored for compliance with applicable codes and policies. In particular,
compliance with the relevant IACUC-approved protocol is imperative.
The IACUC-based protocol review system depends heavily on the volun-
tary participation of institutional scientists. Service on the IACUC rep-
resents good citizenship in support of the institutional research enterprise,
and realizing this, researchers should be thoughtful and generous in con-

sidering invitations to serve on IACUC panels.
Individual scientists have an important role to play by educating the
public, beginning with family and friends, as to why it is sometimes im-
portant to use animals in research. As the visibility of animal rights organi-
zations increases, the importance of scientists helping to educate the public
about the value gained by using animals in research grows. The extent to
which any scientist decides to become involved in the political and philo-
sophical debate over animal rights is a matter of individual choice. Nature
published a collection of feature articles on animal research in February
2011. One of these articles reported on a poll conducted by Nature in
which 55% of the scientists responding indicated that their institutions
encourage communication with the public about the research they con-
duct. However, more than 70% of respondents indicated that it can be
difficult to publicly express the nuanced opinions about animal research
that many scientists have. All scientists have an obligation to educate them-
selves about the animal-use debate, both to ensure ever-increasing stan-
dards of animal welfare and to ensure that society will continue to seek
their counsel when searching for answers to this ethical dilemma.
1. Should the authority of the Animal Welfare Act be expanded to in-

clude rodents and birds? Why or why not?
2. How would you respond to an animal rights activist who says the use
of animals in research is bad science?
3. Can you describe an experiment in which a computer could effec-
tively substitute for the use of an animal?
4. Who bears the responsibility for implementing Russell and Burch’s
maxim to reduce, refine, and replace? Is this an obligation that can
be met collectively (i.e., by having the animal research community
support a small number of scientists who work on the issues full
time)? Alternatively, is this an obligation that is the responsibility of
every animal researcher individually?
Case Studies
6.1 You are beginning a new postdoctoral position at the same time that
your mentor is moving her laboratory into a new building. She is
obsessive about animal care and wants to ensure that the colony of animals
to be established in the new facility is healthy. You are assigned the task of
developing a system of “sentinel” animals to monitor the health status of all
new incoming shipments of animals as well those in the established animal
198 Chapter 6
colony. You establish a system that involves the euthanizing of selected ani-
mals on a regular basis and screening for the presence of specific pathogens
by a contract laboratory. Because these animals are not being used for re-
search, do you have to submit a protocol to the IACUC to cover these activ-
ities? What policies or codes form the basis for your answer?
6.2 Dr. Sheldon Speigel is the director of the division of animal re-
sources at Coastal Medical College. Over the past few months, he
has received several complaints from principal investigators raising issues
about the care of their animals. To date, he has categorized these as “petty
violations,” but a couple of the complaints filed within the last week, if
based in fact, could have serious repercussions leading to the suspension of
animal research at the college. These complaints have come directly to
him, and he has not shared them with any of his staff, intending to investi-
gate these situations himself. In discussions with some of his staff, Dr.
Spiegel learns that his newest animal technician, Janie Halpin, has been
spending an inordinate amount of time consulting with researchers using
the facility. This was brought up because Janie’s preoccupation with the
investigators is interfering with her assigned duties as animal caretaker.
Another colleague tells Dr. Spiegel he saw Janie using her cell phone to
photograph one of the animal rooms a few days ago. He looks at her job
application and finds that she has a degree in information technology and
worked briefly in a veterinarian’s office before joining his staff. Dr. Spiegel
is uncomfortable with the situation and mentions these events to the med-
ical school’s legal counsel, Martha Moreno. A few days later, Martha calls
Dr. Speigel and says she took the liberty of doing a news service search.
She has found Janie’s name repeatedly associated with the activities of an
international animal rights organization. Martha proposes that Janie is
working “undercover” for this organization in hopes of exposing animal
mistreatment in medical research. What should Dr. Spiegel do now?
6.3 You are a graduate student in behavioral pharmacology, and your lab
is conducting a drug discrimination study, an operant procedure in
which rats are trained to identify drugs with stimulus properties similar to
those of a training drug. The primary goal of the present study is to test sev-
eral experimental compounds for their similarity to clozapine, an important
treatment for schizophrenia. The compounds to be tested have been sent to
your advisor as part of a contract awarded from a drug company. The gener-
alization testing portion of the study is nearing completion, with only one
dose-response curve left to obtain. During routine feeding, you notice that 8
of the 10 animals in the study have developed tumor-like growths at the site
of injection on the stomach. Additionally, these animals have begun losing
weight. Finally, you note that the animals do not exhibit any behaviors sug-
gesting that they are experiencing any discomfort. Concerned, you mention
the growths and weight loss to your advisor, who instructs you to continue
with generalization testing. He is concerned that having to train a new set of
animals in order to test one drug would waste large amounts of research
time and resources and may cause problems in interpreting the results. He
further states that the animals will be euthanized as soon as the testing phase
of the study is completed in less than a month and that the animals will be
fine until then. Is your advisor’s suggested course of action legally and ethi-
cally appropriate? If not, what should be done in this case? What are your
obligations in this situation?
6.4 Dr. Jiao Fang is a postdoctoral fellow in the organ transplantation

research lab of Dr. James Zogby. She has just completed her draft
of an IACUC protocol for kidney transplantation research in a rat model.
According to the protocol, the animals are anesthetized for the transplant
procedure but cannot be given standard immunosuppressive therapies
since that would delay the onset of the rejection response she proposes to
study. She includes acetaminophen administration postoperatively to re-
lieve pain, but Dr. Zogby instructs her to remove that treatment from the
protocol because acetaminophen inhibits the immune response to a lim-
ited degree and this would interfere with the ability to study the natural
course of rejection. Jiao counters with the argument that this can be con-
trolled for, and she provides several creditable papers that use acetamino-
phen to control pain in similar transplantation studies. Dr. Zogby holds to
his position, and Jiao makes the modification he wants. The protocol is
approved, and she does transplantations in several animals. She notices
that postoperatively the animals huddle together in the cage, display de-
creased mobility, and are hunched over in posture. She interprets this as
response to pain and brings it to Dr. Zogby’s attention. He dismisses her
conclusion and tells her to hold the course through this observational
phase of the work. A few days later, she notices that the animals now have
diminished appetites and have reduced their intake of water. She again
takes her concerns to Dr. Zogby that the animals are suffering from unre-
lieved pain that can and should be treated with an analgesic. She argues
they should file a protocol amendment with the IACUC to allow acet-
aminophen to be administered. He disagrees vigorously and says she needs
to pay more attention to doing careful research, not conjuring up visions
of unnecessary suffering in her rats. Jiao is very upset with his dismissive-
ness, and she considers his behavior to be a reckless disregard for appro-
priate animal care. She confides in a departmental colleague, who tells her
she should report his behavior to a member of the IACUC committee.
They both realize that this will probably damage, if not destroy, the trust
of the mentor- trainee relationship. Jiao comes to you for a “second
200 Chapter 6
opinion” about what she might do. She firmly believes there must be other
options for solving this without jeopardizing her training career in Dr.
Zogby’s lab. What advice or guidance do you have for her?
6.5 You are the head of the legal office at a large state-supported uni-
versity. The university has received a Freedom of Information Act
(FOIA) request for the names of the individuals serving on the IACUC.
The requestor is a science writer for a local newspaper. Your state has a
broad-reaching FOIA law, but requests for information can be denied if
appropriately justified. The university’s unwritten policy has been to hold
the IACUC roster in confidence owing to threats and acts of violence to-
ward animal research activities and researchers in this country and abroad.
At a staff meeting, one of your lawyers argues that the request be denied
for these very reasons. But two other members of your legal staff recom-
mend releasing the roster. They argue that most of the animal research at
the university is supported by public funds and therefore the roster should
be considered public information. One of them further argues that if the
request is denied, the newspaper will “go public” with its failure to get the
list and this will create negative publicity, perhaps leading to a costly legal
fight. Further, both of these staff members say that failing to honor the
request will appear as though the university has “something to hide.” The
university president is pressing for your recommendation. Do you advise
her to honor the FOIA request and release the names of the IACUC mem-
bers to the reporter? Provide the rationale for your recommendation.
6.6 You are invited as a guest faculty member to judge a local high
school science fair. One entry you judge is entitled “Alcohol Addic-
tion in Mice.” The student has purchased six mice from a local pet store.
One group of three of these mice has been caged and fed standard mouse
chow and given drinking water ad libitum. The other group is fed mouse
chow but is allowed water only once per day. This group of mice is instead
given unlimited access to 20% ethyl alcohol. After 6 weeks, the student
notes a significant weight loss in the latter group of mice as compared with
the control animals. He also notes abdominal distention and states that the
alcohol-fed mice ate significantly less food throughout the study. He con-
cludes that the alcohol mixture depressed the animals’ appetites. At the
end of the study, he destroys the animals by cervical dislocation. You con-
sult the school guidelines regarding the use of animals in science projects.
The guidelines state that the use of animals in science projects is discour-
aged. However, animals may be used with permission of the science
teacher. In this case, the student has sought and received such permission
for his project. What comments, if any, will you offer to the student about
his use of animals? Likewise, what, if anything, will you say to his teacher?
6.7 Dr. Jasmine Tanaka and Dr. Ellen Schwartz, professors in a neuro-
sciences department, both work on age-related neurodegenerative
diseases using rodent models. Their work sometimes puts them in direct
competition, and this creates intradepartmental tension that they typically
handle in a civil and professional fashion. Presently, each has a single NIH
grant, and both grants will have to be competitively renewed within the
next 6 months. Dr. Tanaka and her two postdocs are spending a week
learning a new technique in a research institute overseas. The remaining
members in Dr. Tanaka’s lab, an undergraduate student and a histology
technician, do not work with animals. Thus, prior to her departure, Dr.
Tanaka asked Dr. Schwartz to check a cohort of her rats every other day
during her absence. Dr. Schwarz gladly accepts this responsibility, seizing
the opportunity to be collegial. The five animals to be monitored are part
of an experiment that had been underway for 2 years. As per the protocol,
at 2.5 years of age, the animals are to be anesthetized, perfused so as to fix
brain tissue, and sacrificed, and brain tissue is to be recovered for structural
and histochemical studies. On her third visit to the vivarium to check on
the rats, Dr. Schwartz is confronted with a disconcerting situation. She
finds one of the rats dead in its cage. Two of the remaining four rats appear
gravely ill and, in Dr. Schwartz’s view, close to death. She surmises that if
they die, which would preclude the recovery of the fixed brain tissue, the
remaining two rats are not likely to be a large enough sample size to pro-
vide meaningful data. She immediately formulates a plan to recover useful
tissue from the two dying rats. She will anesthetize them with isoflurane
using an apparatus she has in her own lab. She is trained to do the fixative
perfusion and surgery to recover the rats’ brains, thus saving the needed
tissue from these valuable animals. She will then step up her monitoring of
the remaining two animals to three times a day until Dr. Tanaka returns. If
either of the remaining two animals becomes ill, she will repeat the brain
tissue recovery plan with them. As she mentally reviews her plan, she has
some hesitation because her actions likely fall outside of Dr. Tanaka’s ap-
proved protocol (and she is not listed as an investigator on the protocol).
It’s the weekend, and she contemplates contacting the veterinarian on call
to run her plan by him and seek his approval. But she worries that he may
forbid her to carry it out and order that the suffering animals be eutha-
nized. That would clearly compromise Dr. Tanaka’s long-term experiment,
which would take more than 2 years to repeat. She wonders if she should
risk the possibility that the veterinarian will effectively shut down the ex-
periment. On the other hand, if she preemptively carries out her plan and
it does succeed, she may find herself in deep trouble with the IACUC and
even face sanctions. In addition, looming in the back of her mind is the
notion that if the animals are lost under any circumstances it may look to
Dr. Tanaka like she passively sabotaged the experiments by inappropriate
202 Chapter 6
action or indecisiveness. You happen to be passing by the animal room, and

Dr. Schwartz asks for your counsel on what she should do. What do you
tell her? Are there other options she should consider?
6.8 Your colleague, Dr. Jay Mahata, is an NIH-supported investigator

who has an established collaboration with a field biologist, Dr.
Ellen Yu, in another state. Dr. Yu does not receive any grant support for
her research. Dr. Mahata sometimes receives blood and other tissue sam-
ples for analysis from the wild rodents that Dr. Yu traps for her research.
Dr. Mahata has asked you to read his latest IACUC protocol before its
formal submission. You know about his collaboration with Dr. Yu but note
that it is not mentioned in the protocol. When you ask Dr. Mahata about
this, he says that he “does not have to report this activity to the IACUC
because there are not any animal welfare concerns involved.” He points
out to you that he does not euthanize the rodents or collect the blood and
tissues. He maintains that the relevant animal welfare concerns are be-
tween Dr. Yu and her institution. Last, he suggests that because the NIH
does not support her work, it does not have to conform to the same guide-
lines to which his own work is subject. What is your analysis of this situa-
tion? What is your recommendation for going forward?
6.9 Dr. Carley Featherstone is disappointed that the IACUC has re-
jected her research protocol because it involves the mouse ascites
method of monoclonal antibody production. She appeals to the IACUC,
citing her long use of this practice, prior approval to use the method at her
previous institution in another state, and the loss of time that an immedi-
ate switch to in vitro methods would entail. She asks for permission to
continue using the ascites method for 3 years while she phases in the in
vitro production methods. The IACUC denies the appeal. She then resub-
mits the protocol, reporting that since she has found a commercial source
for the monoclonal antibody she no longer needs to produce it herself.
The protocol is quickly approved. Dr. Emanuel Louis, a member of the
IACUC, has a conversation with Dr. Featherstone a few months later. She
tells him that her commercial source is a custom contract lab that she has
engaged to produce the antibody using her cell lines and to her specifica-
tions (i.e., using the mouse ascites method). Is Dr. Featherstone’s solution
legal? Is it ethical? Why or why not? Dr. Louis comes to you for advice.
Does he have any obligation to report this information to the IACUC?
6.10 You are a graduate student working on a project that involves ad-
ministering nerve toxins directly into the cerebrospinal fluid of
rats by using a special infuser connected to tubing that you have surgi-
cally implanted into the base of each rat’s skull. Administering different
nerve toxins to block specific effects of different types of drugs will help
determine how the drugs work. After surgery, the nerve toxin is given,
and a few days later the investigational drug is given to determine whether
it will have an effect. This protocol has been approved by the IACUC and
is being funded by a grant from the Department of Defense. Over the
past few weeks, you have carefully implanted a catheter into the base of
each rat’s skull and then infused the specified amount of nerve toxin.
When you go to the vivarium to take the rats to the lab to administer the
investigational drugs, you find that a number of the rats are paralyzed or
dead. You did not expect this. The lab director is currently out of town, so
you go to the lab’s senior graduate student, Tom, for advice. Tom will be
able to complete his dissertation writing when this experiment is done,
and he has made it clear that he wants this experiment to run without
delay. You ask him whether you should stop the experiment to determine
why some of the rats are dead or paralyzed. He responds that stopping
the experiment now would waste several weeks of work and delay com-
pletion of his dissertation. Stopping now may mean having to start over
later and could result in using even more rats. He further explains that
the IACUC might even prohibit restarting the experiment, so the rats
would have died for nothing because the data would have to be obtained
another way. He suggests that the paralysis and death of some of the rats
may be due to your inadequate experience in performing rat surgery or
infusions, so your gaining further practice by continuing this experiment
may result in better outcomes for the rest of the rats on which you per-
form surgery. What do you do now? Do you continue performing sur-
gery and infusions on the rats, knowing that more rats may be harmed?
Do you stop the experiment and inform the IACUC, which risks earning
the disfavor of Tom, with whom you have to work? How would you ex-
plain each course of action to the IACUC?
Resources
Print
Anonymous. 1966. Concentration camps for dogs. Life 60(5), February 4, p 22–29.
Carruthers P. 1992. The Animals Issue: Moral Theory in Practice. Cambridge Uni-
versity Press, Cambridge, United Kingdom.
Cohen C. 1986. The case for the use of animals in biomedical research. N Engl J
Med 315:865–870.
Francione GL. 1987. Experimentation and the marketplace theory of the First
Amendment. Univ Penn Law Rev 136:417–512.
Francione GL. 1988. The constitutional status of restrictions on experiments in-
volving nonhuman animals: a comment on Professor Dresser’s analysis. Rutgers
Law Rev 40:797–818.
204 Chapter 6
Francione GL. 1990. Xenografts and animal rights. Transplant Proc 22:1044–1046.
Frey RG. 1980. Interests and Rights: The Case against Animals. Oxford Clarendon
Press, Oxford, United Kingdom.
Frey RG. 1983. Rights, Killing, and Suffering: Moral Vegetarianism and Applied Ethics.
Blackwell Publishing, Oxford, United Kingdom.
Frey RG. 1989. The case against animal rights, p 115–118. In Regan T, Singer P
(ed), Animal Rights and Human Obligations, 2nd ed. Prentice-Hall, Inc, Engle-
wood Cliffs, NJ.
Frey RG, Paton W. 1989. Vivisection, morals, and medicine: an exchange, p 223–
236. In Regan T, Singer P (ed), Animal Rights and Human Obligations, 2nd ed.
Prentice-Hall, Inc, Englewood Cliffs, NJ.
Herzog HA. 1988. The moral status of mice. Am Psychologist 43:473–474.
Institute of Medicine. 2011. Chimpanzees in Biomedical and Behavioral Research:
Assessing the Necessity. National Academies Press, Washington, DC. http://books
.nap.edu/openbook.php?record_id=13257.
Jamison WV, Lunch WM. 1992. Rights of animals, perceptions of science, and
political activism: profile of American animal rights activists. Sci Technol Hum
Values 17:438–458.
Leahy MPT. 1991. Against Liberation: Putting Animals in Perspective. Routledge,
New York, NY.
Midgley M. 1989. The case for restricting research using animals, p 216–222. In
Regan T, Singer P (ed), Animal Rights and Human Obligations, 2nd ed. Prentice-
Hall, Inc, Englewood Cliffs, NJ.
Midgley M. 1992. The significance of species, p 121–136. In Hargrove EC (ed),
The Animal Rights/Environmental Ethics Debate: The Environmental Perspective.
State University of New York Press, Albany, NY.
National Research Council. 1991. Education and Training in the Care and Use of
Laboratory Animals: A Guide for Developing Institutional Programs. National
Academy Press, Washington, DC. http://www.nap.edu/openbook.php?isbn

=0309043824.
National Research Council. 2010. Guide for the Care and Use of Laboratory Ani-
mals, 8th ed. National Academies Press, Washington, DC. http://www.nap.edu
/catalog.php?record_id=12910.
Nature. 2011. Special issue: Animal Research: Anatomy of a Conflict. 470:187–
197. http://www.nature.com/news/specials/animalresearch/index.html.
Office for Protection from Research Risks. 1986. Public Health Service Policy on
the Humane Care and Use of Laboratory Animals. Office for Protection from Re-
search Risks, National Institutes of Health, Bethesda, MD.
Post SG. 1993. The emergence of species impartiality: a medical critique of bio-
centrism. Perspect Biol Med 36:289–300.
Regan T. 1983. The Case for Animal Rights. University of California Press, Berkeley,
CA.
Regan T. 1985. The case for animal rights, p 13–26. In Singer P (ed), In Defence of
Animals. Basil Blackwell, Inc, Oxford, United Kingdom.
Russell WMS, Burch RL. 1959. Principles of Humane Animal Experimentation.
Charles C Thomas, Springfield, IL.
Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards
DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López
CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL,
Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB,
Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano
SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL,
Herndon DN, Davis RW, Xiao W, Tompkins RG; Inflammation and Host
Response to Injury, Large Scale Collaborative Research Program. 2013.
Genomic responses in mouse models poorly mimic human inflammatory
diseases. Proc Natl Acad Sci USA 110:3507–3512. http://www.pnas.org
/content/110/9/3507.full#aff-2.
Singer P. 1990. Animal Liberation, 2nd ed. Avon Books, New York, NY.
Online
Policies and laws
The Public Health Service Policy on the Humane Care and Use of Laboratory
Animals can be found on the National Institutes of Health (NIH) Office of
Laboratory Animal Welfare (OLAW) website (2002 reprint):
http://grants.nih.gov/grants/olaw/references/phspol.htm
A U.S. Public Health Service policy tutorial is available on the NIH

OLAW website:
http://grants.nih.gov/grants/olaw/tutorial/index.htm
The Health Research Extension Act of 1985, Public Law 99-158 (Animals
in Research), is on the NIH OLAW website:
http://grants.nih.gov/grants/olaw/references/hrea1985.htm
Animal Welfare Act and Animal Welfare Regulations. Published in 2013.

U.S. Department of Agriculture website:
http://www.aphis.usda.gov/animal_welfare/downloads/Animal%20Care%20
Blue%20Book%20-%202013%20-%20FINAL.pdf
Guidelines
Guide for the Care and Use of Laboratory Animals, 8th ed (2010), is available
on the National Academies Press website (online as a free downloadable
PDF) at
http://www.nap.edu/catalog.php?record_id=12910
One free copy of the Guide for the Care and Use of Laboratory Animals, as well
as information about foreign language translations, is available on the web-
site of the National Academy’s Institute for Laboratory Animal Research:
http://dels.nas.edu/ilar
206 Chapter 6
Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral
Research was published in 2003 as an expansion of the Guide for the Care and
Use of Laboratory Animals. This book specifically covers the use of mammals
in neuroscience and behavioral experiments.
http://www.nap.edu/catalog.php?record_id=10732
The American Veterinary Medical Association’s (AVMA) AVMA Guidelines

for the Euthanasia of Animals (2013) can be found on the AVMA website:
https://www.avma.org/KB/Policies/Documents/euthanasia.pdf
Resources useful for IACUC members

IACUC Guidebook
http://grants.nih.gov/grants/olaw/GuideBook.pdf
U.S. Department of Agriculture information on IACUC activities and an-

imal use:
http://www.nal.usda.gov/awic/pubs/oldbib/acuc.htm
http://www.aphis.usda.gov/audience/academic.shtml
Compiled links on animal-use topics:

http://netvet.wustl.edu/iacuc.htm
http://grants.nih.gov/grants/olaw/references/outline.htm
Bioethics
Bioethics resources on the Web (compiled by the NIH):
http://www.nih.gov/sigs/bioethics/
Links to information about animal research

The Association for Assessment and Accreditation of Laboratory Animal
Care (AAALAC) administers a voluntary program that evaluates and ac-
credits the laboratory animal care programs of various institutions.
http://www.aaalac.org
Scientists Center for Animal Welfare (SCAW) is an association of individ-

uals and institutions that promotes the humane care, use, and management
of animals in research, testing, education, and agriculture.
http://www.scaw.com/
American Association for Laboratory Animal Science (AALAS) is a profes-

sional association of veterinarians, technicians, and others dedicated to
exchanging information and expertise in the care and use of laboratory

animals.
http://www.aalas.org/
National Association for Biomedical Research (NABR) advocates “sound

public policy that recognizes the vital role of humane animal use in bio-
medical research, higher education, and product safety testing.”
http://www.nabr.org/
The Foundation for Biomedical Research is NABR’s educational arm.

http://www.fbresearch.org/
National Centre for the Replacement Refinement & Reduction of Ani-

mals in Research: Funded by the Government of the United Kingdom,
this site promotes and funds initiatives that replace or reduce the need for
animals in research and testing, as well as improvements in animal welfare.
This site hosts the ARRIVE (Animal Research: Reporting In Vivo
Experiments) guidelines and guideline checklist. Initially published in
2010 in PLoS Biology (http://www.plosbiology.org/article/info:doi/10.1371
/journal.pbio.1000412#pbio-1000412-t002) and 11 other journals, these
guidelines consist of an itemized list of 20 items that describe the mini-
mum information that scientific publications should report in research
using animals.
http://www.nc3rs.org.uk/
http://www.nc3rs.org.uk/downloaddoc.asp?id=1206&page=1357&skin=0
Understanding Animal Research. This organization aims to achieve broad

understanding of the humane use of animals in medical, veterinary, and
environmental research in the United Kingdom. Their website provides
information and educational materials on use of animals in research.
http://understandinganimalresearch.org.uk/
Crisis management and disaster planning

U.S. Department of Agriculture guidance:
http://www.nal.usda.gov/awic/newsletters/v11n1/11n1heat.htm
The Society for Neuroscience’s Guidelines for Crisis Management: Respon-

sible Use of Animals and Humans in Research is available at
http://www.sfn.org/advocacy/animals-in-research/
support-for-members-and-institutions/
208 Chapter 6
Links to information from animal rights groups

AnimalConcerns.org is “a comprehensive resource for individuals, organi-
zations and businesses working for social and environmental change.”
http://www.animalconcerns.org/
People for the Ethical Treatment of Animals (PETA) is the archetype for
animals rights groups in the United States.
http://www.peta.org/
Appendix material
Appendix IV of this book contains the text of an animal subjects protocol.
chapter 7
Competing Interests in Research

S. Gaylen Bradley
Introduction • Conflict of Effort • Conflict of Conscience • Conflict
of Interest • Managing Competing Interests • Conclusion
• Discussion Questions • Case Studies • Resources
Introduction
A s in any profession, scientists encounter situations in which financial

or various other personal considerations come into competition with
one another or with the interests of their employers. This competition
may create an untoward conflict that may compromise or appear to com-
promise the judgment of the scientist. Improperly managed competing in-
terests may bias or have an inappropriate impact on proposing or
performing research, reviewing research, reporting research results, or
participating in research training.
These competing interests are frequently labeled “conflicts of interest.”
Legally, this phrase is used to cover a broad spectrum of situations all of
which are characterized by the possibility of receiving something of finan-
cial or personal value that, in turn, may introduce bias or corrupt the judg-
ment of the scientist. Some federal funding agencies have sought to clarify
this terminology, using the phrase “financial conflict of interest.” Compet-
ing interests also extend beyond the sphere of direct financial gain, and
scientists must be aware of and deal with the dilemmas that such situations
create. These fall into two additional areas called “conflict of effort” and
“conflict of conscience.”
Competing interests permeate the science enterprise and must be ad-
dressed to ensure the responsible conduct of research. Rule makers usually
expand guidelines and regulations to preserve the integrity of the scientific
record and the trust of those who utilize the product of science to include
the appearance or perception of private or personal interests that might
doi:10.1128/9781555818487.ch7
209
210 Chapter 7
compromise objective judgment and professional practice. Governmental

agencies have enacted laws and promulgated rules in order to reassure the
sponsors of research and the consumers of scientific results that the data,
interpretations, and recommendations are free of bias. These laws and
rules constitute the framework within which science operates. Various
constituencies of the scientific community may set higher or more restric-
tive standards than the mandated minimal standard of conduct. The legal
framework that governs conflicts of interest focuses primarily on financial
conflicts of interest, although competition for prestige may equally influ-
ence the decisions of a scientist. Conflict of interest is not derived from
moral intuition but is a relatively recent ethical category, having been in-
troduced in the 1930s and first appearing in a court decision in 1949. The
scope of conflict of interest is still evolving, and it is a situation in which all
scientists are enmeshed. There is a pervasive, innocent view that all con-
flicts of interest must be avoided or eliminated in science, a so-called zero
tolerance level. Having a conflict of interest does not mean a lack of integ-
rity nor constitute corruption, but it requires actions to maintain trust and
confidence that the scientific record and practice are reliable. Each di-
lemma has unique elements, and one size does not fit all in identifying,
minimizing, and governing potential breaches in research integrity.
Conflicts of interest arise at all levels of the scientific enterprise, from
the most junior laboratory worker to the director of a research center. This
may involve corporate entities as well as individuals. Research workers are
subject to multiple demands on their time, have preferences on scientific
approaches, have beliefs about social values, are competing for recognition
in scientific achievement, and may possess information of substantial eco-
nomic value. Different competing interests are controlled by different
strategies, depending on the nature of the conflict and the obligations of
the party with oversight responsibility. Mature scientists, technicians, and
trainees alike are faced with balancing conflicting interests, most of which
are resolved by the individuals directly involved, applying the norms of the
immediate scientific community, whether academic, industrial, entrepre-
neurial, or governmental. Some competing interests have drawn the atten-
tion of news media and the public, especially those involving clinical trials,
leading employers, governing boards, research sponsors, and government
agencies to periodically reexamine their policies and procedures for ad-
dressing conflicting interests.
The professional life of a scientist involves choices on what problems to
study, what methods to use, which literature to cite, how to collect and orga-
nize data, how to interpret data, and how results and interpretations are to
be communicated and to whom. The scientist also faces choices on how
much effort to devote to various research projects, to teaching, to public
service, to professional service, to actual research, to identifying new
Competing Interests in Research 211
problems, to interpreting data, to publicizing achievements, to managing

and coordinating research, and to the search for funds to support the re-
search enterprise. Numerous factors influence the decision on how scien-
tists expend their effort. Some assignments come from the employer, such as
service on institutional review boards (IRBs), patent committees, and
conflict-of-interest committees. Some decisions about allocation of effort
are influenced by the reward system, and some reflect personal attitudes, the
background of the individual, and responsibilities to others. The reward sys-
tem for scientists is varied, including personal income, job security, prestige,
funding for research, recognition by the public, power, and a personal sense
of accomplishment. Most of the factors that influence the choices and be-
haviors of scientists are accepted as normal considerations in the decision-
making process. The scientist is expected to weigh the merits of rewards
that are given for conflicting goals and to arrive at decisions independent of
personal interests. In reality, this is an internally incompatible admonition.
Scientific tradition calls for openness, free inquiry, and free exchange of
ideas, whereas proprietary interests call for restricted access to research di-
rected to products of commercial value. At the present time, scientists are
encouraged to contribute to the financial stability of the employer and to
the economic development of the nation, especially job creation.
Universities and their faculties have entered into business relations with
the private sector for a number of reasons, many external to the university.
The public and government have seen commercialization of research as a
means (i) to create jobs that contribute to the gross domestic product,
thereby generating tax revenues; (ii) to attract domestic and international
investment; and (iii) to restore a favorable balance of trade by decreasing
purchases of foreign goods and products and enhancing sales of domestic
goods and products. Universities and faculty scientists have seen partner-
ships with business as an important source of funds for discretionary ex-
penditures, for research, and for university infrastructure and as revenue to
replace lost federal and state support for education, training, and staff. The
search for new sources of revenue has been viewed as particularly impor
tant during a period when declining endowments and reduced state and
federal appropriations threaten the continuity of research and research
training programs.
Contractual arrangements between industry and a university or an aca-
demic investigator not only raise questions about managing conflicts but
may also change the overall intellectual climate in which academic research-
ers work. Universities and faculty members with financial interest in com-
mercial ventures may lose objectivity in making decisions. An increasing
number of technical journals require authors to disclose to the editor and
readers any financial interest in a company that might be, or could be con-
strued as, causing a conflict of interest. These guidelines call for disclosure
212 Chapter 7
of sources of financial interests that could potentially embarrass an author if

the interests became known, whether or not there is an actual conflict of
interest. Academic science has extolled the virtue of free exchange of ideas,
sharing of data to accelerate scientific progress, and maintaining the quality
and reliability of science by critical peer review at all stages of the scientific
method. Individual scientists and university administrators may feel less in-
clined to discuss research at early stages if there is a perceived potential that
economically valuable intellectual property may be generated. Secrecy is
viewed by many as contrary to academic science, a position taken by many
socially conscious scientists as an argument against university-based re-
search funded by military agencies. There are divergent views about the im-
pact of secrecy on the progress of science. There are those who feel that
progress is retarded by the failure to have free exchange of ideas and data.
Others hold that the added resources for research with commercial value
allow more workers to be recruited to the field, and that this accelerates
achieving applied goals. There are some data indicating that research teams
receiving the majority of their support from industry publish fewer peer-
reviewed articles than those receiving modest amounts of industrial support.
Moreover, there is evidence that papers published by investigators without
any industrial support have greater scientific impact than those published by
colleagues receiving support from industry.
Many science educators have expressed concern about the effects of in-
dustrially sponsored research on research training. One concern is that the
attention devoted to scholarship with economic potential will lead research
trainees to develop research strategies for short-term goals and modest
extension of knowledge rather than formulating truly novel questions
leading to major advances and changes in scientific thinking and creative
problem solving. A related concern is that universities and faculty mentors
will use research training to subsidize their commitments to industrial
sponsors and will give less attention to nurturing curiosity and innovation.
The fear is that mentors will prize well-executed, routine studies over cre-
ative exploration that goes beyond tried and true methodologies. In fact,
students, through their tuition and fees, and benefactors of the university
may be unwittingly subsidizing commercial ventures. On the other hand,
participation in applied research introduces trainees to concepts of quality
assurance and exposes them to the process of translational research. More-
over, experience in industrially sponsored research may lead to rewarding
employment opportunities.
Finally, there is a concern that a growing climate of secrecy and eco-
nomic competition is contributing to a loss in public confidence in the in-
tegrity of science and scientists, if not an actual deterioration in the quality
of science. It should be noted that there is no established correlation be-
tween recent incidents of scientific falsification, fabrication, and plagiarism
and economic conflict of interest. Many of the procedures demanded in

research for industry (for example, careful record keeping and review of
results by a colleague) are believed to prevent falsification and fabrication
of data. Nevertheless, the perception that scientists today are less rigorous
and less self-critical is widely held by the public, news media, legislators,
and the scientific community itself. It is clear that a scientist is subject to a
range of conflicting pressures that have different implications, including
penalties for transgressions. This chapter examines these conflicting pres-
sures in research, which we categorize as (i) conflicts of effort, (ii) conflicts
of conscience, and (iii) conflicts of interest. Although this last category is
typically used to describe conflicts that involve an interest of financial or
tangible value, other conflicts that don’t fall into the first two categories
will be included in the discussion of conflict of interest.
Conflict of Effort
Members of the scientific community enter into research settings with de-
fined expectations. A trainee expects to receive instruction, counseling, and
guidance. A supervisor who has many obligations may not provide ade-
quate direction as measured by the amount of time or quality of advising of
the trainee. Faculty members are called upon to serve on institutional, pro-
fessional, and civic committees; they also strive to excel in their scientific
scholarship by writing papers and grant applications and presenting out-
side seminars and lectures; and they have assigned duties in teaching and
administration. Unscheduled responsibilities such as mentoring research
trainees often suffer in the face of multiple demands on faculty time. Train-
ees, too, are subject to multiple demands on their time; formal course
work, examinations, financial obligations, and interpersonal relationships
compete with time spent designing, conducting, and analyzing scientific
studies. Perhaps the most stressful conflicts of commitment for trainees
relate to financial pressures and personal responsibilities.
Conflict of effort is distinctly different from conflict of interest, al-
though the same set of external circumstances may precipitate both dilem-
mas. A conflict of effort arises when demands made by parties other than
the primary employer interfere with the performance of the employee’s
assigned duties in teaching, research, and service. In general, scientists are
expected to notify their supervisor of outside responsibilities, to seek per-
mission in advance in most instances, and to report annually on outside
professional activities, whether paid or not. Scientists with successful re-
search programs are asked to present seminars and lectures at other insti-
tutions, at conferences, and at meetings. They are also asked to serve on
editorial boards, research advisory panels, and policy advisory boards.
They may be asked to teach in short courses and to offer methods
214 Chapter 7
workshops for peers or professionals in related fields. The university em-

ployer encourages some participation in these activities and uses them as
criteria in evaluation for promotion, salary increases, and tenure. Good
things can be carried to excess, however, and virtually every research-
intensive university has a number of faculty members spending an unac-
ceptable amount of time away from the campus. A conflict of effort is
serious when the scientist is not available for scheduled classes, for student
advising, for guidance of research trainees, for oversight of research proj-
ects and resource accountability, and for assigned administrative and ser-
vice duties. Increasing federal mandates have led to an erosion of the
faculty’s time for scholarship as a result of service on an IRB, the Institu-
tional Animal Care and Use Committee (IACUC), an intellectual property
committee, or a conflict-of-interest review committee. All qualified aca-
demic faculty members must recognize their obligation to share in the
governance of their institution, but administration has a responsibility to
provide adequate staff and technology for efficient use of faculty time and
to establish rotations so that the burden is fairly distributed.
Most universities allow 20% of a faculty member’s effort or 1 day per
week for consultation and outside professional activity. Some entrepre-
neurial faculty members try to define this limitation only in terms of paid
consulting and income generated by outside professional activity and do
not report professional service or speaking engagements that are unpaid or
reimbursed for expenses. This is not the intent of policies on outside pro-
fessional activities, which are more concerned about faculty effort than
faculty compensation. There are those who believe that it is the neglect of,
or inattention to, assigned duties at the employing institution that has led
to the perceived increase in allegations of scientific misconduct.
To avoid a conflict of effort, scientists ought to review their assigned
duties with their supervisors, discussing the effort involved and the value
to the department, institution, or profession. In general, the immediate
supervisor (for example, a departmental chair) is responsible for orches-
trating the resources of the unit and for the appropriate deployment of
personnel. The immediate supervisor, however, is not usually the person
with primary responsibility for making decisions on conflict of interest,
although immediate supervisors have a role in alerting the administrator
responsible for managing conflict of interest of a potential problem. Im-
mediate supervisors may lack the legal knowledge to interpret conflict-of-
interest regulations.
Some of the more difficult conflicts of effort also involve financial con-
flicts of interest. Scientists who establish for-profit companies may experi-
ence increasing demands on their time that interfere with their ability to
fulfill assigned duties. What makes these decisions difficult is that the fac-
ulty members may be on-site, but their effort may be directed to the
interests of their private companies rather than toward the needs of the
primary employer. In addition, the faculty member may meet scheduled
assignments but arrive inadequately prepared. The faculty member may be
inattentive to his or her advisory roles for students, staff, and research
trainees. The immediate supervisor has the responsibility to counsel the
faculty member about his or her concerns. After mutual agreement, if pos-
sible, on the extent of the outside commitments, a date for a follow-up re-
view should be set. If the faculty member and the immediate supervisor
cannot reach a mutual accord, the matter may have to be considered by a
grievance or disciplinary process.
Most conflicts of effort arise from the enthusiastic aspirations of scien-
tists to gain acceptance from their peers and to achieve national and in-
ternational stature as investigators, rather than secondary to financial
conflicts of interest. Universities in particular send mixed messages to
young faculty, placing a premium on professional recognition. Faculty
members usually respond well to discussion on the expected balance of
effort among teaching, research, and service. It is too much to expect
young scientists to find the proper balance without role models, mentors,
and guidance.
Scientists who receive a portion of their salary from federal research
grants or contracts find it difficult to accept that effort is defined in terms
of the fraction of time devoted to the sponsored project, with the denomi-
nator being the total time spent in professional pursuits and not time in
hours or days. Scientists typically devote 60 hours per week to their profes-
sional development, including service to advisory bodies, participation in
professional organizations, and outside lectures. Auditors of effort reports
require that an activity be assigned to only one category and do not recog-
nize that mentoring and research can occur simultaneously. Accordingly,
25% effort on a project for a scientist devoting 60 hours per week to all
professional endeavors computes, in the mind of a federal auditor, to 15
hours per week devoted to the project. Scientists face the dilemma of dif-
ferentiating between their assigned institutional responsibilities and com-
pensated effort and their total effort, which includes activities for personal
satisfaction and achievement.
Conflict of Conscience
Science is a values-free, global process leading to a progressively better

understanding of nature. Scientists, sponsors of research, and those apply-
ing scientific knowledge, however, are values laden, with beliefs about what
is right and what is inappropriate. Deeply held personal beliefs are appro-
priate determinative factors in individual choices. The dilemma arises
when one’s personal beliefs are imposed on others. Today, biomedical
216 Chapter 7
scientists universally agree that it is inappropriate to test the toxicity of

drugs in vulnerable, uninformed human subjects such as patients with
mental illness and institutionalized or incarcerated persons. Similarly, re-
search aimed at the deliberate development of biological weapons is ab-
horred by researchers and professional societies. On the other hand,
research and research results that could be used to provide new knowledge
to diagnose, treat, or prevent infectious diseases could also be used to cre-
ate novel biological weapons by individuals or groups with evil intent. De-
bate over whether such research results should be censored continues on
the moral playing field. A similar example is provided in the debate over
the benefits and concerns of nanotechnology research. The promise of ap-
plying nanoscale technology to solve health, environmental, and even ter-
rorism problems has been broadly promoted. Yet some argue that
nanotechnology applications may have unforeseen risks when used for
some of these purposes. Indeed, organizations and scholarly publications
have emerged that focus on the ethics of nanotechnology research and ap-
plication. Finally, personal beliefs continue to intrude into the content of
curriculum and textbooks about the origin of species and into research on
embryonic stem cells. Failure of the scientific community to reach una-
nimity over issues such as these allows researchers to hold opposing views
that can have an impact on their objectivity. Such personal views can im-
pose an unrecognized bias that may inappropriately affect reviewing of
manuscripts and proposals, writing and reviewing of policy, decision mak-
ing that bears on professional development, and a variety of issues falling
under the responsibilities of research training.
A conflict of conscience does not involve financial reward or personal
gain. Conflicts of conscience become evident when a scientist with deeply
held personal views is asked to sit in judgment of projects whose very na-
ture is unacceptable to him or her. A conflict of conscience arises when the
convictions of an individual are allowed to override scientific merit in
reaching a decision. A scientist who abhors abortion and the use of fetal
tissue may be unable to act dispassionately on any manuscript or grant ap-
plication that utilizes fetal tissue. A scientist who opposes all research using
laboratory animals may be unable to find merit in any study or report that
is based upon such use. These very personal views may not be known to
colleagues at the same institution or elsewhere. Quite often there will be
differences of opinion on whether a conflict of conscience is viewed in a
positive or negative light. To date, there is no agreement on whether or not
to, or how to, manage conflicts of conscience. As with other biases in re-
viewing manuscripts and grant applications, it is likely that responsible
leadership will try to identify and resolve any behavior that shows a pattern
markedly at variance with other members of the deliberative process. At-
tempts to resolve conflicts of conscience as they relate to academic matters
are apt to raise issues of abridgment of academic freedom. In the academic

health science center, delivery of patient care is increasingly confronted
with changing expectations of medical ethics with respect to premature
births, resuscitation, life support systems, allocation of limited medical re-
sources such as organs for transplantation, pain control, and suicide. Med-
ical ethics committees have been formed in academic health science centers
and other large health care systems, but similar committees or procedures
to deal with scientific conflicts of conscience are rare. Public interest
groups are increasingly insisting that nonscientists such as religious lead-
ers, ethicists, and attorneys be included in the membership of institutional
bodies that review laboratory animal use, human subjects committees, en-
vironmental and occupational health and safety committees, medical ethics
committees, and conflict-of-interest review committees.
Conflict of Interest
Orientation
Basic research workers have a tradition of free inquiry and free exchange of
ideas, united in a shared purpose to create knowledge, to critique existing
knowledge, and to disseminate knowledge. The image of the eccentric sci-
entist lacking worldly aspirations and living in a cloistered ivory tower has
given away to that of a greedy entrepreneur, insensitive to the public good.
Science and science administrators have promised, and the public has
come to expect, products of research and technology that improve the
quality of life and spur economic growth. The public has called upon sci-
entists to discover means to prevent or cure cancer, diabetes, heart disease,
mental illness, aging, and moribund obesity and lavishes great rewards
upon those who appear to achieve these goals. It is a small wonder then
that some scientists have lost their innocence and fallen afoul of matters
related to conflicts of interest.
Definitions
“Conflict of interest” or “financial conflict of interest” is a legal term that
encompasses a wide spectrum of behaviors or actions involving personal
gain or financial interest. The definition of conflict of interest, including
the scope of persons subject to the provisions in a code or set of rules and
regulations, varies according to state and federal statutes, case law, con-
tracts of employment, professional standards of conduct, and agreements
between affected parties or corporations or both. A conflict of interest ex-
ists when an individual exploits, or appears to exploit, his or her position
for personal gain or for the profit of a member of his or her immediate
family or household. The identification of members of the immediate fam-
ily and household is in a state of flux, but these individuals include the
218 Chapter 7
spouse and minor children living at home. Case law is evolving with re-
spect to dependent parents, adult children living at home, and “significant
others.” Another critical component of conflict of interest pertains to the
undue use of a position or exercise of power to influence a decision for
personal gain. Many conflict-of-interest codes also prohibit activities that
create an appearance of a conflict of interest. Full disclosure may be the
only means to combat perceptions of undue influence.
For researchers, the federal policies on conflicts of interest that have the
broadest reach are those of the National Science Foundation and the U.S.
Department of Health and Human Services. The latter policy applies to
research scientists and institutions receiving funds from agencies of the
Public Health Service (PHS), including the National Institutes of Health
(NIH), the world’s largest grant funding agency. The PHS policy, published
under the moniker of “Promoting Objectivity in Research,” was signifi-
cantly revised and reissued in the 2011 Federal Final Rule on Conflict of
Interest. This policy requires researchers to disclose all significant financial
interests. The threshold for a significant financial interest is $5,000 and en-
compasses all institutional responsibilities, not just those related to a feder-
ally funded project. The institution must report to the NIH the name of the
investigator with a conflict of interest and how it is managed, the name of
the entity, the nature of the conflict, its dollar value, how the conflict relates
to sponsored research, and the basis on which the institution determined
that there is a conflict. The information collected on significant financial
interests must be publicly accessible on a website or by a written response to
a request within 5 days. Each PHS investigator must complete training ev-
ery 4 years, and the institution must conduct a retrospective review of non-
compliance events and submit a report to the PHS awarding unit.
Conflict of interest is distinctly different from conflict of effort and
conflict of conscience. Conflict of interest is also distinctly different from
bias in research, which is the inability or unwillingness to consider alterna-
tive approaches or interpretations on their merits. Scientists sometimes
develop strong preferences for particular research techniques or become
deeply vested in a particular working model to the exclusion of alternative
explanations. The origin of these prejudices may be subconscious, or at
least unrecognized, reflecting past training, cultural background, experi-
ence, or group dynamics. Legislative bodies, governing boards, and the
public have tended to define and specify penalties for conflict of interest in
science by a unitary code. There is little recognition of a hierarchy of in-
jury to the public well-being. Clearly, the public is harmed to a far greater
extent when a conflict of interest is allowed to influence a clinical decision
to market a drug for human use than when it is allowed to influence the
decision to purchase an item of laboratory equipment from a particular
vendor or to hire a relative to work in the laboratory of a scientist.
The entrepreneurial climate

The federal government has taken a number of actions that encourage
universities to enter into agreements with the private sector, thereby creat-
ing circumstances that ensnare faculty in potential or real conflict of inter-
est. The 1980 Bayh-Dole Act allows a federal contractor to take ownership
of the property rights for inventions created in the pursuit of a grant or
contract. The Bayh-Dole Act specifies that income from the exploitation
of these intellectual properties must be shared with the inventor and the
remainder must be used for scientific research or educational purposes.
The Federal Technology Transfer Act of 1986 extended the incentives for
collaboration with industry to technology developed in a government lab-
oratory. This act allows government laboratories to enter into cooperative
research and economic development agreements with other governmental
agencies and with nongovernmental for-profit and nonprofit organiza-
tions. Income from inventions developed under such an agreement, or
from other royalties negotiated with a commercial entity, is shared with
the government inventor, and the remainder is to be used by the partici-
pating company for technology transfer. The Bayh-Dole Act does not, as
widely believed prior to the Supreme Court ruling in Stanford v. Roche in
2011, diminish the priority of rights of inventors when an invention is con-
ceived or reduced to practice with the support of federal funds. At issue
was the primacy of two agreements by the inventor: (i) a standard univer-
sity intellectual property agreement affirming the intent to assign to Stan-
ford University intellectual property developed using federal funds and (ii)
a confidentiality agreement with an industrial partner that included an as-
signment of intellectual property produced as a result of the partnership to
the company. In reality, the Supreme Court addressed the duality of as-
signment of the invention that arose because the inconsistencies between
the two agreements were not resolved in a timely manner.
The biomedical research enterprise expanded dramatically from the
mid-1950s to the mid-1970s. There followed periods in which funding from
federal agencies such as the NIH and the National Science Foundation re-
mained at the same level when adjusted for inflation. The perception that
federal funds for basic research have become increasingly competitive has
led academic administrators to encourage research workers to seek funding
from industry. Indeed, the amount of industrial money invested in academic
research has increased from about $5 million in 1974 to hundreds of mil-
lions of dollars per year. Over the past 2 decades, health care costs and other
demands on state and federal funds have increased sharply, decreasing the
relative investment in research and forcing scientists and research adminis-
trators to look for alternative sources of funding. Concurrently, biotechnol-
ogy, bioinformatics, genomics, proteomics, and nanotechnology have
emerged as significant economic forces, with the potential to contribute
220 Chapter 7
substantially to the gross domestic product and to the international balance

of trade. Scientists have been encouraged by government and academic em-
ployers to enter into university-industry ventures and to be entrepreneurs in
commercializing new technologies. University employers have seen tech-
nology transfer as a new revenue stream to replace decreasing support from
state and federal agencies. Local communities have developed economic
plans in which research parks are means to provide jobs, tax revenues, and
economic vitality for their regions.
Gifts and gratuities

Conflict of interest is usually thought of in terms of abuse of position for
direct financial gain. It would be considered a conflict of interest if a scien-
tist used his or her position to unduly influence the decision to buy sup-
plies from a company in which an immediate family member held a direct
financial interest. It is also wrong to accept an expensive gift as an induce-
ment to select a particular vendor, but the line between inappropriate in-
ducements and acceptable gratuities is ambiguous. Scientists have
considerable influence on procurement decisions, including equipment
and services. Historically, vendors have used a number of inducements to
convince scientists and purchasing agents of the merits of their products or
customer services. Exhibitors at national professional meetings hold break-
fasts and receptions and give out carrying cases and a variety of mementos
to establish product recognition in the minds of scientists. These modest
gifts and gratuities have become routine, accepted, and expected. Vendors
also give books and video media and host formal lunches and dinners. At
some point, meals and entertainment cross over from token gifts to sub-
stantial inducements. At the present time, frequent flyer credits are a
widely used inducement about which different employers take different
positions. There is no doubt that a few scientists select an airline carrier
according to accumulation of frequent flyer credits rather than cost or
convenience. When this occurs, the scientist has allowed a personal inter-
est to conflict with the interests of the employer.
There is no sharp boundary between gifts and compensation. Is the bio-
medical scientist who is fully reimbursed to attend a conference receiving
compensation, a gift, or a gratuity? Scientific leaders are sometimes invited
to attend a conference, not to give a formal lecture but to lend prestige and
credibility to the program. Bench scientists may be invited to a clinical
conference to lend the aura of solid scientific underpinning even though
the scientists may have no direct experience with the drug or clinical trial.
Local scientists may be invited to a conference to build community good-
will or to fill the audience, or both. There are no universally applicable
guidelines to delineate the boundary between professional courtesy and a
perquisite that has personal fiscal implications and the potential to
influence a decision. Clearly, America’s free economy relies heavily on ad-

vertising, promotion, and inducements to influence purchasing choices.
Scientists are confronted with the dichotomy that what is proper as an in-
ducement to purchase a home television is usually not proper as an induce-
ment to influence selection of a television monitor at work.
It has been proposed that physician-scientists and other clinical investi-
gators ought not to accept any gift, regardless of how trivial, from a phar-
maceutical representative. The practice of providing free samples to
clinicians has also been called into question. Some organizations have in-
stituted the practice of collecting sample prescriptions and pooling them
for use in free clinics. Pharmaceutical companies have also contributed
drugs and hand sanitizers for use during clinical trials to develop name
recognition and goodwill with both participants and clinical personnel.
Pharmaceutical companies have produced attractive, informative pam-
phlets about detection and treatment of disease, which are widely distrib-
uted, often in conjunction with a nonprofit advocacy organization.
Marketing studies have established that distributing free samples is gener-
ally a cost-effective means for promoting sales that rarely rises to the level
of a significant financial inducement. There is wide variation in institu-
tional policies on accepting free samples and trivial gifts, illustrating that
the normative standards are in a state of flux.
Compensation
Academic scientists are employed by their institutions to teach, to carry
out research, and to render service to the institution, the surrounding
community, and the profession. The relative effort in each activity varies
according to the mission of the institution and according to strategies to
effectively utilize the talents of the faculty. Faculty members who are ac-
tively engaged in research have the opportunity to present their results to
colleagues, including those who are employed by for-profit corporations.
In general, universities encourage faculty members to present seminars
and lectures at other research centers and condone payment of speaker’s
fees and full reimbursement of travel expenses. Scientists whose research
bears upon commercial application of a product may be invited to confer-
ences targeting groups that influence purchasing decisions. A scientist
studying the mechanism of action of an antibiotic may be invited to partic-
ipate in a conference sponsored by the pharmaceutical company distribut-
ing the antibiotic, targeted to physicians who will prescribe the drug. The
scientist may be paid a generous speaker’s fee or honorarium and provided
luxury travel and lodging accommodations. There is a broad spectrum of
speaker’s fees, honoraria, and travel accommodations, some of which have
attracted the attention of the Internal Revenue Service as well as the pub-
lic. Honoraria and speaker’s fees above a modest level are increasingly
222 Chapter 7
scrutinized by employers, especially IRBs and conflict-of-interest review

committees.
A consultantship is a formal agreement between a scientist and a corpo-
ration other than the primary employer, and usually with a for-profit com-
pany. Consultants have played critical roles in technology transfer, and
academic scientists gain insights into the needs of industry for personnel
and basic research. In general, consultantships have been beneficial to all
parties: industry, the university, and the individual scientist. Consulting ar-
rangements are usually reviewed and subject to approval by the employer.
There are a number of valid concerns about consulting, however. A scientist-
consultant must not transmit to a private business any information, records,
or materials generated as a result of research sponsored by philanthropic
foundations or governmental agencies unless the same information, records,
or materials are made readily available to the scientific community in gen-
eral. This guideline does not preclude appropriate contractual arrangements
among the research sponsor, the research institution, and a private firm, par-
ticularly in the context of a licensing agreement. A consultantship should be
based on the collective knowledge and experience of the scientist and not
constitute a means to gain access to privileged or confidential information
available to the scientist by virtue of his or her employment or professional
activities on advisory boards. A scientist-consultant must assiduously avoid
the appearance of a conflict of interest whenever the employer is negotiat-
ing a contract with the private organization with which the scientist is a paid
consultant. Scientist-consultants have the responsibility—or, in many cases,
the requirement—to disclose to their employers any agreements to perform
consulting services. Moreover, scientist-consultants should not participate
as evaluators of grant or contract proposals submitted by companies for
which they serve as consultants.
Multiple pay for one job

As relationships for the conduct of research become more complex, several
sources of financial support are used to pay for research, especially that
having potential commercial value. A university-based scientist, paid pri-
marily by institutional funds, may conduct research on a project supported
by a federal agency such as the NIH. In addition, the scientist may hold a
paid leadership position in a venture company that has a contract with the
university, supporting research in the same laboratory for the same or a
closely related study. It may not be clear whether or not the scientist is
being paid by his or her employer and by the for-profit corporation for
technical guidance of the same research. Most employing universities in-
sist on documentation that its employees are not being paid twice for the
same job assignment. This usually involves documentation of the manage-
ment role of the scientist in the leadership of the venture company.
Courseware
Scientists have the opportunity, even the responsibility, to disseminate in-
formation. Quite often, this dissemination of information takes the form of
instructional material: textbooks, computer programs, Web pages, and
video media. The copyright on scholarly scientific works traditionally has
been retained by the creator until assigned to a publisher or distributor
(see chapter 9). There are advocates arguing that authors of technical man-
uscripts ought to retain the copyright on their articles and provide the
publisher with a limited license to produce, distribute, and archive the
work. There is no trend to alter the practice of creators’ retaining the
copyright on creative works unrelated to job assignments. Some educa-
tional institutions, however, hold that instructional materials, especially
those in electronic format, are generated as assigned work with consider-
able investment of resources by the employer. Courseware and sophisti-
cated management software potentially have substantial commercial value.
Friction between creators and employers about distribution of revenue
from the sale or licensing of electronic scholarly materials is not rare, and
many research universities have recently revised their copyright policies to
provide for revenue sharing. There is considerable variation among insti-
tutions in the policies developed. The issues addressed in these policy
statements include (i) the extent to which the current employer may con-
tinue to use and share revenue from copyrighted instructional material af-
ter the creator leaves the institution or takes another assignment within
the institution; (ii) the rights of the creator to use, sell, or license copy-
righted instructional material, particularly to a competing organization;
(iii) the rights of creators to restrict use of their voice and their personal
images in electronic courseware; and (iv) the rights of the employer to as-
sign other employees to modify, edit, and update electronic courseware.
During this period of rapidly evolving practices, the employee-creator is
advised to develop a memorandum of understanding with the supervisor
and the employer’s intellectual property officer.
Nepotism
Most state and federal agencies are subject to statutes or have rules that
preclude a scientist from hiring or supervising an immediate member of
his or her family or of the same household. These statutes are, in part,
rooted in strategies to ensure fair access to employment opportunities.
One of the most frequent nepotism practices is hiring high school-or
college-age progeny by an investigator, particularly for part-time and sum-
mer work. This practice is clearly contrary to equal access to employment
opportunities and career development for underrepresented groups. In ad-
dition, selection of immediate members of the family for employment con-
stitutes use of a position of authority for personal gain. The boundaries of
224 Chapter 7
propriety are not always well delineated. A few organizations prohibit

members of the same family from working in the same department, even if
neither party has direct authority over hiring, promotion, or salary. With a
growing number of two-career families, this limits the ability of some in-
stitutions to recruit highly competent professionals. A few institutions, on
the other hand, have made concerted efforts to recruit two-career families.
There are risks, however. The careers of the two individuals may not ad-
vance in parallel, and a two-career couple may make personal decisions
about their relationship that cause tensions in the workplace. The organi-
zational distance between members of a family or household in the work-
place is not well defined. Is a faculty member permitted to select a member
of the household of a departmental chair, dean, or vice president for a po-
sition in the faculty member’s laboratory? The definition of a member of
the immediate family or household has occasionally been broadened to
encompass individuals with a significant personal relationship but who are
not blood relatives or married. Nepotism regulations will undoubtedly re-
main in a state of flux as the goals of equal access to employment and ca-
reer opportunities conflict with the career aspirations of two- career
families. The American Association of University Professors has developed
guidelines for policies and practices that enable members of an immediate
family to serve as professional colleagues.
Scientific conflict of interest

A successful scientist is afforded the opportunity to participate in the
decision-making process that influences the allocation of resources. The
peer review system, which is considered one of the essential safeguards for
the quality of science, can be abused to serve a personal interest. Members
of editorial boards have occasionally been accused of delaying publication
of the results of a competitor in order to gain priority and recognition that
strengthens applications for funding from granting agencies. Members of
editorial boards have also been accused of being uncritical of manuscripts
that present results favoring a method or product in which the reviewer
has a personal interest. Authors sometimes feel that reviewers have been
unduly critical of manuscripts that describe in a favorable light products
competing with one in which the reviewer has a personal interest. There is
growing concern within the scientific community about the prudence of
allowing employees of commercial firms to review manuscripts evaluating
methods or products having economic value or potential. Many journals
that publish articles related to commercial methods or products are asking
both authors and reviewers to disclose their financial interests. In most
instances, scientists feel that these requirements impugn their integrity
and argue that their financial interests are proportionally so modest that
they cannot be considered a “substantial personal interest.” Nevertheless,
concern about the perception of conflict of interest is growing, especially

in biomedical fields, and demands for financial disclosure by scientists have
increased.
Most national grant review panels and advisory boards have established
conflict-of-interest guidelines. The NIH asks individuals evaluating grant
or contract proposals and applications to avoid participation in the review
of submissions from organizations in which they (i) have a financial inter-
est; (ii) are directors, officers, consultants, or employees; or (iii) are pro-
spective employees or shareholders. The admonition extends to spouses
and minor children, and even to circumstances in which there is only a
perceived conflict of interest. Members of NIH study sections are not al-
lowed to review applications from their own institution or those of a for-
mer student, professional collaborator, close personal friend, or colleague
with whom the evaluator has long-standing professional or personal dif-
ferences. If the excluded category is too large, the most knowledgeable re-
viewers are not allowed to participate in the decision-making process. The
risk of inept evaluation by less- informed reviewers must be weighed
against the adverse effects of a perceived conflict of interest. Unsuccessful
applicants for research grants occasionally feel that a competitor on a study
section has been unduly critical in order to gain an edge in recognition and
future funding. The NIH has developed an appeals process to handle com-
plaints of alleged unfair review of grant applications.
Scientists are increasingly being called upon to serve as experts for exec-
utive, legislative, and judicial deliberations. In addition, scientists have
sought opportunities to testify before legislative committees that appro-
priate funds for research and higher education. Legislators, in turn, may
sometimes view scientists as lobbyists or trade union representatives, advo-
cating self-interest rather than the public interest. The scientific commu-
nity itself is divided over the propriety of direct appeals to fund scientific
projects outside of the peer review system by congressionally earmarked or
“pork barrel” appropriations. Scientists engaged in expert testimony be-
fore the courts have encountered an adversarial culture unlike scholarly
debate. Sometimes scientists are unwilling expert witnesses who have been
subpoenaed to present evidence and research results. Scientists who will-
ingly serve as expert witnesses for pay have been accused of conflicts of
interest and of giving misleading information. Advisory boards of execu-
tive agencies have increasingly insisted on disclosure of past and present
financial interests and have excluded persons with financial interests in the
product or the company. The threshold for determining a perceived con-
flict of interest varies and sometimes is set so low that the guideline leads
to the exclusion of scientists whose financial interests have been limited to
speaker’s fees and associated reimbursement of expenses. The assessment
of the risk of advice from a less knowledgeable panel against the adverse
226 Chapter 7
effects of perceived conflict of interest is often made in the context of the

political sensitivity of the issue rather than the needs of the decision-
making process.
Academic conflict of interest

Academic scientists have special responsibilities to protect academic free-
dom, to disseminate knowledge, to maintain academic standards, to cri-
tique the current state of knowledge, to synthesize existing knowledge, and
to use knowledge to solve basic and applied problems. Faculty members
are increasingly called upon to link the educational process to fund-raising
and revenue-generating enterprises. Research faculty members are some-
times encouraged to market their expertise by organizing and presenting
profitable workshops, particularly for business firms, under the auspices of
the university. In other instances, faculty members have independently de-
veloped for-profit short courses and used the net earnings as a source of
personal income. At some point these entrepreneurial activities, which are
not restricted to academic scientists, have the potential to constitute a con-
flict of interest in which the faculty members utilize the reputation and
even the resources of their employer for personal gain. In addition, the
time and energy devoted to these activities may lead to a conflict of effort.
Corporations and wealthy individuals may want to use their resources to
influence the direction of academic programs. An agribusiness corporation
may want to endow a chair in human nutrition, and a grateful patient may
want to endow a chair in transplantation biology. Universities have devel-
oped sophisticated infrastructures to enhance these sources of support.
Universities give prizes to alumni and business leaders, not totally without
some consideration that the grateful recipients will generously support the
university in the future. Gifts that are consistent with the mission of the
university are aggressively sought. Agreements that proffer undue personal
benefit to the donor, the university, or an employee of the university may
constitute a conflict of interest.
Academic degrees have economic value, and not uncommonly, progress
toward completion of a degree becomes an issue in a conflict of interest.
For example, a faculty advisor might extend the course of study of a stu-
dent to benefit a corporate sponsor. Companies sometimes use opportuni-
ties to obtain advanced degrees as an employee benefit and perquisite to
enhance retention. Companies usually place limits on the time that they
will pay for educational leaves or release time. The duration of educational
leaves is usually inadequate for the average student to complete the degree
program in the expected depth. The student and the student’s supervisor in
the company sponsoring the educational leave may put pressure on the
advisor to make exceptions and to waive requirements. These pleas may be
linked to hints of benefits to the advisor and institution once the employee
graduates and returns to his or her regular or more influential position in

the company.
Insider trading
Scientists conducting research sponsored by industry or who are engaged
in consulting usually have completed confidentiality agreements. The sci-
entist agrees to avoid discussing proprietary information in the presence of
unauthorized parties, including family members and friends. Proprietary
information includes, but is not limited to, the company’s future plans and
ideas, trade secrets, financial information, technical and research data, op-
erating strategies, internal business processes, and technologic improve-
ments that are not generally known to the public. In the course of
proprietary research or consultation, a scientist may become aware of in-
formation relating to the economic value of a product or potential prod-
uct. A toxicologist, for example, may be involved in a project in which a
serious adverse effect of a marketed drug is discovered, and this result will
jeopardize the continued approval of the drug. A chemical engineer who is
consulting for a drug manufacturer may learn that the last hurdle to large-
scale production and formulation of a new, much-needed drug has been
overcome. By virtue of the paid relationship between the scientist and the
company, the scientist is an “insider” and is restricted from using confiden-
tial information to personal advantage, that is, to sell stock of a company
whose drug faces liability suits or loss of market share or to buy stock of a
company on the verge of introducing a highly valued new drug.
Intramural conflict of interest

Faculty members are called upon to review the accomplishments of col-
leagues on many occasions. Perhaps the most onerous of these is service on
a tenure committee. As with other peer review processes, there is a need to
keep favorable and unfavorable bias to a minimum. During a period with
increased emphasis on team research, it may not be appropriate for a col-
laborator to serve on a peer review committee, yet there must be adequate
expertise to assess the candidate’s achievements. Colleagues are also called
upon to serve on patent review committees that approve or disallow insti-
tutional investment in an investigator’s intellectual property. In that funds
for institutional subsidy of technology development are limited, a commit-
tee member is acutely aware that each obligation made may jeopardize
funding for his or her own invention. Likewise, service on an IRB or IA-
CUC may consciously or subconsciously trigger scientific conflicts of in-
terest and certainly contribute to a conflict of effort as the committee
member strives to meet institutional obligations at the highest level. IRB
and IACUC members may be under pressure to approve protocols with-
out adequate review to meet deadlines for research proposals or to approve
228 Chapter 7
protocols or waivers that they believe place the experimental subjects at

undue risk. Compliance with conflict-of-interest policy creates its own set
of conflicts of interest in that researchers are required to share personal
financial interests that they do not wish to have known by others, even
though there is a pledge of confidentiality.
Institutional conflict of interest

Institutions acquire financial interests in the private sector through (i)
earnings on intellectual property, (ii) exclusive contracts with industry, and
(iii) equity ownership in a for-profit company. In general, the interests of
scientist-inventors and their employing institutions are congruent with re-
spect to earnings on intellectual property. When the scientist and the insti-
tution share in revenues based on a predetermined rate, the more successful
the product, the better each fares. There are several areas in which the
scientist and the institution may have conflicting interests. The scientist
may seek a generous consulting arrangement as part of a licensing agree-
ment. The institution may have limitations on this type of consulting ar-
rangement or may seek other concessions from the company seeking a
license at the expense of the scientist’s self-interest. Similarly, scientists
may seek research and development funds for their laboratories as a part of
licensing agreements. This entails assigning rights of first refusal to the li-
censing company, a commitment about which the scientist and the em-
ploying institution may have divergent views. In addition, the institution
may have restrictions on this type of grant or contract, particularly if it
involves assessment of the efficacy of the invention or product. Moreover,
the institution and the licensing company may feel that the invention will
be developed more rapidly and to a greater extent without the parallel par-
ticipation of the inventor.
Some institutions have entered into exclusive contracts with industry to
give preferential access to research results to a company. The company
usually awards the institution a large multiyear umbrella award. Invention
disclosures are called to the attention of the sponsoring company, and
technology transfer officers of the university may encourage scientists to
work in areas of interest to the company. Several conflicts are arising from
these blanket agreements between a company and an institution. Any one
company, regardless of its size, has a reasonably well-defined scope. Scien-
tists whose inventions lie outside the interest of the company may not re-
ceive adequate assistance from their employing institution in patenting
and licensing efforts. There is a potential conflict between scientists whose
work is supported by other commercial firms and the institution, which is
striving to fulfill its contract with the company with an exclusive agree-
ment. There is growing concern, too, that funds from government agen-
cies and from tax-exempt foundations are being used to preferentially
subsidize the research and development of for-profit companies, many of

which are foreign owned.
Equity interests
Members of the academic scientific community are receiving conflicting
admonitions from government, employers, and the public. Scientists are
urged to accelerate the transfer of basic science knowledge into application
and commercialization. Advocacy groups in particular have expressed con-
cern that science is not sufficiently responsive to public need and that the
lag from laboratory discovery to application is too long. National, state,
and local governments and business communities have turned to research
as the means to maintain economic competitiveness. Scientists quickly
learn that most of their research discoveries with potential for commer-
cialization require substantial development before established industry is
willing to invest in university-generated intellectual property. Scientists
who are convinced of the market potential of their inventions soon find
that the patent process and product development are expensive and time-
consuming. In addition, most scientists lack experience in writing a busi-
ness plan and in securing venture capital. Quite often, the scientist will
enter into an entrepreneurial corporation as an equity owner. Scientists
inevitably feel that they are the most qualified to lead the technical devel-
opment of the invention. It is at this stage that concerns about conflict of
interest arise. In general, public institutions restrict the circumstances un-
der which scientist-entrepreneurs may receive grants or contracts through
their universities from a corporation in which they are in management
positions or equity owners or both. Private institutions usually have fewer
restrictions on faculty entrepreneurship than do public institutions. It is
imperative that faculty entrepreneurs disclose possible conflicts of interest
to their administration. Failure to do so, or the intentional withholding of
information about potential conflicts of interest, constitutes a violation of
the rules and procedures of most universities.
Universities, too, are being offered equity interest in entrepreneurial
ventures involving faculty members. A research institution that accepts an
equity position in a start-up company is likely to offer encouragement to
the scientist-entrepreneur at critical times. In addition, the investors are
not depleted of cash necessary for successful development and marketing
of the product. The ultimate return to the university from an equity hold-
ing has the potential to exceed the income from royalties and licensing
fees. University administrators, in such circumstances, find themselves
called upon to make decisions in which the interests of the venture corpo-
ration and those of the university faculty may not be identical. University
administrators may become unduly interested in the economic success of
the venture company, even at the expense of educational responsibilities of
230 Chapter 7
the university. There is also a question of whether or not an institution that

holds equity in a commercial venture will allow that financial interest to
influence staffing decisions or other allocations of resources. When a posi-
tion becomes vacant, will the employer preferentially seek candidates who
will contribute to the development of the product in which the employer
has an interest? When decisions on the allocation of limited resources for
the purchase of equipment are made, will research administrators favor
those units working on proprietary projects in which the employer has an
interest?
A university is under increasing pressure to take equity in start-up com-
panies based on the intellectual property of one of its own faculty mem-
bers. The institution may provide release time for the faculty member,
technical assistance for the project, and access to equipment and other re-
search infrastructure in return for substantial ownership in the company.
Proponents of equity ownership by institutions emphasize that this is an
inexpensive investment with the potential for enormous economic returns.
Opponents of equity ownership by institutions argue that institutional re-
sources are diverted to the personal benefit of one or two scientists and the
investors in the venture-capital deal. The equity-holding institution has an
exceptional interest in the success of the venture and may use its research
and public relations resources to promote the venture without adequate
safeguards on fiduciary responsibility or critical scientific peer review. Eq-
uity ownership of companies based on the research of the scientists of an
institution has come under increased public scrutiny, legal challenges from
other members of the institution, and restrictive regulations from federal
funding agencies.
Institutional prerogatives
Universities have a strong sense of self-preservation or self-protection when
confronted with issues that are likely to have major adverse effects on them.
Universities are reluctant to cancel lucrative contracts when a faculty mem-
ber is found to have a serious conflict of interest. The reputation of a leading
research university is based on its extramural support and achievements that
attract positive public attention, such as patents, prizes received by faculty,
and scientific breakthroughs of general interest. Universities are doubly
threatened by scientific misconduct: there is the potential loss of grant fund-
ing and the loss of prestige. In addition, an investigation of scientific mis-
conduct is expensive. As a result, universities are not eager to invite
complaints of scientific misconduct or conflict of interest.
The bureaucrats within the university are reluctant to be drawn into pro-
ceedings pertaining to scientific misconduct or conflict of interest. Adminis-
trators are insecure about their mastery of the process, are fearful of political
repercussions within the institution when a distinguished scientist is the
subject of a complaint, and are anxious about criticism from news media that
frequently focuses on individuals rather than issues. Colleagues within the
university, too, are reluctant to become involved in deliberations about con-
flict of interest or scientific misconduct because it is perceived as taking
sides with the complainant or the alleged perpetrator. Scientists are also
aware of the potential financial damage to their institution and the negative
effect on the institution’s image and feel some need to protect their em-
ployer and to attenuate adverse effects of the allegation.
Some critics have charged that universities have failed to take the lead
in addressing scientific misconduct and conflict of interest. These allega-
tions have been reinforced by news media and some legislators who sug-
gest that universities are inept or even recalcitrant in assuming
responsibility for the behavior of the members of their community. Uni-
versities are particularly concerned about the increasing administrative re-
sponsibilities assigned to them by state and federal governments, because
many of these requirements are unfunded mandates and are perceived as
placing university administrators at odds with the attitudes and aspirations
of their own scientists. There is little doubt, however, that the public and
legislators are increasingly insisting that universities accept responsibility
for monitoring the integrity of the science carried out by their employees
and trainees, and for the personal interests of employees that may affect
the independence of decision making. Judgments on these complex issues
are best vested in those who understand the normative standards of the
discipline and the particular environment in which the conduct being ex-
amined occurs.
Managing Competing Interests
It is neither possible nor desirable to avoid all competing interests. Suc-

cessful scientists have multiple demands on their time, expertise, and at-
tention that compete with their primary missions of creating new
knowledge and synthesizing critically, evaluating, and disseminating exist-
ing knowledge. Nevertheless, participation in the peer review process, in
formulating public policy, and in coordinating activities of his or her em-
ploying organization are important responsibilities of a scientist. Research
workers will find it useful to, and have the obligation to, discuss these com-
peting demands with their supervisors and colleagues to determine an ap-
propriate balance between personal scholarship and professional service.
In some instances, an employer will decide that selected outside activities
are in the best interest of the organization, and it will encourage and re-
ward the scientist for these activities. In other circumstances, the employer
may place a higher priority on managing a research program, supervising
junior workers, and maintaining research or clinical productivity and will
232 Chapter 7
discourage outside activities that compete with the institutional priorities.

Although scientists have considerable latitude in personal interpretation of
normative standards for outside professional activity, the supervisor has
the responsibility to ensure that allocation of effort is consistent with the
guidelines of the organization.
There is a wide range of policies and practices among institutions per-
taining to financial return on outside related professional activities. A re-
search worker and the supervisor need to discuss the guidelines for
speaker’s fees, consulting fees, and other financial incentives. In some orga-
nizations, fees for outside professional activities are collected by the unit
and redistributed as part of the reward system. More commonly, the re-
search worker is permitted to collect speaker’s fees and consulting fees
with some sort of disclosure and approval process. Moreover, there is a
growing concern that consultants may not be equally critical of products
marketed by their benefactors and by competitors of their benefactors, and
authors and speakers are increasingly asked to identify financial relation-
ships with commercial firms.
It is in the area of commercialization of the intellectual property of a
scientist that the rules of the game continue to evolve rapidly. Employees
of public institutions are subject to conflict- of-interest statutes. Many
states allow and even encourage personal interests under the aegis of an
economic development agency. All U.S. institutions receiving federal funds
for research are required to develop policies and procedures for disclosure
of potential conflicts of interest and for developing safeguards and pro-
cesses for managing conflicts of interest. These range from barring the
individual with a conflict of interest from participating in certain decisions
to establishing an oversight committee that periodically monitors activity
for bias in personnel utilization and interpretation of experimental results.
The latter approach may be viewed as intrusive and adversarial, but when
properly implemented, it protects the integrity of the relationship between
the scientist and commercial sponsor and adds value to the quality of the
research program.
Conclusion
Conflict of effort pertains to allocation of time on behalf of the primary

employer. Although a conflict of effort may arise from the same activity
that creates a conflict of interest, more often, a conflict of effort arises from
diversion of the commitment of an individual by requests to engage in
public service and outside professional activities. At some point, service on
advisory boards, governing boards of professional and public organiza-
tions, and editorial boards and participation in seminars, symposia, confer-
ences, and workshops will impair the ability of individuals to meet their
responsibilities to their employer, subordinates, trainees, and colleagues.
“Conflict of interest” is an umbrella term for a wide range of behaviors and
circumstances. Conflict of interest at some level involves the use of posi-
tion or authority for personal gain. Although most attention has been di-
rected toward personal financial gain by individuals, it is also true that
universities and other corporations may engage in practices that create a
conflict of interest between the organization and individuals, most often its
own employees, or with other corporations.
Some financial conflicts of interests are obvious. Others are not neces-
sarily obvious and are defined by regulations and statutes. Still others are
gauged by normative professional standards that vary with time or across
disciplines. Various arbitrary thresholds have been established in statutes,
institutional guidelines, and federal regulations that define the level of a
financial interest that creates a conflict of interest. Some laws may forbid
participating in activities or entering into contracts that create a conflict of
interest; for example, an employee of a state agency may not receive more
than $10,000 in compensation from an outside contractor doing business
with that agency. Most often, the individual is required to disclose a finan-
cial interest that may be perceived as creating a conflict of interest. A sym-
posium speaker receiving a consulting fee from a pharmaceutical company
is expected to disclose that arrangement to the organizers and audience as
a prerequisite to participation in a conference addressing the merits of the
company’s commercial products.
Scientific conflict of interest involves the use of position to influence de-
cisions on publication of manuscripts, funding of grant applications, and
formulation of regulations on the use or commercialization of a product.
There is no general agreement at this time on the circumstances that create
a scientific conflict of interest. With increased emphasis on commercializa-
tion of intellectual property generated by academic scientists, there is con-
cern about the effect of financial interest on the direction and interpretation
of research. Can a scientist who holds a patent on a pressure sensor impar-
tially compare the efficacy of that device to a competitor’s sensor when the
conclusions will affect royalty income? Will an advisor with substantial
funding from the private sector allow trainees the opportunity to explore
their own ideas that may not directly relate to the industrial project? Should
a scientist employed by a pharmaceutical company be appointed to the edi-
torial board of a journal that publishes articles on the efficacy of therapeutic
agents? Should a scientist review the grant application of a collaborator or a
competitor? Clearly, the definition of scientific conflict of interest cannot be
made so broad as to exclude from the evaluation process most individuals
knowledgeable in the field.
234 Chapter 7
Institutional conflict of interest is less well defined than individual

conflict of interest. In general, employees assign the rights to commer-
cialize their intellectual property to the employer. The institution has the
responsibility for managing the potential conflicting interests of the fac-
ulty entrepreneur with respect to supervision of trainees, use of institu-
tional resources, and segregation of projects funded by other sponsors
from those funded by the personal venture. An institutional conflict of
interest arises when the interests of a university diverge from those of its
faculty and staff. Most notable is an exclusive contract between a univer-
sity and a corporation giving the corporation preferential access to re-
search results. Universities often become co- owners of companies
established to commercialize the results of faculty research. There is con-
cern in some sectors that this commitment to economic development is
leading universities away from their traditional roles as educational and
scholarly sanctuaries.
Issues concerning conflicts of conscience rarely come to the attention of
research administrators compared with incidents of conflict of effort and
conflict of interest. Conflicts of conscience, which usually are not recog-
nized by others, arise when personal beliefs and convictions influence sci-
entific decisions. The responsibility for acknowledging conflicts of
conscience rests with the researcher alone, and failure to report the con-
flict is likely to be undetectable except by inadvertent disclosure. There are
no generally accepted methods for dealing with identification of conflicts
of conscience or the failure to manage them.
1. Excluding examples given in this chapter, what are some conflicts of

conscience that might be faced by scientists? For any examples, con-
sider that the scientist in question has come to you for advice. De-
scribe the advice you would provide, along with your rationale.
2. Describe a conflict of effort that might be faced by a predoctoral
trainee. Propose a mechanism for managing the conflict.
3. Describe a financial conflict of interest that might be faced by a post-
doctoral trainee. Propose a mechanism for managing the conflict.
4. A journal that publishes basic and applied biomedical research find-
ings plans to change its peer review policy, eliminating the inclusion
of editorial board members and reviewers who work for corporate
entities. Defend or critique this proposal.
5. Conflict-of-interest management plans may involve the use of exter-
nal experts who provide oversight, review data, read reports, and
make recommendations to relevant administrators and monitoring
committees. Who should provide the resources to underwrite these
activities? Is it appropriate and plausible to anticipate such costs and

include them in research grant budgets?
6. What are the differences in equity ownership of common stock and
a mutual fund? Do mutual funds and common stocks create the same
level of financial conflict of interest?
Case Studies
7.1 Dr. Raymond Rodriguiz, the chair of a molecular genetics depart-

ment, creates a search committee of three faculty members to
screen candidates for an assistant professorship in the department. A na-
tional search is conducted, and four qualified candidates are brought to
campus for 2-day interviews. After extended deliberation, the search com-
mittee recommends Dr. Helen Grace for the position. Dr. Rodriguiz offers
the position to Dr. Grace, and she accepts. Dr. Hope Bono, one of the
other candidates, writes to Dr. Rodriguiz and complains that the search
committee was not legitimate because two of its members are married. Dr.
Bono argues that spouses should never serve together on committees that
involve judgment of people (promotion, tenure, faculty searches, etc.). Dr.
Bono states that she will file a complaint with the Equal Employment Op-
portunity Office of the university. Discuss the validity of Dr. Bono’s argu-
ment. What should Dr. Rodriguiz do?
7.2 Andre Cesar is completing his degree at Research University. He

has conducted some successful and exciting research in the labora-
tory of Dr. Ellen Zinderoff. Dr. Zinderoff’s project was supported in part
by a research contract with Innovations, Inc. Dr. Zinderoff and the mem-
bers of her laboratory developed new, rapid, accurate assays that can be
adapted to kits for direct sale to the public. Innovations, Inc., is consider-
ing developing and marketing these kits but has not made a definite deci-
sion. Leaper Enterprises offers Andre a position in a new unit of the
company to apply his training to develop kits based on the technology that
he learned and helped develop in Dr. Zinderoff’s laboratory. Discuss any
conflict that Andre may have in accepting a position in a company that
competes with Dr. Zinderoff’s sponsor. How is the situation altered if An-
dre was paid or not paid by funds from Innovations, Inc., while a student?
7.3 Dr. Mera Bupe, working on a university-funded project, has invented

a device to measure nerve impulses and muscle coordination in legs.
Orthopedic surgeons have found that the device is useful for identification
of both local and brain lesions. Dr. Bupe filed a disclosure with the university
intellectual property office (UIPO), which paid for the successful patent
submission. She has discussed the invention with a biomedical device
236 Chapter 7
company, which might be interested in funding further research on extend-

ing the utility to predict the need for hip replacement and for monitoring
the function of older hip prostheses. Dr. Bupe is interested in pursuing this
research and is in need of funding to sustain her research program. The di-
rector of the UIPO has identified another biomedical instrumentation com-
pany that has developed processors with the capability to collect and analyze
the signals from Dr. Bupe’s device. This company has its own biomedical
engineers and has no interest in funding Dr. Bupe’s research. The director of
the UIPO is positioned to execute an attractive license that includes a sub-
stantial one-time payment for the device. Although Dr. Bupe would receive
one-third of the revenue directly, this arrangement severely limits the possi-
bility of future funding for research on the device. On the other hand, the
university would gain funds for several short-term proof-of-concept grants
and to assist the university in establishing start-up companies. Dr. Bupe
challenges the director on his decision to close the deal, arguing that it is
shortsighted and disregards her contributions to date and her plans. Using
the perspective of this scenario, what is a fair and equitable approach to bal-
ancing the interests of the individual investigator and the university?
7.4 Dr. Cecilia Jonas is on the editorial board of the leading chemical
engineering journal. Dr. Jonas receives a manuscript for review re-
porting results similar to those in her draft manuscript. Dr. Jonas is await-
ing replication of one experiment involving a novel method of polymer
separation in order to prepare a new figure with better-defined graphical
data. Although Dr. Jonas’s manuscript has content distinctly different from
the one received for review, she believes it is likely that the impact of her
publication will be greatly reduced by publication of the competing manu-
script. Dr. Jonas redirects her effort toward completion and submission of
her manuscript, setting aside the manuscript to be reviewed. Within 2
weeks, her well-prepared manuscript is submitted to another quality jour-
nal in the field of chemical engineering. Dr. Jonas then, over the next sev-
eral days, critically reviews the manuscript that she received; makes a
number of insightful suggestions, as she usually does; and returns the man-
uscript to the editor with the recommendation that the paper be accepted
after major revision. She also requests that the revised article be sent to her
for a final consideration on publication. What are the real or perceived
conflicts of interest confronting Dr. Jonas as a member of an editorial
board? Has she acted ethically and responsibly? If not, what do you think
she should she have done in this situation?
7.5 Yoon Kim is senior technician in the laboratory of Dr. Sun. Dr.
Sun’s laboratory is well funded and has several technicians, gradu-
ate students, and postdoctoral workers. The laboratory uses large amounts
of a variety of reagents, supplies, consumables, and equipment. Billie Mar-

celli represents a major scientific supply company and visits Dr. Sun’s lab-
oratory at least once each month. Billie routinely drops off a few samples
of new products that might be of interest to the members of Dr. Sun’s
laboratory, along with a box of cookies or snack items. Yoon mentions to
Billie that Dr. Sun has been awarded a new grant that will involve purchas-
ing new automated digital equipment and related supplies. Billie takes
Yoon to lunch to learn more about the anticipated purchases so promo-
tional materials can be distributed to Dr. Sun and the members of the lab-
oratory. Later on, when Billie comes by the laboratory to offer service in
expediting delivery of anticipated orders, Billie gives Yoon an attractive
home weather station and suggests that his company would provide a re-
frigerator free of charge if the new orders exceed $20,000. Has Yoon done
anything inappropriate to this point? What competing interests might he
be facing if Billie continues to engage him? How are inducements to make
purchases from a vendor different in the institutional setting as compared
with personal home purchases?
7.6 Dr. Amud El-Abdul is the chief of internal medicine at a large

community hospital. He frequently participates as a coinvestigator
in clinical research with faculty at a nearby academic medical center. He is
one of two coinvestigators on a protocol that is being reviewed by the
medical center’s IRB. The protocol proposes to conduct a quality of care
and health survey. It will be administered to patients at three large private
practice offices in the immediate metropolitan area. Dr. El-Abdul has par-
tial ownership of one of the practices, and he has disclosed this to the med-
ical center’s conflict-of-interest committee (COIC). The COIC did not
find a financial conflict requiring management. Despite no action on the
part of the COIC, one member of the IRB panel feels strongly that infor-
mation about the ownership should be disclosed in the consent form. Oth-
ers on the panel disagree, arguing that the ownership issue would not
impact subject participation or the possible outcome in terms of increased
financial benefit to the practice. The chair of the IRB individually polls
each of the panel members. What is your position? What are your
reasons?
7.7 Sally Mancini, assistant professor of mechanical engineering, is

submitting a proposal for a $250,000 grant to InterProbe Devices,
Inc. to do validation studies on the company’s next-generation fiber optic
probe for monitoring metal fatigue in commercial aircraft engines. On her
grant application form, she checks the box indicating that she has no con-
flict of interest to report in connection with the proposed research project.
However, she is unaware that InterProbe provides an annual unrestricted
238 Chapter 7
$50,000 gift to her dean. This gift is used to provide three competitively
awarded research fellowships to graduate engineering students selected
annually by the dean. Moreover, the president of her university currently
sits on the corporate board of InterProbe, for which he receives a retainer
fee and corporate stock. His total compensation package amounts to
$150,000 over a 3-year period. Are there conflict-of-interest issues that
need to be addressed in the submission of Sally’s proposal? If so, what are
they? Are they manageable?
7.8 Dr. Evan Mills is a leading international investigator in biostatis-

tics, a department chair, and a member of a national panel on bio-
medical education. Dr. Mills also edits a textbook for medical and graduate
students. Dr. Mills selects a number of leading scientists from large medi-
cal schools to write chapters for this textbook. The contributors of chap-
ters and Dr. Mills are paid for their time and expertise in preparing chapters
for the textbook. The publisher promotes sales of the textbook by elec-
tronic and print material that emphasizes the reputation of Dr. Mills and
the other contributors of chapters and of the medical schools where they
serve as faculty members. Colleagues and students of Dr. Mills and of the
other contributors are asked to write endorsements for use in promoting
sales of the textbook. Is it appropriate to use the name of the employing
institution in promotional material? Under what circumstances? How
does one obtain candid reviews of the textbook from students? Under what
circumstances is it appropriate to use Dr. Mills’s textbook in his institu-
tion? What are the obligations of contributors of chapters to address real
or perceived conflicts of interest if the textbook is used in their institu-
tions? What circumstances might make it inappropriate to require stu-
dents at Dr. Mills’s institution to purchase his textbook?
7.9 Dr. Rudee Prasad is an independent consultant in drug-related

toxicology. Dr. Prasad also holds an adjunct faculty position at the
local university, where he lectures to pharmacology graduate students and
medical students. He also serves occasionally on state and federal advisory
panels on product safety. Dr. Prasad invests a portion of his income in
stocks of biomedical companies. A candidate drug being developed by a
company for which he is consulting has impressed Dr. Prasad, and he has
made sizable investments in the company. The company contracts with Dr.
Prasad for a final toxicological assessment before submitting a request to
initiate a clinical phase 2 study to determine the efficacy of the candidate
drug. Dr. Prasad is astonished and alarmed to discover during his review of
materials from the animal studies and the phase 1 study that use of the
drug is associated with serious and extensive nuclear aberrations in bone
marrow and gonadal tissue. Dr. Prasad realizes that these findings will
result in a delay or cancellation of the proposed phase 2 study. As he pre-

pares his detailed report for the company, he notifies his investment coun-
selor to sell all of his stock in the company over the next several weeks.
What are Dr. Prasad’s obligations to avoid using confidential information
for personal gain? What are Dr. Prasad’s real or perceived conflicts of in-
terest? What third parties may be harmed by Dr. Prasad’s actions?
7.10 Dr. Marcella Prevot and Dr. Charles d’Andreas met and subse-
quently married while postdoctoral fellows. Marcella’s research fo-
cused on public health and epidemiology, whereas Charles’s research
focused on biostatistics and health outcomes. They were fortunate to both
be hired into the public health sciences department at Research University.
Each has been successful in obtaining extramural support for their re-
search, and both are effective teachers and have attracted graduate stu-
dents. They publish independently and attend different professional
meetings. Overall, the couple is well perceived in their department.
Charles’s career advances somewhat faster than Marcella’s, and Charles is
tenured after only 4 years at Research University. Later on the department
chair of the public health sciences department leaves Research University
unexpectedly and Charles is named interim chair. This is the year that
Marcella is being evaluated for a tenured position in her department. Pol-
icies at Research University, however, prohibit a spouse from supervising,
setting salary, or recommending promotion of a direct member of the fam-
ily. What are the professional and ethical reasons for nepotism rules, that
is, prohibitions on favoritism to family members? What options are avail-
able to Drs. Prevot and d’Andreas?
Resources
Print
Anderson MS, Steneck NH (ed). 2011. International Research Collaborations: Much
To Be Gained, Many Ways To Get in Trouble. Routledge, New York, NY.
Brockway LM, Furcht LT; FASEB. 2006. Conflicts of interest in biomedical
research—the FASEB guidelines. FASEB J 20:2435–2438. http://www.fasebj
.org/content/20/14/2435.full.pdf+html.
and Health Sciences, 2nd ed. Cambridge University Press, Cambridge, United
Kingdom.
Campbell EG, Gruen RL, Mountford J, Miller LG, Cleary PD, Blumenthal
D. 2007. A national survey of physician-industry relationships. N Engl J Med
356:1742–1750.
Campbell EG, Weissman JS, Ehringhaus S, Rao SR, Moy B, Feibelmann S,
Goold SD. 2007. Institutional academic-industry relationships. JAMA 298:
1779–1786.
240 Chapter 7
Committee on Science, Engineering, and Public Policy. 2009. On Being a Sci-

entist: A Guide to Responsible Conduct of Research, 3rd ed. National Academies
Press, Washington, DC. http://www.nap.edu/openbook.php?isbn=0309119707.
Goodstein D. 2010. On Fact and Fraud: Cautionary Tales from the Front Lines of Sci-
ence. Princeton University Press, Princeton, NJ.
National Research Council. 2009. Conflict of Interest in Medical Research, Educa-
tion, and Practice. National Academies Press, Washington, DC. http://www.nap
.edu/catalog.php?record_id=12598.
Steneck NH. 2007. ORI Introduction to the Responsible Conduct of Research, revised
ed. U.S. Government Printing Office, Washington, DC. http://ori.hhs.gov
/documents/rcrintro.pdf.
Online
On the American Medical Association (AMA) website is the AMA’s Code
of Medical Ethics, listing guidelines including 8.03 (Conflicts of Interest:
Guidelines), 8.031 (Conflicts of Interest: Biomedical Research), 8.0315
(Managing Conflicts of Interest in the Conduct of Clinical Trials), and
8.061 (Gifts to Physicians from Industry):
http://www.ama-a ssn.org/ama/pub/physician-r esources/medical-e thics/code
-medical-ethics.page?
Department of Health and Human Services final rule (42 CFR 50, 42 CFR
94): Responsibility of Applicants for Promoting Objectivity in Research
for Which Public Health Service Funding Is Sought and Responsible
Prospective Contractors (Federal Register, Aug. 25, 2011, Vol. 76, No. 165,
p 53256–53293):
http://grants.nih.gov/grants/policy/coi/fcoi_final_rule.pdf
The National Institutes of Health’s Office of Extramural Research website

on conflict of interest:
http://grants.nih.gov/grants/policy/coi/index.htm
The National Institutes of Health and the U.S. Department of Health and
Human Services have developed the resources to help ensure transparency
regarding outside activities and proactive management of conflict- of-
interest issues:
http://www.nih.gov/about/ethics_COI.htm
Recommendations on partner accommodation and dual-career appoint-

ments were prepared in 2010 by a subcommittee of the Committee on
Women in the Academic Profession of the American Association of Uni-

versity Professors, but without endorsing a particular policy or practice for
dual-career appointments:
http://www.aaup.org/AAUP/comm/rep/dual.htm
The Supreme Court on June 6, 2011, ruled that the Bayh-Dole Act does
not automatically vest ownership of patent rights in universities when the
underlying research was federally funded. More information can be found
on IPWatchdog.com:
http://ipwatchdog.com/2011/06/06/supreme-c ourt-a ffirms-c afc-i n-s tanford-v
-roche-on-bayh-dole/id=17594/
chapter 8
Collaborative Research
L. Michelle Bennett and Francis L. Macrina
Overview • Drivers of Collaborative Research • A Case in Point
• Challenges of Collaborative Research • The Nature of
Collaboration • Collaborative Agreements and Institutional
Commitment • Fundamentals for Successful Team and
Collaboration Dynamics • Mentoring in the Era of Team Science
• Diversity • Authorship • Data Sharing, Custody, and Ownership
• Managing Conflict and Promoting Disagreement • Collaborations
with Industry • Collaboration with International Partners
• Conflict of Interest • Miscellanies • Conclusion • Discussion
Questions • Case Studies • Resources
Overview
Most of the work still to be done in science and the useful arts is precisely
that which needs knowledge and cooperation of many scientists . . . that is
why it is necessary for scientists and technologists to meet . . . even those in
branches of knowledge which seem to have least relation and connection
with one another.
Written by Antoine Lavoisier more than 200 years ago, these words reflect
a longstanding appreciation of the importance of collaborative research.
Today, the scale and complexity of biomedical research problems in-
creasingly demand that scientists move beyond the confines of their own
disciplines and explore new organizational models for team science. For
example, imaging research often requires radiologists, physicists, engi-
neers, cell biologists, and computer programmers to work together in inte-
grated teams. Although many scientists will continue to pursue individual
research projects, opportunities to get answers to difficult questions will
often be found in the pursuit of interdisciplinary research. Along with con-
tinued growth in specialized technology, this will drive the continued
growth of research collaboration in many fields.
doi:10.1128/9781555818487.ch8
243
244 Chapter 8
Advances made in the sciences today are rarely the result of the labors
of single investigators. Even the paradigm for the training of new scientists
is a collaboration, with the mentor and the trainee contributing individu-
ally to a working relationship that is expected to produce positive out-
comes for both. To be sure, significant scientific contributions do
sometimes emanate from the work of single individuals. Geneticist and
Nobel laureate Barbara McClintock was the sole author on over 90% of
her more than 70 scholarly publications. But historically, collaborative re-
search has played a dominant role in advancing our knowledge of the
world and contributing to the betterment of humankind. Today, the soli-
tary scientist—armed with the knowledge and tools of a single discipline—
seeking to conquer some devastating disease is largely a romantic myth.
Whether we are trying to unlock a fundamental secret of life or to turn
basic knowledge into a practical application, collaborative relationships
usually offer us the best chance of success.
Drivers of Collaborative Research
In biomedical research, trends to create and enhance collaboration are

widely evident. Universities foster interdisciplinary collaboration by form-
ing research institutes or centers that are populated with investigators
from different backgrounds. The concept of organizing faculty under the
umbrella of these types of institutes or centers is decades old. But present-
day science is marked by an increased growth and diversity of such initia-
tives. Some universities are building new facilities expressly for colocalizing
investigators from different scientific backgrounds to catalyze collabora-
tive research. Such interdisciplinary activities might be organized as a vir-
tual center, with collaborators having primary appointments in their home
departmental laboratories and adjunct positions in the virtual center. Al-
ternatively, defined space or even a whole building might be dedicated to
this type of research center or institute.
Interdisciplinary training programs at both the pre-and postdoctoral
levels also fertilize collaboration. When graduate and postgraduate train-
ing is based on interdisciplinary approaches, faculty from various depart-
ments and disciplines may be stimulated to explore and pursue
collaborations. Such training environments are likely to spawn new re-
searchers with an awareness of the benefits of collaboration and insights
into implementing collaborative arrangements. Science in the early part of
the 21st century is integrative, reflected by the growth of broad-based cen-
ters and institutes that draw together biology, medicine, mathematics, and
engineering. “Integrative biology,” “systems biology,” “biological complex-
ity,” “computational biology,” and other terms are being used to describe
these sweeping interdisciplinary initiatives. And the forms they are taking
Collaborative Research 245
range from freestanding, privately supported research institutes to for-

mally organized academic units.
Another aspect of interdisciplinary training is the increasing implemen-
tation of university courses at the graduate level focused on gaining knowl-
edge about how to conduct interdisciplinary research. Many of the training
courses, in addition to didactic work, include opportunities for groups to
work together on a short-term interdisciplinary challenge and present the
conclusions to the rest of the class.
The interdisciplinary theme has been reaffirmed by the National Insti-
tutes of Health (NIH), the major grant provider for biomedical research in
the United States, as well as other funding agencies such as the National
Science Foundation (NSF). These agencies are playing a role in catalyzing
interdisciplinary efforts by making funds available for researchers to reach
across established disciplinary boundaries. In recognition of the increasing
emphasis on collaborative research, the NIH also has adopted a co-
principal investigator model for grant applications. This mechanism per-
mits principal investigators to receive equivalent credit for their role in
leading the proposed scientific effort.
Another example of grant funding focused on bringing researchers to-
gether around a common focus is the Clinical Translational Science Awards
(CTSA) housed in the National Center for Advancing Translational Sci-
ences at the NIH. The focus of the CTSA program is to catalyze collabo-
ration in the translational research and training arena by bringing basic,
translational, and clinical researchers together around a common vision.
The CTSA award mechanism emphasizes both intra-and interinstitu-
tional collaboration. In recognition of the opportunities in leveraging
knowledge in the physical sciences with that of cancer biology and transla-
tion, the National Cancer Institute (NCI) established the Physical Science
and Oncology Centers and the Integrative Cancer Biology Program. Each
Physical Science and Oncology Center is run by a principal investigator
from the physical sciences and a co-principal investigator from the cancer
field. Collaboration is fostered within each center as well as among them.
Finally, the NSF has demonstrated commitment to interdisciplinary sci-
ence by funding both training and research grants. The NSF uses both
solicited and unsolicited mechanisms to catalyze interdisciplinary propos-
als to address complex scientific problems.
The theme of collaboration is regularly exemplified in modern genetic
research. The Human Genome Project provides a continuing example of
interdisciplinary collaboration as investigators of different backgrounds
join forces to link nucleotide sequences with human disease. Basic research
on gene structure, location, replication, and repair can be connected to
general problems of disease etiology through collaborative efforts. Epide-
miologic observations coupled to biochemical and genetic data through
246 Chapter 8
collaborative research can produce rapid progress. The resulting molecu-

lar understanding of disease allows the rapid development of novel diag-
nostic, therapeutic, or preventive applications.
A Case in Point
Examples of the power of collaboration are easy to find across many scien-
tific disciplines. The application of genomics in medical research has gen-
erated a trove of such examples, of which the discovery of the von
Hippel-Lindau (VHL) tumor suppressor gene is a particularly robust and
illustrative case. von Hippel-Lindau (VHL) syndrome is a hereditary dis-
ease that predisposes individuals to a variety of cancers that include central
nervous system hemangioblastomas (blood vessel tumors) of the brain and
spinal cord and retinal angiomas. Affected individuals are also at increased
risk for developing clear cell renal cell carcinoma (cRCC), the most com-
mon form of nonhereditary kidney cancer. Other features associated with
VHL syndrome include a specific tumor of the adrenal gland, kidney cysts,
pancreatic tumors, epididymal cystadenomas (tumors of a structure con-
nected to the testicle), and tumors of the ear that may cause hearing loss.
The leading cause of death in patients with VHL disease is metastatic
cRCC.
The story of the discovery of the VHL gene and its role in cRCC be-
gan in the 1980s prior to the Human Genome Project. Marston Linehan
and his colleague Berton Zbar at the NCI sought to identify the cause of
cRCCs. Recognizing that genetic approaches held the key to understand-
ing cancers, Linehan and his colleagues began studying the DNA ex-
tracted from cRCC tumors removed from his patients. These studies
established that a segment of chromosome 3 was consistently missing in
these tumor cells. Given the technology of the day and the absence of a
detailed human genome sequence map, Linehan and Zbar recognized
that the search for the actual genetic locus associated with cRCC would
be lengthy and arduous, if not impossible. The extensive collaborative
effort that would evolve into the search for the VHL gene thus began
with conversations involving other scientists about a more efficient and
promising means to locate it. A decision was made to study individuals
with the inherited form of kidney cancer associated with VHL. cRCC
that does not show a pattern of inheritance in VHL and its association
with the syndrome is termed “sporadic.” The underlying rationale for the
search strategy was that it would be easier to analyze genetic differences
in individuals who had chromosomes passed on to them from relatives
than to look for chromosomal DNA changes in unrelated persons. This
required Linehan, Zbar, and their colleagues to assemble a large team of
multidisciplinary, international collaborators comprising basic and
clinical scientists, nurses, and pathologists to study the inherited form of

VHL-associated kidney cancer. The skill sets of the collaborators ranged
from clinical expertise to genetic analysis to clinical pathology to cell and
molecular biology, DNA sequencing, and bioinformatics.
It took approximately a decade, but the approach worked, and by 1993
Linehan, Zbar, and a third NCI collaborator, Michael Lerman, were able
to home in on a region of chromosome 3 that they named VHL. The paper
reporting the discovery of the VHL tumor suppressor gene was published
in Science in 1993. Apropos of the major collaborative effort, the paper had
35 coauthors, with Linehan, Zbar, and Lerman being the last three indi-
viduals listed in the byline. The author’s affiliated institutions were the
NCI (United States), Cambridge University (United Kingdom), and Cen-
tre d’Etude du Polymorphisme (France). The results of the paper con-
firmed that VHL was a tumor suppressor gene. Alterations in tumor
suppressor genes result in structural changes in the proteins they encode
(single or multiple mutations) or partial or complete loss of the protein
(deletions). The alteration or loss of the protein interferes with or elimi-
nates its normal function of preventing cells from growing in an uncon-
trolled fashion, the hallmark of malignancy. Not only did their findings
establish mutations in VHL as the cause of VHL syndrome, they also re-
vealed this gene to be a tumor suppressor for cRCC. This collaborative
work distinguished the whole team by contributing, at the molecular level,
precise information about the genetics and cell biology of cancer causation.
Equally important, this work set the stage for clinical applications and
deeper research that continues into this millennium. The identification
and eventual complete DNA sequence determination of VHL was trans-
lated to a blood test for gene mutations, which now provides the basis for
diagnosis of VHL disease. Further, this genetic testing affords the ability
to identify those at-risk family members who may be affected by the dis-
ease. The sequence of the VHL-encoded gene product has led to the
discovery of its biochemical function and its molecular structure. This
work provided the foundation for the development of targeted therapeutic
approaches for patients with advanced cRCC. To date, the Food and Drug
Administration has approved seven targeted therapeutic agents for the
treatment of patients with advanced cRCC. Clinical trials to evaluate addi-
tional agents targeting the VHL pathway are under way.
Challenges of Collaborative Research
The increase of interdisciplinary collaborative research has created some

challenges that merit discussion. Research universities generally are orga-
nized according to a departmental structure that is based on disciplines.
Where traditional departments prevail, collaborations may encounter
248 Chapter 8
problems as departmental heads attempt to deal with issues of space, re-

source allocation, and curriculum. Collaborations may be seen by some as
undermining the integrity of the traditional departmental infrastructure of
universities.
At the level of peer review for grant funds, collaborative research may
also pose challenges. Although the organization of NIH study sections
(initial review groups) has been moving toward interdisciplinary and inte-
grated membership, a grant application could consist of diverse experi-
mental approaches to a complex problem developed by collaborating
investigators from disparate disciplines. In such cases, the study section
might not have the membership diversity to perform a rigorous scientific
review of the entire application. Typically, this problem is solved by invit-
ing ad hoc reviewers to sit with the group and provide the needed expertise
to fairly and rigorously evaluate the proposal. The successes of collabora-
tive research indicate that these issues do not present insurmountable bar-
riers. But they must be considered and constructively addressed as scientific
research continues to embrace and foster collaboration as a strategy.
Publication is another area of challenge. For example, it is not unusual
for collaborators across disciplines to find it difficult to know where to
submit a paper for publication. The discipline-specific journals do not al-
ways embrace the interdisciplinary approach taken in the paper. Such im-
plications are best contemplated by potential collaborators as the
collaborative effort is being formed. Discussions relevant to collaborative
research appear in guidelines for authoring scientific papers (see chapter 4
and its resource list).
Finding a collaborator begins with a personal decision that your re-
search must be augmented by engaging another scientist whose expertise
is needed to move the work forward. Finding a qualified collaborator can
be accomplished by networking in person or via electronic communica-
tion. Using the published literature to enhance your exposure to possible
collaborators is also useful. Finding someone who is qualified and is also
willing to enter into a collaborative arrangement with you presents a
greater challenge, however. The assessment of a collaborative opportunity
involves a dialogue between you and a potential collaborator that leads to
the mutual belief that the collaboration will be of benefit to the science
and to both of you. To this end, the discussion will cover a breadth of issues
including institutional considerations, location, timing, funding, individual
accessibility, potential conflicts of interest, and trainee implications. As this
discussion unfolds, the potential collaborators should strive to appreciate
the degree to which their scientific agendas and styles are compatible. A
resulting feeling of trust (discussed in more detail later in this chapter) and
good personal chemistry are usually the ultimate catalyst in allowing the
collaboration to go forward. Collectively, this due diligence will take time
and effort. Finding collaborators can be difficult at times, and you may
have to make several attempts to find the right ones. Cutting corners to get
there or making decisions based on incomplete information can lead to
unproductive arrangements that will frustrate the collaborators and may
even harm their professional relationship.
If you are considering collaborating, does your institution take a posi-
tion on the importance of such activity? The tenure and promotion poli-
cies of many institutions are silent on the implications of collaborative
research. This leaves open the possibility that publications resulting from
collaborative work may be underweighted in deciding promotion and ten-
ure because they represent shared effort in a professional environment
where independent productivity is the desired standard. When in doubt
about this, you should seek clarification from your chair or your dean. On
the other hand, some institutions recognize the need for and nature of
collaborative research and accept publications coauthored by collaborators
as appropriate scholarly productivity. In fact, the use of annotated curricula
vitae in the evaluation setting is increasing. By annotating their curricula
vitae, faculty researchers can clearly articulate the role they played for each
publication and what the consequences would have been if they had not
participated.
The emphasis on interdisciplinary research and the formation of collab-
orations to accelerate research progress has helped catalyze training op-
portunities, as well as practical experience, for graduate students and
postdocs. Formal course work, informal brown-bag lunch sessions, and
short-term team projects can all provide rich opportunities for developing
the knowledge and skills to successfully participate in research teams.
Alignment of institutional messages about the importance of collaboration
with the training curriculum is also important. If the institution is going to
support and encourage interdisciplinary training in its graduate programs
and among postdoctoral fellows, it should also make sure it is supporting
the career growth and development of individuals choosing a team re-
search career path. Establishment of agreements with trainees, as described
in the next section, can be one way for the institution to help make sure it
is providing the support required to ensure the trainees are successful in
their next endeavor.
The Nature of Collaboration
Is it collaboration?
Consider the initiation of a collaboration that is clear-cut. Dr. Shivi, a mo-
lecular biologist, needs to analyze the peptide fragments produced by the
action of a protease she has genetically engineered. She knows that Dr.
Harris, an expert physical chemist, will be able to characterize her peptides
250 Chapter 8
by mass spectroscopy. When Shivi approaches Harris, we expect she will

propose that they set up a collaborative relationship. Assuming Harris is
receptive, they will work out the details of their collaborative project. The
implications of collaboration are obvious to all parties here. Harris’s exper-
tise is critical to moving Shivi’s project forward.
Now consider Dr. Rivera, who gives a new gene expression system to
Dr. Singh. A description of the plasmid and its host strain—extremely use-
ful in protein overexpression—has not been published. Instead, Rivera de-
scribes the usefulness of the plasmid to Singh at dinner, rendering a map of
the plasmid and its features on a napkin. Singh welcomes having the strain
sent to her and uses it successfully to gain important results that she now
intends to publish. Neither Rivera nor Singh had mentioned anything
about collaboration when they talked at dinner. Singh considers the send-
ing of the strain a professional courtesy, similar to requesting a strain that
had been described in print. She believes that simply thanking Rivera in
the paper’s “Acknowledgments” section is sufficient. Rivera, on the other
hand, had believed he was making a critical contribution to Singh’s work
by allowing her to isolate a protein that was previously impossible to purify
in reasonable quantities. Rivera demands that he and his postdoctoral asso-
ciate be coauthors on the planned manuscript. In contrast to the first sce-
nario, a collaborative relationship is not obvious here. Failure to have
considered collaboration in the beginning now creates problems, given the
assumptions of the two investigators.
Working out the details of a collaboration after the fact is usually not a
smooth process. It is relatively easy to agree on various facets of the collab-
oration when the stakes are defined and the outcomes are unknown. But
once we are aware of the outcomes, our new vested interests strongly influ-
ence our negotiations. Communication among scientists proposing to
work together is a necessary first step in deciding whether an arrangement
is going to be collaborative. Once this is agreed to, then defining the ex-
pectations, activities, and responsibilities of all parties in the collaboration
is essential.
Accountability
Different layers of accountability may accompany collaborations. First,
one or more of the parties to the collaboration may be involved in re-
search that is subject to formal policies, regulations, or laws. Such activi-
ties could include working with human subjects, animals, controlled
substances, hazardous substances, or select infectious agents. All partici-
pants in the research need to confirm their compliance with appropriate
regulations. In some instances, this confirmation will entail having sought
and obtained the appropriate approval or authority to carry out the work.
For example, a collaboration between a clinical research group and a
basic research group at different institutions might involve the sharing of

patient data. The basic researchers must be fully aware of and honor all
patient confidentiality issues mandated under the approved human-use
protocol filed by the clinical researchers. In all likelihood, the basic re-
searchers will also need a human-use protocol approved at their own in-
stitution to engage in the collaboration (see chapter 5). Among other
things, this would mean that the basic researchers would need to have
successfully completed human subjects research training and submit a
protocol to the institutional review board (see chapter 5). Further, the
clinical researchers are responsible for informing the basic researchers
about any potential biohazards of working with clinical materials of hu-
man origin.
Second, collaborations that enjoy extramural support will be subject to
grant management regulations mandated by the funding agency as well as
the grantee institution. Any regulations regarding the expenditure of funds
and reporting requirements to the granting agency will have to be met by
the responsible parties of the collaboration. Consider federal funds sub-
contracted from a grant at collaborator A’s institution to collaborator B’s
institution to pay for a component of an investigator’s salary. There may be
a requirement that such funds be dedicated to this purpose. Rebudgeting
this salary money to cover the costs of supplies or travel would be forbid-
den and would likely have negative repercussions at both collaborating
institutions.
Finally, collaborations may have outcomes—planned or otherwise—
that have implications for the development of intellectual property (IP).
Partners in the collaboration should be aware of the necessary steps in-
volved in protecting research results that might have potential commercial
application. By disclosing results publicly and prematurely, one research
group might compromise the ability to seek patent protection for some-
thing codiscovered by the collaborators. Furthermore, there may be insti-
tutional and granting agency requirements relating to the prosecution and
ownership of IP, and these should be familiar to all parties of the
collaboration.
All collaborators must be aware that the failure of anyone associated
with the project to comply with any regulations may carry consequences
for all of the scientists involved in the study.
Collaborative Agreements and

Institutional Commitment
There are many different names attached to collaborative agreements,
such as team charters, “prenuptials” for scientists, team research plans,
pretenure agreements, and joint appointment agreements. Regardless of
252 Chapter 8
what they are called, the purpose is clear. Agreements among people par-
ticipating in a collaborative project or between an individual and his or
her organization provide a robust way of setting clear expectations and
outlining roles and responsibilities.
A collaboration may start out informally, as described above, and you
may not realize you are collaborating until you’re in the middle of it.
Whether a collaboration is formally initiated or happens organically, once
you realize it is happening, it is time to start putting something down in
writing to outline the research as well as to keep the team on track.
An agreement need not be extremely formal; it can, for example, be in
the form of e-mail exchanges documenting conversations. But capturing
the information and having it memorialized in some way is very beneficial
to the team. It provides documentation that any member of the group can
refer to and thereby recall the agreement and the associated responsibili-
ties. It provides a platform for having conversations about how roles and
expectations will change when an existing member leaves the team or a
new person joins. An added benefit to working on such a document is that
it can serve as a scaffold for building trust.
Many people have a visceral reaction to the suggestion of developing an
agreement. The arguments can include stating that great working rela-
tionships do not need this type of formality, that an agreement suggests up
front a lack of trust in the other people involved in the project, and that it
simply wastes valuable time when there is science that needs to be done.
While there may be some truth in each of these statements, they do not
take into account that relationships can falter, memories can fade, and time
well spent planning in advance of or even at the beginning stages of work-
ing together can avert many months of untangling messy situations if ma-
jor conflict does erupt within the group.
Collaborative agreements
A collaborative agreement, or what some affectionately term a “prenup-
tial” for scientific collaborators, can be constructed through a formal pro-
cess or informally by documenting over time conversations and decisions
made. The approach taken may very well depend on the people who are
interacting. And getting them involved in how to approach an agreement
in the first place can help set the stage for the scientific work ahead.
Collaborative agreements typically have several sections addressing
some major issues around which it is healthy to have some agreement.
One topic to cover is the goals and objectives for the collaboration, in-
cluding when the project is “over.” Roles and responsibilities can be as-
signed and clarified. It is important to lay out who will do what. Affirmation
that the collaborators take appropriate responsibility and are accountable
for their behavior is critical.
Another important area for discussion revolves around how informa-

tion, results, data, and reagents will be shared and stored. For example,
who will take responsibility for keeping track of precious reagents, how
will data be stored, and how will results be disseminated to the full group?
Developing joint agreements about the criteria for determining author-
ship and how credit will be assigned is essential. This is especially relevant
in the context of early-career researchers who are involved in the project.
What if the media wants to talk to one of the researchers? How will that be
decided? Coming up with criteria for attribution and making decisions
about who will give presentations or make comments publicly before the
opportunities present themselves help eliminate hasty decisions that may
risk confusion and misunderstanding.
Clearly outlining how the group will communicate, and when, should
be included. Whether the group members are local or in different parts of
the nation or world, agreeing on what types of meetings will be held, the
purpose of each, and how they will be scheduled and conducted sets expec-
tations as to when and how the science will be discussed.
Just as important is deciding how the group will manage conflict should
it emerge. Each person in the group should feel empowered to act on the
plan. So, open and honest discussion about how that will happen can go a
long way to preempting conflict before it gets out of hand. This includes
discussing “What if . . .?” scenarios and establishing rules of engagement,
especially if a more junior person wants to speak up.
Finally, there should be some discussion about IP as well as conflict of
interest. This of course is typically focused on the anticipation of IP that
could emanate from the collaboration. If IP results from the collaboration,
who will take responsibility for managing it and how will attribution be
decided? These discussions should also include any relevant existing IP
already held by the collaborators. Anticipating whether such IP could
come into play during the collaboration should be discussed. Regarding IP
in general, if there are any potential conflicts or should they develop during
the collaboration, there should be discussions about them and strategies
put in place to mitigate them.
Offer letter or “pretenure” agreements

Just as there are collaborative agreements for the scientific team, docu-
ments can be crafted between individuals and their affiliated institutions.
For example, to reduce perceived or real risks associated with junior fac-
ulty members being involved in collaborative efforts, clear criteria, ex-
pectations, and organizational commitment can be worked into a letter
that satisfies the needs of both parties as it relates to collaborative work.
While some of the same areas would be covered as in the collaborative
agreement, new territory such as clearly defining how recognition and
254 Chapter 8
reward will occur is included in these agreements. Such a letter might be

crafted as a memorandum of understanding and contain the following
elements.
• A section on roles, responsibilities, and expectations will set out
expectations of the early-career scientist, the department chair or
supervisor, as well as the department as a component of the overall
organization. Success can be defined for the individual participat-
ing in or leading an interdisciplinary team as well as for the
organization.
• A clear description focused on review and reward will outline the
criteria for assessing the progress and success of the scientist for in-
terdisciplinary work in the context of the collaboration as a whole. In
addition, language related to any data or sample sharing policies can
be included.
• Finally, a mentoring section may be extremely relevant to this agree-
ment, especially for early-career scientists, who can benefit from in-
put about balancing multiple ongoing projects and developing
increasing independence while at the same time participating as a
member of a group effort. Strategies can be put in place to be sure
the individual can navigate a collaboration while also being mindful
of the need for recognition based on accomplishments. The agree-
ment can state whether the individual will have a single mentor, have
several mentors, or engage a mentoring committee. It also provides
the investigator an opportunity to develop a plan for how he or she
will mentor junior members of the team and to identify training that
would be expected or beneficial when participating in or leading an
interdisciplinary effort.
Joint appointments
In some institutions it may make sense to set up adjunct appointments for
investigators to work across disciplinary boundaries. Among the items that
need to be discussed and decided are reporting structure and determining
where the administrative home resides, what resources are available to the
investigator from both disciplines, and how annual reviews will be con-
ducted, including scientific review if required. What each department can
expect of the individual as well as what the individual can expect from each
department should be articulated. And finally, a clear and agreed-upon
process should be outlined to make changes to the agreement.
Collaborative grant application submissions

Perhaps the highest degree of formality is achieved when investigators
planning a collaboration decide to seek grant support. In this case, the
application to the funding agency will contain a letter from the collabora-
tor describing his or her role in the research. The collaborator’s biograph-
ical sketch also will be included in the application. There might even be a
budget request for the collaborator’s salary commensurate with his or her
effort, as well as requests for collaborator supplies and travel. If the princi-
pal investigator of the proposal and the collaborator are at different insti-
tutions, officials from both institutions usually must approve the proposal
if it involves budgetary items. In any event, collaborations that are written
in grant proposals epitomize formality because their existence is clearly
documented in materials that are seen by many people at the institutional
level and the funding agency (e.g., program officers, peer reviewers).
Fundamentals for Successful

Team and Collaboration Dynamics
“It’s not the science you need to worry about in the collaboration; it’s the
team dynamics.” This is a phrase uttered by many researchers who have
engaged in scientific collaborations. Coming together around a goal or a
vision of how to tackle a particularly thorny scientific problem is exciting
and energizing. However, if the leaders and participants of the research
project do not share fundamental common elements of collaborative en-
gagement, the science can derail and put the scientific effort at risk. The
factors that are particularly important to focus on include establishing
trust, creating a vision, defining roles and responsibilities, agreeing on how
data will be shared and stored, deciding who will have access, establishing
criteria for authorship, and managing conflict while creating a safe envi-
ronment for scientific disagreement.
Model of team development

In the 1960s, Bruce Tuckman introduced his model of team development
after studying scientific teams, as well as others. Many decades later this is
still a useful framework for understanding many of the critical milestones a
team must meet as it moves through the four stages: forming, storming,
norming, and performing. The fact that they rhyme may help people re-
member them and relate them to others as they move through them.
Forming is characterized by bringing a group together to focus on a
scientific problem not easily addressed by one person. Groups can be
formed from the top down or bottom up. Regardless of approach, support
from the institutional leadership is critical for achieving success. The storm-
ing phase is the most critical. If a team cannot get through this stage, they
cannot progress to the next level. Storming, as its name suggests, is charac-
terized by a lot of activity and oftentimes conflict as well. This is the stage
when roles and responsibilities are defined, expectations are set, differences
256 Chapter 8
are recognized, and people are learning how to work with each other. Most
importantly, people are learning to trust one another during this stage. As
will be described later, trust is absolutely critical for collaboration. Storm-
ing is not optional, and once the team is formed, should there be any
changes in team membership, the group will go through smaller bouts of
this stage. Norming is the next stage, and it is here that the group settles
into a comfortable rhythm. Trust is solidified, group norms for behavior
and functioning are established, and people develop comfort in working
with each other. The last stage, performing, can be likened to the operation
of a well-oiled machine. The group is functioning well together, is generat-
ing results, and is communicating effectively as an integrated unit.
In the 1970s, the phases of transforming and concluding were added to
the model. These stages recognize the importance of celebrating the work
done together once the project, or a phase of it, is completed. It is impor
tant in the early stages of work together to be clear about when the project
ends. If transforming, the group may re-form, by letting go of some mem-
bers and having others join, in order to take on a new project or initiative.
Trust
Of all the factors that are critical for collaborating with others, trust is
among the most important. Just as it is important for the mentor-trainee
relationship described in chapter 3, it is critical for collaborators, regard-
less of career stage.
It can be difficult for scientists to feel comfortable talking about, or
even reading about, trust. It does not always seem like a very concrete
topic. In fact, some people think of it as a pretty fluffy topic. However, if
you think about it, establishing trust is absolutely critical as a foundation
for open and honest discussion, sharing data and information, and sharing
credit.
In an effort to make the conversation about trust more tangible, it helps
to think about three different types of trust as described in the literature:
calculus-, competence-, and identity-based trust. Calculus-based trust can
be thought of as a very superficial form of trust. It is based on the relative
rewards of trusting. For example, if the policy in a lab or clinic is that the
person who uses the last of a reagent replenishes it, and people do that,
they will earn the trust of the others. However, if one person habitually
ignores the policy, colleagues will learn that there is no reward in placing
trust in that person. A situation like this can cause friction and even con-
flict among lab members. Competence-based trust is very common in the
lab setting. Almost everyone can think of someone with “golden hands”—
someone who always seems to be able to make tricky protocols work or
can troubleshoot a problem well. Individual competence then becomes a
platform for trusting another in the context of the work or project being
performed. Identity-based or relationship trust is the most intimate type of

trust. It is based on personal familiarity and repeated interactions charac-
teristic of long-term associations. People may or may not achieve this level
of trust with their work colleagues. This is a form of trust that builds slowly
over time and is the basis for very deep relationships.
Another dimension of trust relates to how an individual enters into a
relationship with someone else. While each situation is different, some
people tend to start relationships with high levels of trust. That is, they
give the other person the benefit of the doubt, and then it is up to that
person to sustain trust at that level. Others start with low trust, and in
those situations it will be important to earn trust over time. Knowing what
builds and sustains trust is valuable to your working relationships.
Being aware of trust as a critical foundation for work being done in a
collaboration enables the leader(s) as well as the participants to develop
and propose strategies for not only building the trust but maintaining it as
well. Building trust can be done in many different ways, and underlying
them all is putting in place strategies for regular conversation. Lab meet-
ings, journal clubs, and setting time aside to talk about how the lab or
clinic is operating can contribute to building trust. These forums provide
chances for people’s concerns to be heard, for processes or procedures to
be adjusted, for data to be reviewed and its significance discussed, as well as
for reviewing the joint goals regularly to determine if the group is on track
or whether a new course needs to be charted.
A tool that can help establish a foundation for trust in the scientific set-
ting is the collaborative agreement, as described earlier in this chapter. By
taking the time to talk about how people will communicate; agreeing on
the goals for the project; and discussing how information, data, and credit
will be shared, the members of the group will start forming trust. This can
be done informally with a follow-up by e-mail or more formally by devel-
oping a shared document. Either way, it provides something tangible to
which the group can refer to help guide the overall effort.
One caution is worth mentioning. Going out bowling, celebrating
birthdays, or making a run for pizza together can indeed help solidify or
enhance trust. However, it cannot substitute for the critical work described
above, which really provides the foundation for trusting relationships.
Creating and sustaining a vision

If you take a moment to reflect on a project or initiative you were involved
in that was extremely exciting, it is quite likely that you can clearly articu-
late the vision, goal, or desired outcome for that project. People are willing
to align themselves with visionary leaders precisely because they can see
the path being taken, understand where they are headed, and share the
enthusiasm. It is exciting to be part of an effort where the future goal is
258 Chapter 8
clearly articulated. Thus, developing a shared vision for the group is among
several factors that are truly critical for successful team functioning.
The vision can originate with one individual or can be cocreated by two
or more people. Once you have a group of people working together on a
project, you want to be sure that each member of the team is very clear on
the overall goal, as well as his or her individual work and how it fits into
the big picture. Keeping everyone engaged and revisiting the overarching
goal with the group should be done at regularly scheduled group meetings.
Science moves quickly, directions for individual work can change suddenly,
and course corrections need to be made. Recognizing that and developing
strategies for revisiting goals and objectives at various intervals will keep
everyone focused.
Crafting vision statements can be a very useful exercise for a team.
Working together a couple times a year, the team can write out the overall
goal for the project followed by each member articulating his or her own
goal and what makes it a critical component of the whole. Vision state-
ments provide great material for collaborative agreements or team char-
ters documenting the activities of the team. In addition, these can be kept
on a website, in an online collaboration space, or in the form of short “ele-
vator ride” videos to post as reminders to everyone about how each team
member is contributing to the overall effort.
The inability of the team members to describe the vision toward which
they are expected to devote so much energy can result in dampened enthu-
siasm over time. Vaguely understanding the purpose or how their efforts
are interrelated and contributing overall can lead to people choosing to
work on projects where they can see a more immediate payoff. While we
often think about the leader as providing the vision for the team, if any
participant is having trouble seeing the end goal, it is likely that others are
too. Team participants have a critical role to play in making sure the work
of the entire group stays on track; this may include spearheading the dis-
cussion about individual as well as overall group goals.
Building a team
Teams can be built from the bottom up, wherein a group of investigators
come together with an interest in solving a scientific problem. Alterna-
tively, they can be formed from the top down, where the leaders of the in-
stitution have an idea around which they form a team. Both strategies can
work. However, for teams to really thrive, they need support from the
leadership.
Identifying people to join the team may happen organically in the be-
ginning. At some point, the members collaborating may actively seek out
additional people to join the project, as described earlier in this chapter.
While it may sound easy to identify a new team member, in practice it
might be more difficult. Think about it this way: if you are contemplating
participating in a team effort, that means you will not spend time doing
something else. It requires balancing your time and thinking about what
level of effort you are willing to commit.
Once you have decided to reach out to identify new collaborators, you
will want to think about the scientific expertise your group requires, the
time you will ask individuals to devote to the effort, and the degree to
which you would like each person to be integrated into the project. With
these things in mind, you can begin your search. It is a good idea to de-
velop questions for potential participants to help you determine if their
interests and motivations align with what you are looking for in a
collaborator.
There are three common strategies for developing interview questions
that can be useful to consider. They include behavior-, performance-, and
values-based questions. Behavioral-based interview questions focus on un-
derstanding how a potential team member would behave in very specific
circumstances. The candidate is asked specific questions about his or her
reactions, behaviors, or skills in specific situations. An example here would
be to ask the candidate how he or she managed conflict with another per-
son when working in a group setting. The performance-based approach
determines whether the person being considered for the position can actu-
ally do the job for which he or she is being considered. While a curriculum
vitae might say the candidate “led a team to successfully identify a gene
that modifies disease susceptibility,” the interviewer would ask the person
to “please describe how you successfully led a team to achieve the accom-
plishment.” Values-based questions are designed to learn about the values
of the candidate and to determine if they match those of the “ideal collab-
orator.” For example, these questions might focus on what interviewees
value most in their work environment as well as what annoys them. The
group identifies the most important characteristics for the ideal candidate
to have and then selects interview questions that will help them determine
if the candidate has the values of interest.
Will it work every time? Dr. Morales was excited about bringing on a
new team member. She prepared her questions for potential collaborators
so as to be sure there would be close alignment with the ongoing effort
with an emphasis on fit. Among the most important questions asked by
each person who talked to a candidate was some version of “Do you like
working in a team setting?” Everyone agreed that Dr. Miki would be a
good addition to the team based on discussions with him. About 3 months
into the project, it was becoming increasingly clear that although Dr. Miki
had the right scientific expertise and had great ideas, he was much more
interested in making sure he was receiving individual recognition and
credit for the team effort. He was leveraging the team’s work to get invited
260 Chapter 8
to give talks without consulting with the rest of the group. He was missing
many group meetings. And it appeared he was less than forthcoming when
it came to sharing data and results at lab meetings when he did come. Al-
though it was a challenging situation, Dr. Morales had a difficult conversa-
tion with Dr. Miki about the apparent difference in their individual
professional goals for participating on the team. They came to the mutual
agreement that Dr. Miki would no longer participate fully, but should the
group need his advice, he would still be willing to provide it.
Building a team also requires the leaders and participants to consider
what each person wants out of the collaboration. From professional growth
and development to accomplishment to feeling like they are helping make
a difference, the motivations behind the commitment can help the team
members support each other and ensure that each person’s goals are being
met—and if not, that they can work together to figure out how they can do
better.
Setting expectations
Who will lead the collaboration? Will it be a single leadership model or
will there be co-or multiple leaders? Who will do what in the collabora-
tion? How will the group members be held accountable for their responsi-
bilities? How will authorship be determined? Who speaks to the media if
they call for an interview? These questions, as well as many others, are
complex ones, often because the initial discussion(s) about the collabora-
tion is among a small group of people who may or may not be representing
others. How will the work assignments be allocated at both the intra-and
interlaboratory levels? Fleshing this out completely may take multiple dis-
cussions if several people will be involved.
The leaders from all sides of the collaboration should also talk about
how decisions will be made. One of the major threats that face people en-
tering collaborations is the need to share power, autonomy, and status.
Things the leaders could do alone may now need to be done together.
Things like adding new members to the collaborative team and determin-
ing when and how to terminate the collaboration (owing to either success
or failure) and how credit will be shared, with special attention to the more
junior members of the team, should be considered. To the extent possible,
all participants of the collaboration should share in the decision-making
process.
As mentioned previously, a collaborative agreement provides a strong
template for establishing expectations among team members as well as
clearly delineating roles and responsibilities. Agreeing to revisit and revise
this document at regular intervals is a good management idea both to cap-
ture changes in the direction the project is going and also to revisit the
roles and responsibilities of the team members.
Among the things to discuss when setting expectations is a proposed

time frame for the project. It may also be useful to establish checkpoints or
milestones: dates or events that prompt scrutiny and evaluation of the
project’s progress. These can be used to make decisions about continua-
tion, modifications, course changes, or termination of the work. Every-
body involved in the collaboration should be informed about these dates,
the expectations associated with them, and the expected duration of the
project.
Creating conditions for open and honest discussion

When considering the value of real estate, we are often advised that “loca-
tion, location, and location” are the three most important issues. Just sub-
stitute the word “communication” to make the same point about scientific
collaborations. Once a collaboration is established, sustaining and nurtur-
ing communication are imperative. Open and honest conversation about
every dimension of the collaborative process and its ongoing products is
vital to collaborative success.
Consider the following scenario. A recently tenured investigator asked
for a meeting with his mentor to talk about concerns he had about a col-
laborative project he was leading. He described the weekly group meetings
as having low levels of interaction; very few questions or challenges to the
data, analysis, or interpretation (even when it was clear something was not
working); and overall what he would characterize as little enthusiasm or
motivation in spite of the project being very exciting. The investigator and
mentor agreed that she would sit in on the next group meeting to observe.
Her brief 60 minutes at the meeting were enough for her to provide some
meaningful feedback to the team leader. When they debriefed, she asked
him if he ever noticed that each time someone tried asking a question
during the presentation he told them to hold their questions until the end.
And at the end, when he did permit questions, did he realize that he him-
self answered the questions, only permitting the person giving the presen-
tation to add something when he was done? She noted that there was
tension in the room. He was telling the group he wanted more discussion,
but when people tried to talk, and they did so tentatively, he dominated the
interactions. She suggested that the group members did not believe that
their input, observations, ideas, or suggestions were truly valued. They
were playing it safe by not speaking up. Trust and a safe environment had
not yet been established.
Collaboration is valuable precisely because people bring different per-
spectives to the project. Talk about your data. Talk about your ideas. Share
everything you can with your collaborators. Question the results. Ask if
there can be other interpretations. And most importantly, listen to the in-
put that is provided. Do not dismiss it out of hand. Give every idea and
262 Chapter 8
thought a fair hearing. Ask if others agree or disagree. And discuss it some
more.
There are many articles and books that talk about active listening. To
emphasize the importance of everyone giving his or her full attention during
group meetings, consider a ban on phones and mobile devices during the
meeting time. In addition, review the characteristics of active listening,
which include paying attention, as evidenced by looking at the person speak-
ing and focusing on what he or she is saying. People can show that they are
listening and that they understand by nodding their heads and asking clari-
fying questions if something is confusing. Also, try not to interrupt before
the speaker has finished. At that time, respond appropriately.
Schedule regular meetings to discuss data and take a look at the current
trajectory of the project. Has it shifted? If so, make the needed adjustments
to the project or the vision. Decide on the best approach for data sharing
and discussion. Refusal to share data, results, and information will breed
mistrust over time. Once mistrust emerges in a collaboration, it threatens
to derail the project if efforts are not made to address the issues at hand. It
is strongly recommended that if you suspect that trust is eroding you
should follow the agreed-upon approach for discussing it as quickly as pos-
sible and develop a strategy to repair it.
Keeping all of the team “in the loop” on the progress of the project makes
a lot of sense. While it can be challenging for groups working in different
buildings or locations at the same institution, not to mention different insti-
tutions in different states or countries, commitment to strategies to keep
everyone on the same page facilitates the efficiency of the collaboration and
keeps the opportunity open for anyone to contribute at will.
There are many electronic collaboration tools available, some of them
as open-source or free solutions, to keep the whole team up-to-date. A fi-
nal word on communication: be proactive. Don’t leave it to the other per-
son or even the leader. If you are not getting the information you need, it
is likely that others are not either. Bring the issue to the attention of the
group and offer up some ideas for how to correct it, which can then be
discussed and a final solution identified. And don’t assume that just because
you’re collaborating with a colleague in your department, proximity will
substitute for communication. It won’t. When collaborating, you have to
work as hard at communicating with someone in the next lab as you do
with someone on another continent!
Language
Different disciplines speak different languages. As such, when people
come together across disciplinary boundaries, it is good to be aware that
all researchers may not speak all the scientific languages represented by
the group members. Engineers, clinicians, basic scientists, and epidemiol-
ogists all use words, phrases, and jargon that may be unfamiliar to the
other disciplines. It is really obvious when we do not understand some-
thing because we are not familiar with the definition of the word we are
hearing—or we clearly hear it in a different context—and we can ask for
more information.
With science being more global, it is also common to find collaborators
from many different countries for whom the language in which the team is
conversing is a second language. Being aware of language as a difference in
an interdisciplinary group helps people ask clarifying questions, for con-
text, or about definitions when those situations occur.
It is just as important to realize that it is the words we have in common
but use differently in the different areas of science that can cause the most
trouble if we are not prepared for it. For example, at a meeting between
some scientists and information technology specialists who were working
together to develop an analytical tool to make available on a website, the
word “risk” was used. The meeting quickly devolved into a heated discus-
sion about whether the work should really be done. While the scientists
were discussing the work in the context of “high-risk/high-reward” re-
search, the information technology experts were thinking of the word
“risk” in the context of security and privacy concerns. Both groups had
their concept of the word, but failure to understand that the other side was
not using the same definition and construct took some time to sort out.
Teams will also sometimes create their own definitions for words or
sometimes metaphors in order to achieve shared understanding. While
this might be useful for the group, the members also need to remember
that they now have their own jargon that others will not be able to under-
stand. Again, awareness about the differences in language goes a long way
to helping avoid frustration and misunderstanding among the group mem-
bers or between the group and others with whom they are interacting.
Power
Power comes in many shapes and forms. It can show up in the form of
personal characteristics such as one’s skills, charisma, or work ethic. It can
also be conveyed by someone’s performance, output, or results. A person’s
reputation as well as his or her supporters, networks, and relationships can
contribute to the perception of power. It can also be conveyed by position,
role, title, and the ability to reward or punish others. Having information
is another form of power. If one person has information and others do not,
the person is in a powerful position as he or she decides whether to share
or withhold it. Finally, physical size and stature can serve as a source of
visible power.
We see and are provided with examples constantly about how power is
appropriately or inappropriately used during collaborative projects.
264 Chapter 8
Individuals with more power in the team setting have a responsibility to

proactively create environments where the participants feel safe. Team
leaders who can do this and minimize existing or emerging power imbal-
ances have better-performing teams. Through active listening, acting on
others’ suggestions, increasing communication, actively including others
in seminars or meetings where they had not previously been invited, and
not overreacting to mistakes, a leader can reduce the power imbalance in a
group setting. As a side benefit, these actions can also positively affect the
building of mutual trust and respect.
The inappropriate use of power can lead to a lack of psychological
safety. People with less power will cede to those with more. They do this to
protect themselves from rejection and for self- preservation. This, of
course, can cause tension. Types of power that can cause imbalance in
teams include the status of the position someone holds, for example, the
power imbalance that exists between a trainee and a supervisor. Another
type is role based, that is, the function someone plays in an organization.
As an example, an administrative role can become very powerful if it serves
as a gatekeeper to a person with high status or as a means to get critical
paperwork approved.
Examples of situations in which there is not a sense of “safety” in a sci-
entific setting include using power inappropriately to prevent a fellow or
junior investigator from going to a meeting or taking a professional devel-
opment seminar in order to keep him or her in the laboratory doing exper-
iments. Another example is instilling fear in junior colleagues such that
they believe that if they do not accommodate the desires of the more se-
nior scientist their careers will be in jeopardy. Another example would be
giving results generated by one person in the collaboration to another to
incorporate into a paper without discussing it with first person, not to
mention providing attribution or credit. In cases where the rationale for
the decisions being made is not transparent, communication about the jus-
tification is not occurring, or the actions are taken to demonstrate the
power one holds over another, a discussion is merited about power in the
scientific setting in the context of scientific integrity.
Collaboration can pose a threat to individual power, autonomy, and sta-
tus. For a truly collaborative effort, a single scientist is typically no longer
completely in charge. Instead, leaders share decision-making activities;
work with each other to define goals, scope, and objectives; and must be
willing to share status.
When people start working together, the different forms of power that
each may have are often shared with the rest of the group, although not
always explicitly discussed. As the group goes through the storming phase,
both leaders and participants should be aware that people are trying to find
their place within the group and to understand how they are going to
contribute substantively. Active management and facilitation of discussions

that help people see their role and place more clearly can help the group
move into the norming phase. Once a group is working well together, the
individual demonstrations of power will moderate and the group will func-
tion more as a collection of peers. Leaders who are interactive, provide
feedback, are receptive to new ideas, and are willing to be vulnerable with
their groups set the mood for the entire team.
In 2003, Amy Edmondson published a study that reported on the facil-
ity with which operating room teams learned a new surgical technique.
Those teams that had leaders who had created a psychologically safe envi-
ronment were more successful in making the change than those that did
not. These leaders created environments in which people with less power
were encouraged to speak up and challenge those with a higher rank and
true active listening was promoted. In those teams that were less successful,
people did not feel safe speaking up if they noticed a problem and they had
little power to question others. As a result, they stayed silent, even when
they had a valuable observation or input to offer the team.
Mentoring in the Era of Team Science
Serving as a mentor for individuals participating in a collaboration requires

a sensitivity to those characteristics that are required for successful team
functioning. Whether the mentee is participating as part of the group or
has been asked to lead a component of the project, he or she has a respon-
sibility to understand the opportunities associated with working on a col-
laborative project as well as some of the challenges, as set forth in this
chapter.
Developing self-awareness about how one interacts with others con-
tributes to effective work relationships. Understanding one’s own person-
ality characteristics, one’s approach to conflict, and how trusting one is at
the start of a relationship can provide a strong foundation for interacting
well with the group as well as further developing skills and abilities over
time. The ability to not only be aware of emerging conflict but also to
know what to do to try to preempt it is likely to be another area where a
mentor can help guide and advise the mentee. It would be surprising to
have a collection of people come together around a topic they are passion-
ate about without some disagreement. The key is in how that disagree-
ment is managed.
The final word about mentoring in this section would be to encourage
mentors to help mentees develop written agreements that articulate their
goals, roles, expectations, etc., in the context of the team work they are
contributing to. These agreements provide a way to keep the needs of the
mentee in focus and establish clarity on both what the mentee can expect
266 Chapter 8
from the collaborative experience and what the overall effort can expect of
the mentee. For a full discussion on mentoring, see chapter 3.
Diversity
The case for diversity in the scientific setting is being made at academic
institutions across the nation. Having people from different identity
groups bring their various skills, insights, backgrounds, and experiences
together adds value to the challenges before a group and the strategy used
to address it.
Barry Coller published a paper in 2008 that hits the nail on the head
when comparing the cultures of the physician and the basic scientist. The
contrasts he outlines in 10 areas, from adhering to standards of practice
versus being encouraged to challenge paradigms, to wearing suits and ties
versus dressing in jeans and T-shirt, resonate well for people who live in
these worlds. It is also striking that when physicians and basic scientists see
these differences presented in black and white, they have aha moments.
They get it, and the differences that can cause friction are suddenly put
into a context that is understandable and helps ease tensions.
There is a body of literature providing a case for diversity with respect
to problem solving and innovation. Having people who think about the
world in different ways; have different backgrounds and experiences; and
are familiar with a spectrum of tools, approaches, and knowledge bases can
have more impact when developing a strategy or solving a problem. Solv-
ing complex problems can be enhanced by maximizing differences such as
work styles, norms, values, and worldview.
Differences in personality, race, culture, and gender are equally valuable
and also require effective management in the team setting. The value of
greater diversity can be seen in various ways. In the medical setting, diver-
sity provides a strong advantage to truly understanding the needs of the
patient by bringing together different perspectives, backgrounds, and
experiences.
Increasing the diversity in the biomedical workforce is valuable pre-
cisely because each person will come to science with different perspectives
on what the most important problems facing us today are. For example,
men and women will have different perspectives on female and male re-
productive diseases and challenges. People from different racial or cultural
backgrounds may have very different views of disease and approaches to
detection, diagnosis, and treatment that can greatly influence how the
problem is approached.
It can be helpful to distinguish between diversity and inclusion. Diver-
sity has been described as the noun and inclusion as the verb. Whereas
diversity describes the composition of the workforce and provides a
definition for differences among team members, inclusion refers to the

actions and behaviors. Inclusion is demonstrated by active participation in
group decision making and through contributions to critical organiza-
tional processes.
Authorship
Discussions about authorship and authorship criteria should begin at the

outset of the collaboration if it is clear that publications will emanate from
the work. Certainly, deciding authorship on papers that report the results
of collaborative projects should parallel accepted norms (see chapter 4).
However, collaborative work can introduce some new considerations, and
working together to align the needs of those involved is well worth the
time and can avoid problems later.
Discussions of authorship should begin with the leaders of the collabo-
rative parties and subsequently involve all other participants in the project.
However, if the leaders do not initiate these discussions, a team member
should certainly call a meeting to discuss authorship criteria with the
group. This should be done early in the project, even though these deci-
sions can be difficult to make before the results of the project begin to
unfold. These discussions can be useful if for no other reason than that
they emphasize the value placed on credit attribution and establish rational
discussion as a means to achieve it. The question of proper credit needs to
be addressed at every point in the research process and with every person
involved in the effort. Discussions similar to those defining authorship are
also needed to decide who will be acknowledged in the published paper.
This, too, should involve all members of the collaborating teams.
In sum, the strategy for assigning credit and responsibility should be
established early in a research project, reviewed regularly, and revised as
appropriate. Participants in the collaboration need to remain flexible in
this regard. Contributions made by various collaborators during the pro-
gression of the project may change dramatically. This will change credit
attribution and, in turn, authorship priority.
Data Sharing, Custody, and Ownership
Collaborators must establish ground rules for the sharing of data that
emerge from joint research projects. The trust that must accompany a suc-
cessful collaboration undergirds data sharing activities. But unexpected
situations may arise, and collaborators must be prepared to deal with them.
Consider two labs collaborating to clone a transcription factor. Lab A has
purified the protein and prepared antibodies; lab B will screen an expres-
sion library to identify the clone. Clearly, lab B will receive a portion of the
268 Chapter 8
highly specific monoclonal antibody, and the resulting DNA clone will be
shared. Will lab B also receive the hybridoma cell line?
In a similar vein, consider a case in which lab C has isolated and deter-
mined the sequence of a cDNA that appears to encode a new member of a
protease family. Lab C collaborates with lab D—experts in that protein
family— by sending it in vitro translated protein for characterization.
Should lab D also expect access to the cloned cDNA? Cases like these of-
ten arise. Sometimes the same answer seems obvious to both parties; fre-
quently it does not. The resolution has obvious bearing on the abilities of
the individual labs not only to replicate portions of each other’s work but
also to undertake independent work at the conclusion of the collaboration.
The advisable course of action is to discuss and settle these issues as soon
as they can be foreseen.
All of these elements are things that can be included in a formal or in-
formal collaborative agreement. It cannot be emphasized enough that
written agreements can form very good scaffolds for building trust. They
capture the agreed-upon process that the group developed together. As the
group builds trust and becomes more cohesive, documenting decisions will
become part of how the group works together.
It is also necessary that all parties to the collaboration have a clear under-
standing of data ownership and custody issues. Usually, ownership will be
governed by the type and source of funds that have been used to support the
research. In the case of NIH funding, the data are owned by the grantee
institution (see chapter 9), and this will have implications for collaborative
research that is done at different institutions and supported by the indi-
vidual NIH grants of the collaborating principal investigators. The princi-
pal investigators and their respective grantee institutions will be subject to
the policies governing ownership, custody, and retention of data imposed by
the granting agency. Data books and research data created at one site will
thus remain at that site, in keeping with the policies governing the grantee
institution. But the sharing of materials— both during and after the
collaboration—must be worked out by the collaborators. The NIH data
sharing policy provides useful guidance on a wide range of topics related to
sharing research data and is recommended as a guide for collaborators.
Typically, guidelines on collaboration (and authorship) say that if some-
one provides research materials that are part of published results, the do-
nor of the materials is acknowledged in subsequent publications. Simple
provision of materials already described in the public domain usually does
not constitute grounds for collaboration. A National Academy of Sciences
report on sharing data states explicitly that “it is unacceptable to require
collaboration or co-authorship as a condition of providing a published ma-
terial, because that requirement can inhibit a scientist from publishing
findings that are contrary to the provider’s published conclusions.” Yet
situations involving exchange of materials are not always clear—again re-

call Drs. Rivera and Singh. When in doubt, be open and candid about the
interactions you and your colleagues may be heading toward.
Managing Conflict and Promoting

Disagreement
The major forms of conflict in the collaborative scientific setting fall into
two categories: disagreements about the science and personal conflict.
Managing scientific disagreement is probably the more comfortable of the
two. Many of the norms associated with working in a laboratory or clinical
setting on a scientific problem involve an iterative approach of advancing
knowledge. Scientific results are evaluated, discussed, and often debated.
The results from an experiment are sometimes anticipated, but often they
take researchers in a new direction. Not only is all of this expected, but it
forms the basis for robust and healthy scientific challenges and question-
ing, rethinking, and reformulating in the face of the interpretation of the
results.
So, not only do we encourage healthy conflict and lively discussions
about the science, it is expected. Forums, such as team meetings and jour-
nal clubs, are created specifically to promote disagreements and then to
chart a path forward. It is when the conflict turns personal, when emotion
hijacks someone in the group, that it is important to have tools at hand to
either preempt or resolve the issue.
Awareness of conflict styles, like awareness in other areas, can be ex-
tremely useful for all group members. Kenneth Thomas and Ralph
Kilmann studied conflict and developed an assessment that helps people
understand how they react in a conflict situation. In addition, their work
provides a rich construct for understanding how we and others view con-
flict. Armed with this awareness, groups can develop strategies for working
more effectively with people who approach conflict from a different
perspective.
Thomas and Kilmann characterize conflict along two different axes. In
one dimension they look at the level of cooperative behavior, and in the
other they look at assertive behavior. This then forms a 2  2 matrix in
which they place five descriptors of conflict behavior. At the low ends of
cooperativity and assertiveness they place “avoiding.” An “accommodat-
ing” approach is characterized by low assertive and high cooperative be-
havior. The “competing” style is placed at the junction of high assertive
and low cooperative behavior, and the “collaborating” style aligns with
high assertive and cooperative behaviors. At the intersection of these four
is a fifth descriptor, termed “compromising,” reflecting midlevel behavior
for both assertiveness and cooperativity.
270 Chapter 8
High
Compete Collaborate
Assertive behavior
Compromise
Avoid Accommodate
Low
Low High
Cooperative behavior
Adapted from the Thomas-Kilmann Conflict Mode Instrument
Each of the conflict styles has pros and cons. And each may be appro-
priate in a different situation. Typically, the major considerations boil down
to relationships and time. When you care about the relationships you are in,
you want to take an approach to the conflict that preserves that dynamic.
For example, if a relationship is important to you but the outcome of the
issue is not, you may choose to use an accommodating approach. However,
if time is critical, such as in an emergency, making the decision quickly out-
weighs the relationship and so the competing approach would be most ap-
propriate. When people are tired or under stress, they will fall into using
the approach that is most natural to them. This knowledge can help you
anticipate reactions to situations by your coworkers. It can also help you
learn that if you are going to try practicing a different style, it is better to do
so when you’re not tired or under stress.
Assessments are great, as they help us develop insights into our own
behaviors and characteristics, as well as those of others. The major draw-
back to them is that people who find it convenient to use descriptors as
labels can misuse them. The intent of the Thomas-Kilmann and other as-
sessments is to build self-awareness, provide a catalyst for exploring other
styles and approaches depending on the situation, and understand those
around us better with the intent of creating strong work relationships.
When you do find yourself in a situation that requires a difficult conver-
sation, there are steps you can take to maximize the chances of getting
through it successfully. The more frequently you practice, the better you
will get. And even if that means moving from horrible to not bad, that is a
great accomplishment.
The first step when you find yourself in a conflict situation is to deter-
mine whether it is important enough to try to resolve. Ask yourself, “What
is the purpose of pursuing a conversation to resolve the conflict?” If you
have a good answer, then it makes sense to move forward. Start with some
planning. Decide what outcomes are important for you at the end of the
conversation and the best approach for the discussion. Invite the other per-
son to meet with you and let them know ahead of time why you want to
meet with them. This gives them a chance to plan for the discussion as well.
Once you get together, share with the other person why you asked to meet
with them, frame the situation you are in, and invite them to talk about their
perspective first. By asking them to speak first and by listening actively, you
are letting them know you value their side of the story. In addition, when it
is your turn to speak, they are more likely to pay closer attention. Since they
have just spoken, they will not be mentally preparing what they are going to
say to you while you are talking. Once you both have had a chance to share
your side and perspective, see if you can identify what is called the “third
story,” that is, the explanation for how the disagreement arose that is likely
somewhere in between your two stories. The next step is to establish a path
forward. How can you get past this disagreement, and what can you do to
prevent disagreements in the future? Productive conversations require both
people to want to work together to solve the problem.
We recognize that the above paragraph makes this sound easy. It is not.
Having conversations like this is very difficult, and sometimes it is not pos-
sible to engage someone when the conflict is extremely strong or you feel
that it would be a risk to bring up. In situations like that, it is best to bring
in a third party to help facilitate or mediate the conversation. This can be a
colleague who is trusted by both parties or an ombudsman from the insti-
tution whose job is to help resolve conflicts in the work setting.
The best time for collaborators to decide how to manage conflict is
while they are starting to establish their working relationships. Just as
talking about the shared vision or setting expectations is important for
successful team functioning, so is agreeing ahead of time how the group
members will intervene, and giving them permission to do so, if it senses
emerging or active conflict among the project participants.
Collaborations with Industry
Collaborative research can involve the partnering of different sectors of

the research community. Joint projects involving various combinations of
academic, government, industry, and research institute participants should
272 Chapter 8
be guided by the above principles. But the operating practices of these

different entities can vary significantly, underscoring the need to define
and understand the constraints that affect the role of the participants and
the overall performance of the research. This is particularly important in
the case of any collaboration involving industry or those occurring inter-
nationally. Communication and understanding of requirements that are
part of these collaborations are critical to the success of joint projects.
University researchers increasingly enter into collaborative arrange-
ments with industry. These arrangements may bring with them restric-
tions on public disclosure and publication of the research. These constraints
may be inconsistent with pre-and postdoctoral training philosophies and
may have to be carefully weighed in that context. Is a project or subproject
appropriate as a dissertation or thesis topic? How might this affect the
trainee’s ability to publish results, which might be a requirement for com-
pleting his or her degree?
Then there is the issue of sharing research materials with the scientific
community. Collegiality and sharing are widely held as normative behaviors
in science, and these norms may be threatened by collaborative arrange-
ments involving corporate research partners. Again, careful consideration is
warranted as the benefits of the research are weighed against conditions im-
posed by the collaboration. Written collaborative agreements, as discussed
above, are important here; for industrial partners, this will be comfortable,
as they are accustomed to such things.
Special requirements may be imposed on decisions to publish material,
presentations at meetings, or the preparation of invention disclosures and
patent applications. Similarly, there may be confidentiality issues that go
beyond what a nonindustrial researcher is used to dealing with. There may
be implications unique to trainees.
A joint research project involving industry may fall under the aegis of
Good Laboratory Practices (GLP). This might be necessary because the
industry plans to use the research results to support applications for inves-
tigative or marketing permits. GLP prescribe procedures for document-
ing, recording, reviewing, and retaining experimental protocols and results.
The nonindustrial collaborator must be made aware of the intentions for
use of the data, and obviously, he or she must implement GLP to complete
a successful collaboration, which is a substantial commitment.
Collaborations with industry may directly and regularly involve more
participants than are usually encountered in other collaborations. For ex-
ample, lawyers, technology transfer and patent officers, marketing person-
nel, and sponsored research officials from both sides of the arrangement
may be involved in the collaboration.
Finally, there may be restrictions on the sharing of data or research ma-
terials both before and after publication. Frequently, industrial research
laboratories require the completion of a material transfer agreement

(MTA) before sharing research materials. However, these agreements are
increasingly used by academic or government laboratories as well, espe-
cially if there is some inherent IP value in research materials.
Typically, an MTA will specify the parties of the agreement, designating
them as “donor” and “recipient.” It will also specify what materials are be-
ing transferred to the recipient, possibly describing them in precise quali-
tative and quantitative detail. Then, depending on the nature of the
agreement, various other items will be listed. These may include (i) limita-
tions on use of the material (e.g., the material is only to be used for non-
commercial, research purposes); (ii) limitations or restrictions on
distribution of the material (usually the recipient is forbidden to transfer,
sell, or otherwise make available the material to any third party); (iii) con-
ditions of use (e.g., prohibiting use of the material with human subjects or
animals); (iv) conditions of publishing results obtained using the materials
(e.g., there may be a requirement to provide any manuscripts to the donor
before the submission for publication); (v) conditions for acknowledgment
of the donor in any disclosure of research involving the materials; (vi) war-
ranties concerning the material (usually the donor provides no warranty);
(vii) a “hold harmless” clause, releasing the donor from any legal liability
resulting from the recipient’s use of the materials; (viii) conditions for the
return of unused material, if appropriate; and (ix) the requirement of any
associated fees or financial conditions related to the transfer of the materi-
als to the recipient. Last, the MTA usually must be signed by individuals
legally authorized to represent the institution. For example, if the agree-
ment involves a company, the president, the chief executive officer, or a
designee might sign. If it involves a university, the authorized signator
might be a sponsored program or technology transfer official; the princi-
pal investigator may sometimes be required to sign the agreement as well.
Collaborations with International Partners
A collaboration between scientists in a modern industrialized country and

those in a developing country might involve a clinical trial of a new drug or
experimental vaccine aimed to control or prevent an infectious disease.
The developing country is a desirable location for this research because its
population is at high risk for the infection.
Awareness that collaborations involving international partners can en-
counter ethical and cultural standards in clinical research that differ from
country to country is critical. The culture and the ethical standards of
this country may influence the seeking of informed consent. For example,
a village leader or elder may speak for the members of the community.
Because of this, the scientists from the developing country may suggest
274 Chapter 8
that informed consent not be sought from each individual out of respect
for the cultural traditions of the community. An additional dimension of
this problem surfaces if we suppose that in this small village-based society
the concept of the germ theory of disease is unknown or is not accepted
by its members. Can there be a realistic expectation of informing poten-
tial experimental subjects of research concepts and risks under these
circumstances?
The existence of international guidelines addressing the use of humans
in biomedical experimentation, especially the Declaration of Helsinki,
should always set the tone for such research (see chapter 5). The position
that local traditions should never compromise scientific or ethical stan-
dards has been affirmed by some. Clearly, there is a need to identify and
deal with potential problems linked to ethical and cultural issues that have
an impact on international clinical research. These matters must be care-
fully discussed by all collaborators before any research begins, and tools
such as collaborative agreements are used to guide those discussions.
It is worth mentioning that when collaborating internationally, there is
a need to be mindful of cultural competence. Learning about a country’s
customs, expectations, and signs of respect in advance of a visit or interac-
tions is critically important. In addition, when it comes to the documents
this chapter has encouraged using, such as collaborative agreements, it is
important to step slowly to be sure the norms of the culture are well un-
derstood so that the suggestion of an agreement is embraced and not inter-
preted as a slight.
Potential conflicts that might affect the collaboration or the participating

investigators should be disclosed. For example, one investigator might be
supporting a small part of the collaborative research with a grant from a
biotechnology company. Suppose the research results have positive impli-
cations for a diagnostic test sold by the company. A collaborative paper is
written, submitted, and accepted for publication, but disclosure of the bio-
technology company support is not made. This fact becomes known after
publication, creating misunderstanding and suspicion that has an impact
on everyone involved in the collaboration. Thus, collaborators need to in-
form one another about all sources of support for joint research projects.
Together they must make appropriate decisions about disclosing potential
conflicts when presenting collaborative results, preparing papers, writing
reports, or submitting new grant applications.
Other potential conflicts of interest can arise as the result of collabora-
tions. Consider Dr. Salley, who chairs the Nicholas Foundation’s review
panel, which recommends funds for postdoctoral fellowships. Salley has

just started a collaborative research project with Dr. Strauss. Robert
Murphy, a postdoctoral fellow in Strauss’s lab, applies for a prestigious
Nicholas Foundation fellowship. Because the Salley-Strauss collabora-
tion is new, few outside of their labs know about it. Because Murphy is
not involved in the collaboration, Dr. Salley does not consider himself in
conflict as a reviewer. He provides a glowing review, and Murphy is
awarded a fellowship. But later, when the collaboration becomes well
known, other members of the review panel suspect Salley of bias in favor-
ing the Murphy application. Perceived or real, this conflict now has neg-
ative implications for both sides of the collaborative relationship,
including a potentially negative impact on Murphy, a bystander to the
collaboration. As discussed above, collaborators need to share informa-
tion that might create conflicts in peer review or other activities related
to the conduct of scientific research.
Miscellanies
Do not assume that previous successful collaborations will ensure the suc-
cess of future ones with the same colleagues. Positive collaborations some-
times create an environment for working together on subsequent joint
projects. But you must forge each new project with previous collaborators
using the same care and attention to detail as you did in the past.
Last, a word on collaboration and professional development of scien-
tists is in order. Institutions and review committees find it difficult to al-
locate appropriate credit for publications generated by faculty in
collaborative research projects. Because independent work is the prevail-
ing measure of scientific identity, junior scientists establishing their ca-
reers need to recognize the importance of balancing collaborative and
independent work.
For those involved in collaborative work prior to tenure, again, it is valu-
able to set up a pretenure agreement (described above) with the department
or institution that clearly outlines expectations for both sides. Some institu-
tions are collecting annotated curricula vitae for evaluation at tenure. An an-
notated curriculum vitae provides the investigator with the opportunity to
clearly state his or her role on every paper listed. Letters of support for
tenure, typically requested from noncollaborations, can also be collected
from active collaborators, as is done in the physics field. This is a robust way
to have the reviewer provide commentary specifically about how the scien-
tist under review is viewed by his or her peers with respect to leadership and
contributions to the collaborative work. The reviewer can distinguish active
contributions from riding on the coattails of the group effort.
276 Chapter 8
Conclusion
The value of collaboration in scientific research has been long recog-

nized. Modern-day collaboration has become commonplace, driven by
the need for interdisciplinary research to address questions in all fields,
especially the biomedical and life sciences. Consequently, collaboration
has become a critical component of scientific discovery. This is evident in
the authors’ bylines of papers and even in the awarding of Nobel Prizes.
The recipe for successful collaboration is dominated by communication
among the research team. This begins with the earliest discussions lead-
ing to the commitment to collaborate and spans all aspects and temporal
points of the relationship. The collaborative relationship is based on trust
and must be able to accommodate conflict and disagreement. Certain
kinds of collaborations—in particular those with industry or with inter-
national partners—present challenges that must be carefully addressed
using careful negotiation, relevant policy and guideline documents, and
in some cases, law. Beginning investigators should consider collaborative
opportunities, seeking advice from mentors, supervisors, and institutional
officials. The perceived need to collaborate should not outweigh the need
to demonstrate independence—a critical element in building a portfolio
of professional development needed for promotion.
1. Consider the faculty mentor-predoctoral trainee relationship. Do you

consider it to be a scientific collaboration as the term is discussed in
this chapter? If not, why? If so, is it fundamentally different from the
collaborative relationship between two faculty scientists? How?
2. Should scientific publishers limit the number of authors that appear
in the byline of collaborative papers? Why or why not?
3. Suppose you have been invited to collaborate on a research project
with someone you have never met. How will you proceed to reach a
decision on whether or not to accept the invitation?
4. Some journals allow shared first authorship on scientific publications
and some federal agencies allow co-principal investigators on grant
applications. How do you envision these policies having an impact—
positive or negative— on collaborative research? How could you
measure that impact?
Case Studies
8.1 Dr. Shirika Sands receives an e-mail message from Chris, a doc-
toral student in another department, asking her if she would be
willing to meet with him to talk about his research project. Chris explains
that he is setting up appointments to talk to some researchers who might

have some insights into the interdisciplinary project he is working on and,
more importantly, is also looking to identify someone who might be will-
ing to provide some mentoring. Dr. Sands, who has a strong reputation as
a collaborative and interdisciplinary researcher on campus, agrees to meet
him the next day for coffee. When Dr. Sands arrives, she is surprised to see
Chris in a wheelchair. She is not prepared for this, and many thoughts start
running through her head. She has mentored many students over her ca-
reer, but none with physical disabilities. Her surprise upon seeing Chris
gives way to thoughts of being uncomfortable about what she thinks might
be challenges associated with mentoring someone who is wheelchair
bound. Although anxious and distracted by her own reaction of surprise,
she has coffee with Chris, insisting that she pay for them both. Over coffee,
Chris tries explaining his project to Dr. Sands but starts to become con-
cerned that she seems distracted and is not really paying attention to him.
After about 20 minutes, Dr. Sands looks at her watch and says she needs to
get to another meeting. When Chris asks if he can contact her again, she
says yes, but that she is pretty busy and cannot promise anything. Chris is
left at the table wondering if he said or did something that caused Dr.
Sands to be so short with him. What could Chris or Dr. Sands have done
so that this encounter would have had a more positive outcome? What
advice do you have for Chris about the next steps in this process?
8.2 Dr. Aijuan Lee, a tenured associate professor of physiology, had an

idea she thought would be a great new translational project. To get
some more input and thoughts about her idea, she invited a few colleagues
to her office to discuss it informally. During the meeting there was lots of
discussion, ideas were thrown around, and a fair amount of enthusiasm
seemed to be building. In the end, the concept for the project had shifted
considerably and several of the invitees committed to collaborating on the
project. The new project team agreed to meet weekly to firm up the goals
of the project as well as to discuss how they were going to get some initial
data to demonstrate proof of concept. The following week the group
launched into talking about the project and designing experiments to find
a solution to the major structural hurdle, which had been elusive to other
researchers and would have tremendous scientific impact. As the meeting
progressed, Dr. Kelly, a colleague and Dr. Lee’s department chair, started
delegating duties to the rest of the group for completion by the next meet-
ing. Dr. Lee tentatively tried to intervene and suggest a different approach
to assigning duties, but Dr. Kelly appeared not to have noticed. Dr. Crispin,
an untenured assistant professor, pulled back from the table and became
hesitant about speaking up as more discussion ensued and assignments
were given. At the third meeting, Dr. Kelly opened the discussion and
278 Chapter 8
asked for reports from each of the participants. Dr. Kelly was visibly upset
when Dr. Crispin reported that the experiment assigned was trickier than
originally thought and it would take another week to generate results. Dr.
Lee, stepping in to try to lend support to Dr. Crispin, was again ignored by
Dr. Kelly, who moved on to hear from Dr. Anad. At this point of the meet-
ing, Dr. Anad, a full professor in the genetics department, invited the group
to take a short break before the next update. Dr. Anad had been both par-
ticipating and observing the dynamics of the meetings. After the break, Dr.
Anad, instead of giving a scientific update, invited the group to have a dis-
cussion about the overall project and the group dynamic. What should the
group talk about at this stage of their collaboration? Specifically, if you
were Dr. Anad, how would you frame the discussion that needs to take
place? What would be your goal, and how would you guide the conversa-
tion to move toward it?
8.3 Jane Watanabe, a professor of marine biology at Western State

University (WSU), studies evolutionary relationships among sea
turtles. Her federally funded research involves the isolation and analysis of
DNA extracted from blood samples obtained from an endangered species
of turtles. She arranges to spend 3 months at the Pacific Chelonian Re-
search Institute to obtain the necessary blood samples for her use. This
private research institute has a captive population of the endangered turtle
species she intends to study. It also owns property that includes beach and
tidal pool habitats where this same species of turtle can be trapped and
sampled in the wild. The director of the institute verbally authorizes her to
obtain samples from both the captive and wild turtle populations. In prepa-
ration for this work, Jane submits an animal-use protocol that is approved
by WSU’s Institutional Animal Care and Use Committee. She also pre-
pares an application for a Threatened and Endangered Species Collection
Permit, which she is granted. She is the principal investigator on both doc-
uments, with her university being listed as her sole professional affiliation.
She provides these documents to the institute director prior to her arrival.
Over the course of her stay, she collects several dozen blood samples,
which she processes and stores using the research institute’s centrifuges
and freezers. At the end of her stay, the institute director tells Jane that the
samples must remain at the institute. He guarantees her full access to all of
them but declares that the institute has ownership rights over these sam-
ples. He connects this to the institute’s custody of the captive turtles and
the wild turtles being sampled on the institute’s property. Jane disagrees
and argues that this is not in the spirit of the collaborative arrangement
that they verbally agreed upon. She suggests that the institute’s position
encroaches on her experimental design, and further asserts that the autho-
rizing documents—both protocol and permit—were issued to her as a
WSU faculty member and not to the institute. She calls you, the dean of
her school, and asks for advice and intervention to move the blood samples
back to the university. What do you tell Jane, and what, if any, actions will
you take to resolve this disagreement? What could have been done to pre-
vent this disagreement from taking place?
8.4 Dr. Anna Kryniak is a physician-scientist who is preparing a clini-

cal trial proposal to test an experimental drug for hemostasis (in-
duction of blood clotting) discovered by Meecham Pharmaceuticals. She
does not believe she will have enough patients to enroll at her own institu-
tion. On the recommendation of her supervisor she recruits two
investigators—Dr. Fazar and Dr. Miller—from other institutions to col-
laborate with her. Prior to contacting them upon the recommendation of
her dean, she knew neither Fazar nor Miller. Working with her new col-
laborators, Anna writes a proposal to Meecham to conduct a multicenter
trial with her institution as the coordinating site. The proposal is approved
and funded, and the study begins enrolling patients at all three sites. About
9 months into the trial, Anna learns from a colleague that Dr. Miller is on
the speaker’s bureau for the Meecham Pharmaceuticals. Concerned that
Miller never disclosed this to her, Anna thinks this constitutes a conflict of
interest. She immediately phones him for an explanation. Dr. Miller read-
ily admits that he is on Meecham’s speaker’s bureau but is adamant that he
only accepts speaking engagements when the topic is related to another
drug that is already approved by the Food and Drug Administration and is
unrelated to the experimental hemostasis drug. He claims that this frees
him from any conflicts of interest involving the hemostatic drug and that is
why he never disclosed his Meecham relationship to her. Anna absolutely
needs to have Dr. Miller’s institution stay engaged in the trial if she is to
accrue enough patients to be successful. Presently, enrollment at his insti-
tution exceeds the combined enrollment of the other two institutions. She
also fears that any papers from the study that Miller coauthors may be
dismissed by editors due to the perception of conflict of interest. Anna
ponders the formation of the collaboration: should she have done some-
thing differently that could have prevented this dilemma? Assuming that
she does have a problem now, what are her options for pursuing a solution?
She comes to you for advice.
8.5 Nicholas Cole and Lauren Hunter work on the genetics and bio-
chemical bases of asthma using mouse models. Their work has
overlapped at times, causing some intense debate between the two at na-
tional meetings. But a few years ago they entered into a productive collab-
oration. Nicholas, a biochemist, developed a powerful new assay for
components associated with the activation of immune cells. Lauren, a
280 Chapter 8
geneticist, had constructed a set of interesting knockout mice. Bringing

their respective contributions together, they collaborated to describe a
new signaling pathway of potentially great significance in the onset of
asthma pathology. Based on these findings, they coauthored and published
a major paper in a prestigious journal. They have not collaborated since
that publication, but both continue to contribute independently to the
field. Nicholas has just published a paper containing results that have neg-
ative implications for the pathway he and Lauren published 4 years ago.
Not only do his findings alter the understanding of the pathway, but they
call into question the validity of one of Lauren’s knockout mice used in the
collaborative study. Lauren is shocked when she reads the paper and im-
mediately writes to Nicholas with accusations about his conduct. She ar-
gues that the paper was an extension of their collaboration and that he
should have sent her a copy to review and comment on before submitting
it for publication. She is especially upset because she claims to have data
that would help inform his interpretations in this new paper. She argues
that she should have at least been named in the “Acknowledgments” sec-
tion but stops short of making a case for authorship on the paper. She
firmly criticizes his actions and declares that her trust of him has been un-
dermined to the point that she would not consider collaborating with him
in the future. She concludes the letter politely, mentioning that she has just
been appointed to a 4-year term on a federal study section. This is the
study section that has reviewed and is likely to continue to review all of
Nicholas’s grant applications. Nicholas is quick to view this as a threat.
Comment on the issues of collaboration raised in this case. In particular,
what is your analysis of Nicholas’s actions? What, if anything, would you
recommend he do now? Comment on the appropriateness of Lauren’s let-
ter to Nicholas.
8.6 You have had a radical idea regarding how to get eukaryotic cells to
take up large DNA fragments much more efficiently than was pre-
viously possible. You tell your colleague Maria about your idea and how
you plan on testing the hypothesis. Maria is not in your field of expertise,
but you spend some time explaining to her the details of your plan and the
expected outcomes. Maria offers a number of unsolicited suggestions on
how to improve the study. Because of her lack of experience, many of her
ideas are not practical or are very elementary and part of your study any-
way. However, Maria suggests some valuable control experiments involv-
ing DNA competition assays, which help you make a compelling case for
the novelty and efficiency of your method. Maria talks to you frequently
about the project and comes to several of your lab presentations. She com-
ments critically on your work and makes other suggestions, including the
idea that you try different cell types to further build your case. She offers
to try your method on several cell lines that are routinely maintained in
her laboratory. You are reluctant to do this, but you suggest that she give
you the cell lines so you can do the experiments. She complies, and the
experimental results you obtain with her cells further support your hy-
pothesis. You decide to submit a provisional patent application and then
submit your exciting results as a short communication to a prestigious
journal. Maria argues strongly that her name should be included both as a
coinventor on the application and as a coauthor on the manuscript. How
do you respond? What is the rationale underlying your response?
8.7 Dr. Catharine Reynolds directs a research team for a large pharma-
ceutical firm, MedScope, Inc. Dr. Reynolds has developed a genetic
cassette for cloning, identifying, and expressing eukaryotic cDNA. She has
used a commercially available, patented vector purchased from a biotech
company, Vector, Inc., as the platform to demonstrate the utility of the
cassette. In keeping with MedScope’s policy on reporting basic research,
she submits a manuscript for corporate review coincidentally with sending
it off for consideration by the journal Cloning Tools and Techniques. While
the manuscript is under peer review, Dr. Reynolds is notified by Med-
Scope’s legal review office that she may publish the paper but will not be
allowed to distribute the vector to anyone requesting it, even under the
authorization of an MTA. The reason given is that Vector, Inc. owns the
vector sequences in her construct, so they are not hers (or MedScope’s) to
distribute, even in derivatized form. Dr. Reynolds calls you, the editor-in-
chief of Cloning Tools and Techniques, and explains her dilemma. She pro-
poses to append a footnote to the paper indicating that corporate policy
prevents distribution of the construct described in the paper. However, she
will make the purified cassette available to anyone who requests it. This
will allow the construction of the ultimate vector. If the paper receives a
favorable review, will you allow it to be published with Dr. Reynolds’s sug-
gested modification? Why or why not? Are there other solutions to Dr.
Reynolds’s dilemma?
8.8 You and your collaborators, Drs. Arun Rao and Rachel Redhouse,
have submitted a coauthored paper reporting on the regulation of
a gene introduced by transfection into fibroblasts. The paper is returned
by the editor of the journal with two very positive reviews, suggesting only
minor revisions. While the paper is being revised, one of Dr. Rao’s post-
doctoral fellows—Ursula Enquist—presents data at a lab meeting demon-
strating that the results of the gene regulation experiments are dependent
on the concentration of DNA used to transfect the cells. Dr. Enquist pre
sents data showing that if the concentration of the gene construct is in-
creased 5-fold, the previously reported regulatory effects are completely
282 Chapter 8
abolished. In light of these results, Dr. Rao argues that the paper should be
withdrawn and not allowed to go to press. Dr. Redhouse strongly objects
to this. She argues that the results of the paper are reproducible and the
interpretations of the results are straightforward. Instead, she suggests that
the new results may be the basis for a whole new paper and that these data
should not even be mentioned in the present manuscript. In summary, Dr.
Redhouse argues that the paper should be published with the minor revi-
sions suggested by the reviewers. Your collaborators turn to you for your
opinion and for guidance on how to settle this dispute. What do you say?
8.9 The Biomolecular Technology Study Section of a federal funding

agency is reviewing two applications: one by Dr. Lisa Bitter and
one by Dr. Bob Doi. Both investigators have a long-standing reputation
for collaboration and coauthorship. In this case, however, neither investi-
gator lists the other as a coinvestigator on the application. During the
review process, the study section discovers that the introductory sections
of both applications are similar. In fact, several paragraphs in each appli-
cation are identical. A study section reviewer also points out that a major
section of experimental methods in each application is remarkably simi-
lar. Not only are there clearly identical paragraphs, but identical typo-
graphical errors exist in each application’s “Methods” section. During a
coffee break, informal discussion among some of the study section mem-
bers reveals that Bitter and Doi have had a falling-out and no longer talk
to each other, much less collaborate. After the break, the study section
meets and decides to review each application on its scientific merit and
not be concerned with the implications of the investigators’ relationship.
However, one member of the group objects strongly to this, saying that
plagiarism is involved in this situation, even though it cannot be sorted
out with the information at hand. He argues that every definition of sci-
entific misconduct he knows of lists falsification, fabrication, and plagia-
rism as transgressions that constitute misconduct. He accuses the study
section of “looking the other way” and neglecting its moral responsibili-
ties. Discuss the issues raised by the study section member, and suggest a
course of action for this review group.
8.10 Professor Sarah Samuels is collaborating with Global Pharmaceu-

ticals, Inc. Global has paid a small DNA sequencing company sev-
eral million dollars for the exclusive rights to the genome sequence of a
bacterial pathogen. Global makes the genomic sequence of this bacterium
available to Dr. Samuels, and she identifies several novel genes that encode
putative surface proteins. Using gene knockout technology, she determines
that one of these genes encodes a virulence factor that is likely to be a very
good target for an antimicrobial agent. She writes a major paper reporting
her research, and it is submitted to you, the editor of New Chemotherapies.

You proceed to solicit two ad hoc reviews. One reviewer is very positive and
recommends acceptance with minor modifications, but the other reviewer
recommends rejection. His decision is based on the fact that Dr. Samuels’s
discovery would not have been possible without access to Global’s genomic
database. He objects that, besides the company, Dr. Samuels is the only
person with access to this information. The journal’s policy is that all se-
quence data must be on file in a database freely accessible to the scientific
community. You reread Dr. Samuels’s paper and note that she does not re-
port any DNA sequence data in the paper. She characterizes the gene
product and demonstrates that a mutation in the gene renders the organ-
ism nonpathogenic. How will you act on this manuscript and why?
Resources
Print
Bennett LM, Gadlin H. 2012. Collaboration and team science: from theory to
practice. J Investig Med 60:768–775.
Bennett LM, Gadlin H. 2014. Supporting interdisciplinary collaboration: the
role of the institution, p 356–384. In O’Rourke M, Crowley S, Eigenbrode SD,
Wulfhorst JD (ed), Enhancing Communication & Collaboration in Interdisciplinary
Research. SAGE Publications, Inc, Thousand Oaks, CA.
Bennett LM, Gadlin H, Levine-Finley S. 2010. Collaboration and Team Science:
A Field Guide. NIH Publication No. 10-7660. National Institutes of Health,
Bethesda, MD. https://ccrod.cancer.gov/confluence/download/attachments
/47284665/TeamScience_FieldGuide.pdf?version=2&modification
Date=1285330231523&api=v2.
Burroughs Wellcome Fund. 2009. Excellence Everywhere: A Resource for Scientists
Launching Research Careers in Emerging Science Centers, p 145–156. Burroughs
Wellcome Fund, Research Triangle Park, NC. http://www.excellenceevery
where.org/images/book/excellence_everywhere.pdf.
Making the Right Moves: A Practical Guide to Scientific Management for Postdocs
and New Faculty, 2nd ed, p 201–210. Burroughs Wellcome Fund, Research Tri-
angle Park, NC, and Howard Hughes Medical Institute, Chevy Chase, MD.
http://www.hhmi.org/sites/default/files/Educational%20Materials/Lab%20
Clark PE, Cookson MS. 2008. The von Hippel-Lindau gene: turning discovery
into therapy. Cancer 113(7 Suppl):1768–1778.
Coller BS. 2008. Translational research: forging a new cultural identity. Mt Sinai J
Med 75:478–487.
Depret EF, Fiske ST. 1993. Social cognition and power: some cognitive conse-
quences of social structure as a source of control deprivation, p 176–202. In
Weary G, Gleicher F, Marsh KL (ed), Control Motivation and Social Cognition.
Springer-Verlag, New York, NY.
284 Chapter 8
Edmondson AC. 2003. Speaking up in the operating room: how team leaders pro-
mote learning in interdisciplinary action teams. J Manag Stud 40:1419–1452.
Estrada M, Brown J, Lee F. 1995. Who gets the credit? Perceptions of idiosyn-
crasy credit in work groups. Small Group Res 26:56–76.
Gabarro JJ. 1987. The development of the working relationship, p 172–189. In
Lorsch J (ed), Handbook of Organizational Behavior. Prentice-Hall, Upper Saddle
River, NJ.
Gadlin H, Bennett M. 2012. Dear Doc: advice for collaborators. Transl Behav Med
2:495–503.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin
I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Glenn GG, Rich-
ards FM, Crossey PA, Ferguson-Smith MA, Le Paslier D, Chumakov I,
Cohen D, Chinault CA, Maher ER, Linehan WM, Zbar B, Lerman MI.
1993. Identification of the von Hippel-Lindau disease tumor suppressor gene.
Science 260:1317–1320.
Lee F. 1993. Being polite and keeping MUM: how bad news is communicated in
organizational hierarchies. J Appl Soc Psychol 23:1124–1149.
Linehan WM. 2012. Genetic basis of kidney cancer: role of genomics for the de-
velopment of disease-related therapeutics. Genome Res 22:2089–2100.
National Research Council. 2003. Sharing Publication-Related Data and Materials:
Responsibilities of Authorship in the Life Sciences. National Academies Press, Wash-
ington, DC. http://www.nap.edu/catalog.php?record_id=10613.
National Research Council. 2004. Facilitating Interdisciplinary Research. National
Academies Press, Washington, DC. http://www.nap.edu/catalog.php?record
_id=11153.
National Research Council. 2011. Examining Core Elements of International Re-
search Collaboration: Summary of a Workshop. National Academies Press, Wash-
O’Rourke M, Crowley S, Eigenbrode SD, Wulfhorst JD (ed). 2014. Enhancing
Communication & Collaboration in Interdisciplinary Research. SAGE Publications,
Inc, Thousand Oaks, CA.
Thomas KW, Kilmann RH. 2002. Thomas-Kilmann conflict mode instrument.
CCP, Inc., Mountain View, CA. (Online access to the Thomas-Kilman
Instrument available for a fee at http://www.kilmanndiagnostics.com/catalog
/thomas-kilmann-conflict-mode-instrument).
Travis J. 1993. New tumor suppressor gene captured. Science 260:1235.
Tuckman BW. 1965. Developmental sequence in small groups. Psychol Bull
63:384–399.
Tuckman BW, Jensen MA. 1977. Stages of small-group development revisited.
Group Organ Stud 2:419–427.
University-Industry Demonstration Partnership. 2012. The Researcher Guide-
book: A Guide for Successful Institutional-Industrial Collaborations. Georgia Tech
Research Corporation, Atlanta, GA. http://www.industry.gatech.edu/files/
UIDP-Researcher-Guidebook.pdf.
Online
National Institutes of Health (NIH) information on multiple principal in-
vestigators on grant applications:
http://grants.nih.gov/grants/multi_PI/
The NIH data sharing policy:

http://grants2.nih.gov/grants/policy/data_sharing/data_sharing_guidance
.htm#goals
NIH Clinical and Translational Science Awards program:

https://www.ctsacentral.org/about-us/ctsa
NIH National Cancer Institute Web pages exemplifying integrative and

interdisciplinary research approaches:
http://physics.cancer.gov/
http://icbp.nci.nih.gov/
National Science Foundation information on interdisciplinary research is

available at
http://www.nsf.gov/od/iia/additional_resources/interdisciplinary_research/index.jsp
chapter 9
Research Data and

Intellectual Property
Thomas D. Mays* and Francis L. Macrina
Introduction • Research Data • Rights in Tangible Personal
Property • Trade Secrets • Trademarks • Copyrights • Patents
• Patent Law in the Age of Biotechnology • Seeking a Patent
• Conclusion • Discussion Questions • Case Studies • Authors’ Note
• Resources • Glossary
Introduction
I ntellectual property is a unique creation of the human mind. It neither

has tangible form nor exists apart from the context of the applicable
governmental jurisdiction. An observation of a natural phenomenon may
not constitute intellectual property. However, certain forms of commercial
utilization or graphic or electronic representation of such a phenomenon
would represent intellectual property. In fact, intellectual property only
exists as an exercise of a legal right of ownership conferred under statute or
common law. Intellectual property is usually categorized by associating it
with the laws covering its use and protection. Such classification yields
four types of intellectual property: patents, copyrights, trademarks, and
trade secrets. The protection of intellectual property was guaranteed in
1787 by the United States Constitution, which provides that
The Congress shall have Power . . . To promote the Progress of Science and
useful Arts, by securing for limited Times to Authors and Inventors the ex-
clusive Right to their respective Writings and Discoveries . . . (U.S. Consti-
tution, Article 1, Section 8)
*Counsel for Intellectual Property, Federal Trade Commission. The views ex-
pressed are those of the author and do not necessarily reflect those of the Federal
Trade Commission or any of the commissioners or staff.
doi:10.1128/9781555818487.ch9
287
288 Chapter 9
In 1980, a U.S. Supreme Court ruling had an important impact on bio-

technological intellectual property. Specifically, the Court ruled in Dia-
mond v. Chakrabarty (447 U.S. 303) that nonhuman life forms could be
patented if there was evidence of human intervention in their creation (see
Appendix V).
Every scientist who pursues a course of research using the analytical
methodology of observation along with hypothesis formulation and test-
ing follows a long tradition of experimental study. It has been the hallmark
of civilization that written records communicate observations, personal
impressions, and experimental designs to others geographically and tem-
porally distant from the immediate observer. Through such records, sub-
sequent researchers are able to build upon the work of others. This reflects
the central characteristic of scientific discovery; it is a process that builds
knowledge incrementally and then pieces that knowledge together in ways
that lead to major discoveries. Such discoveries contribute to our under-
standing of the world, and they often can be applied to practical situations,
leading to advancements that improve the quality of life. This serial ad-
vancement in scientific and technological fields has acted as an engine of
change that has helped transform societies from agrarian villages to robust
industrial centers. While this engine of progress may be fueled by curiosity
and personal interest, without a means of engagement, much like the oper-
ation of a clutch in an automobile, the progress of science and the useful
arts would stall or would have little forward movement. The creators of
the U.S. Constitution, in true “serial advancement” fashion, borrowed
from and improved upon the experiences of Europe dating back to the
13th century. Specifically, they authorized the protection of ownership of
intellectual property by authors and inventors.
The decades following the U.S. Supreme Court’s decision in the
Chakrabarty case have witnessed an explosion in the commercialization of
biotechnology. The certainty of intellectual property ownership in its
products has been cited as of utmost importance in preserving competi-
tiveness in the biotechnology industry. Biotechnology is viewed as one of
the most research-intensive industries in the world. In 2012, the top 10
biotechnology companies alone spent approximately $12 billion on re-
search and development.
The potential for biotechnological application makes a basic under-
standing of intellectual property important to scientists in the biomedical
disciplines. Of course, other scientific disciplines and areas of research—
including software development, electronics, and materials science—have
been similarly stimulated by rapid commercial growth and investment.
Such growth and development depend in large part on the protection of
new technologies as intellectual property. While this chapter will highlight
those aspects of intellectual property that relate to the biomedical sciences,
Research Data and Intellectual Property 289
this in no way is intended to suggest that intellectual property and data

ownership are limited to the biomedical sciences. Many of these principles
can be easily applied to new organic chemical processes, novel supercon-
ducting ceramics, devices for the high-speed transmission of data, and
many other research and development areas.
In this chapter, the principles of intellectual property will be discussed,
distinguishing between the ethical obligations and the legal rights of own-
ership in the results of scientific research. We will begin with a discussion
of the ownership of research data as a basis for building upon the concepts
of intellectual property. Through the use of the case study method, the
reader is encouraged to consider critically the responsibilities of the scien-
tific researcher under the principles relating to intellectual property rights.
Research Data
Ownership of research data

Dictionaries typically define “data” as facts or information that serve as the
basis for decision making, discussion and reasoning, or calculation. In the
biomedical sciences, intellectual property is almost always grounded in one
or more data sets. Thus, we will consider the basic tenets of data ownership
before discussing the various categories of intellectual property. The anal-
ysis of ownership of research data begins with the question: Who collected
the data? However, equally important is the question: Under whose intel-
lectual direction and guidance were the data collected? If the answers to
both questions are the same, that person(s) is the tentative owner. The
third question that must be asked is whether or not there was a valid obli-
gation to assign the rights in the data to another. This follows the old com-
mon law doctrine that workers are entitled to the benefits of their work
product, unless they are obligated to give that work product to another,
whether in exchange for money, under terms of employment, or under the
terms of some rule or law (e.g., the “work for hire” doctrine; see below).
When the National Institutes of Health (NIH) of the U.S. Department
of Health and Human Services awards a research grant to a university, any
and all data collected as part of that funded project are usually owned by
the university (commonly called the grantee institution). For example, the
data books of the principal investigator, predoctoral and postdoctoral
trainees, and other staff members working on the project are the property
of the grantee institution. Trainees should not be allowed to take their
original data books with them when they complete their training programs
and leave for new positions. However, the removal of copies of original
data or data books may be permitted on a variety of grounds, including
duplicative safekeeping and availability of information for manuscript and
report writing. Removal of duplicate copies of data should be subject to
290 Chapter 9
the approval of the principal investigator. If an investigator were to leave

his or her institution during the tenure of an NIH research grant, original
data generated as a result of the funded research would still remain the
property of the grantee institution. Grants can be transferred from one
institution to another when such relocation occurs, but this transfer must
meet with the approval of the original grantee institution as well as the
NIH. If a principal investigator does not elect to initiate the transfer of the
grant from his or her present institution to the new location, then the orig-
inal grantee institution must petition the NIH to appoint a new principal
investigator who would thereafter serve in that capacity.
Ownership is, in reality, an exercise of a property right (i.e., who is able
to exert control over the data, at what times, and under what conditions).
As in the exercise of any property right, the ownership is dependent on the
context of the property. The context of the property in turn depends on
how one protects the data, and this is defined by intellectual property law.
Release of research data into the public domain

The scientific community and the public can gain access to original re-
search data obtained as part of federally funded research grants or con-
tracts under the Freedom of Information Act (FOIA). This law allows one
to request nonclassified information that is available at any agency of the
federal government. Before passage of the Omnibus Appropriations Bill
for fiscal year 1999 (Public Law 105-277), a key consideration regarding
the data was whether they were in the possession of a federal agency, such
as the NIH. Thus, data records prior to 1999 that were not in the posses-
sion of the funding agency were not subject to an FOIA request. However,
under current federal regulations, those data records relating to published
research findings developed under a federal grant or contract—even if the
records are only in the possession of the grantee institution (i.e., the labo-
ratory of the principal investigator)—must now be produced, if not other-
wise exempt, in response to a request under the FOIA. This applies to any
data relating to published research findings regardless of the grantee’s re-
porting (or nonreporting) of the data to the NIH. Examples of such re-
ported data routinely found in the possession of a federal granting agency
would be those contained in a final report or a progress report that accom-
panied a new, competing, or continuation grant application. An FOIA re-
quest may be denied if the information is classified under a specified
exemption (e.g., trade secrets, commercial or financial information, or in-
trinsically valuable data used to support a patent application or to support
a request to the Food and Drug Administration for approval of a new
drug). The NIH routinely notifies and consults with institutions and in-
vestigators whose NIH-related research and training records would be af-
fected by release under a federal FOIA request.
States also have open records laws or freedom of information laws that
allow the scientific community and the public to request information in
the possession of state agencies including public universities, state-
supported research institutions, and the like. Similar to federal laws, state
laws have provisions for granting exception from release in order to pro-
tect sensitive information (e.g., unpublished research data). State universi-
ties typically have an office or an individual who receives and coordinates
the responses to requests for material under the state law. Often the uni-
versity will have a page on the institutional website that outlines the pro-
cess for submitting and handling requests. Researchers at public institutions
should be familiar with this process so as to ensure that such requests for
information are handled under the proper protocol and in compliance
with applicable laws. Researchers should never attempt to respond individ-
ually to a request for information made under the FOIA or an FOIA-like
law. Instead, requests made directly to them should be referred to the uni-
versity official in charge of the FOIA response process. Finally, private uni-
versities are not generally subject to state open records or FOIA-like laws.
However, research or training-related data requested from the NIH under
the federal FOIA law could lead to the public release of such information
held by the private institution.
Retention of research data

As discussed in chapter 10, the current rule regarding retention of research
data provides that the data be retained for 3 years from the date of the final
expenditure report filed with the granting agency. However, the rights to
data access of the granting agency exist for as long as the grantee is in pos-
session of these records. For example, if one should retain data books from
an NIH project that ended 17 years previously, the NIH would still have
access rights to them throughout that period. Finally, the NIH has the
right at any time to inspect any records of the grantee that are pertinent to
the award “to make audit, examination, excerpts, and transcripts.” Such
regulations for data retention may vary from agency to agency (e.g., public
funding agency or private foundation). Principal investigators should al-
ways be aware of the pertinent rules and regulations that are applied by
their funding sources. Also, many states have laws that address record
keeping that may extend the period required for retention, and researchers
should be familiar with and abide by such laws.
Data sharing
Topics related to the sharing of research data have appeared elsewhere in
this text. In chapter 4, we discussed the common practice of journal pub-
lishers making the sharing of research materials a condition of publication.
Such materials are expected to be shared at the cost of provision, in
292 Chapter 9
reasonable quantities, and must not be used for commercial purposes. In

addition, publishers commonly require authors to deposit specialized data
sets (e.g., macromolecular sequence data) in publicly available databases
for inspection and use by other researchers. We also discussed the mandate
from the U.S. government to certain federal research funding agencies to
formulate plans allowing for public access to peer-reviewed publications
resulting from research conducted with federal funds. This mandate also
includes improving public access to digital data—not necessarily contained
in scholarly publications—resulting from federally funded research. In
chapter 8, we discussed the importance of including language in collabora-
tive agreements that establishes rules for sharing data produced in joint
research projects. Here, we extend this topic, discussing the policies of
both the NIH and the National Science Foundation (NSF). Both of these
agencies explicitly support and expect the sharing of data and materials
that emerge from research carried out under their grants.
The NIH policy on sharing of research data is framed around the con-
cept of “final research data.” This term is defined as “recorded factual ma-
terial commonly accepted in the scientific community as necessary to
validate research findings.” Importantly, the definition excludes “labora-
tory notebooks, partial datasets, preliminary analyses, drafts of scientific
papers, plans for future research, peer review reports, communications
with colleagues, or physical objects, such as gels or laboratory specimens.”
The NIH declares the importance of data sharing and offers the following
reasons in support of this. Data sharing:
• reinforces open scientific inquiry

• encourages diversity of analysis and opinion
• promotes new research and the testing of new or alternative hypoth-
eses and methods of analysis
• supports studies on data collection methods and measurement
• facilitates education of new researchers
• enables the exploration of topics not envisioned by the initial
investigators
• permits the creation of new data sets by combining data from mul-
tiple sources
The NIH specifically mentions data sharing in its Grants Policy Statement
as applying to research carried out under all NIH grant awards. The state-
ment reads:
NIH believes that data sharing is essential for expedited translation of re-
search results into knowledge, products, and procedures to improve human
health. NIH endorses the sharing of final research data to serve these and
other important scientific goals and expects and supports the timely release
and sharing of final research data from NIH-supported studies for use by
other researchers. “Timely release and sharing” is defined as no later than
the acceptance for publication of the main findings from the final data set.
There also are specific requirements in the NIH data sharing policy.
First, all NIH applications that will produce novel, genetically modified
variants of model organisms are expected to include a plan for sharing such
organisms or a statement explaining why sharing will be restricted or not
possible. Model organisms include but are not restricted to (i) nonhuman
mammalian models such as mice and rats and (ii) nonmammalian models
such as budding yeast, social amoebae, roundworms, Arabidopsis, fruit flies,
zebrafish, and frogs. Second, the NIH requires that investigator-initiated
grant applications with budgets of over $500,000 in direct costs in any
single year contain a plan that addresses how data sharing will be managed.
The NIH also may impose, at the agency’s discretion, the requirement of
the inclusion of a data management plan on specific funding opportunity
announcements regardless of requested budget amounts. Examples of
NIH data management plans may be accessed using information provided
in the “Online” section under Resources at the end of this chapter.
The NSF requirements for data sharing are broadly inclusive compared
with the NIH policy. The NSF data sharing policy first articulates the ex-
pectation that all NSF-funded investigators will share “primary data, sam-
ples, physical collections and other supporting materials created or
gathered in the course of work under NSF grants.” The NSF defines
“data” as covered by its data management plan requirement as that “deter-
mined by the community of interest through the process of peer review
and program management.” Data in this context may include “data, publi-
cations, samples, physical collections, software and models.” On the issue
of supporting data, the NSF says:
All researchers are expected to be able to explain and defend their results.
Doing so usually entails maintaining complete records of how data were col-
lected. The manner in which one maintains such records and makes them
available to others will vary from project to project. What constitutes rea-
sonable procedures will be determined by the community of interest through
the process of peer review and program management. These standards are
likely to evolve as new technologies and resources become available.
This statement affords latitude in the release of certain types of data

forms that are specifically exempted by the NIH policy (e.g., data books).
The language used by the NSF reflects the significant difference in the
missions of the two agencies. The disciplines that enjoy funding from the
NSF are broad and diverse compared with the NIH, which is mandated
to support human health- related research. Thus, the NSF embraces
seeking and using specific guidance from both outside and inside the
294 Chapter 9
NSF when dealing with what may or may not be considered reasonable
in terms of sharing materials and data. As an example, the NSF Director-
ate for Biological Sciences suggests that data management plans for grant
applications it oversees be organized according to the following
elements.
1. Describe the data that will be collected, and the data and metadata
formats and standards used.
2. Describe what physical and/or cyber resources and facilities (includ-
ing third-party resources) will be used to store and preserve the data
after the grant ends.
3. Describe what media and dissemination methods will be used to
make the data and metadata available to others after the grant ends.
4. Describe the policies for data sharing and public access (including
provisions for protection of privacy, confidentiality, security, intellec-
tual property rights, and other rights as appropriate).
5. Describe the roles and responsibilities of all parties with respect to
the management of the data (including contingency plans for the
departure of key personnel from the project) after the grant ends.
Legal protection of research data

The United States and many other countries recognize four specific forms
of intellectual property for which legal protection is available to the owner.
These include (i) trade secrets, (ii) trademarks, (iii) copyrights, and (iv) pat-
ents. The current body of laws providing for ownership or the exercise of
property right over these forms of intellectual property has developed over
a period that began with the articulation of intellectual property rights in
the U.S. Constitution. Under the federal system of government in the
United States, the states exercise primary jurisdiction over enforcement of
trade secrets and, to an extent, share jurisdiction with the federal govern-
ment over trademarks and copyrights. It should be noted that the Copy-
right Act of 1976 provided that federal law would exclusively govern the
protection and enforcement of almost all copyrights. Patent law has been
the exclusive purview of the federal government since the passage of the
Patent Act of 1790. While the original colonies granted patents (and some
granted copyrights), federal law quickly replaced that of the various states.
However, the legal right to exercise control over research data is a dif-
ferent consideration from when and how to ethically exercise such rights.
Because scientific research is based on the sharing of research data and
materials following publication, researchers may find that the failure to
share published information and materials may run counter to the publica-
tion policy of the journal in which they publish and the agreement be-
tween themselves and the journal publisher. Additionally, those funded
under a federal research grant or contract may have further obligations

regarding the sharing of data and research materials (see chapter 4).
Rights in Tangible Personal Property
There are generally two forms of property: real property, which pertains to
real estate or land; and personal property, which pertains to all other forms
of property. Personal property rights can be categorized as to whether the
property is tangible (having physical form) or intangible. Intellectual prop-
erty as generally discussed is intangible. While an embodiment of intellec-
tual property has a tangible form (e.g., a paper document for which an
author holds a copyright), the intellectual property itself has no physical
form. However, personal property rights, in addition to intellectual prop-
erty rights, exist in the tangible material itself (e.g., a personal property
right in the paper document per se, such as the right to possess). Similarly,
biological research materials, such as immortalized cell lines, are tangible
personal property for which the creator or assignee holds rights, in addi-
tion to any intellectual property rights that may exist in the materials.
As with any tangible personal property, the physical possession of the
property is one of the property rights. Other rights may include rights to
use, dispose, transfer, or assign. For example, most computer software li-
censes state that the licensee is a user of the software, but not an owner.
This reflects the rights in the limited use(s) of the intellectual property
(i.e., copyright). But the use of the physical embodiment of the software,
such as exists on a disk, is restricted. The licensor software vendor has the
right to take back possession of the software from the user.
To promote a policy of ensuring the public availability of results and
accomplishments from research funded by the U.S. Department of Health
and Human Services, institutions that have been awarded an NIH research
grant or contract are required to make available for commercialization or
research those products of research developed with federal funding that
are patentable but unpatented. Obviously, those products of research that
are patented were already covered under the regulations. A grantee institu-
tion may satisfy this requirement by granting a license under personal
property rights in the tangible research materials (e.g., biological materials
license), provided the license terms are no more restrictive than the terms
of a patent license, if those materials were patented.
The NIH found that in some instances grantee institutions, which have
a right to elect title to patentable inventions developed with federal funds
(see “Patents”), were not making the research materials publicly available
or were agreeing to license them only under restrictive terms that inhib-
ited public access. Under the prior regulations, the NIH could only elect
title to those patentable inventions for which the grantee institution
296 Chapter 9
declined to elect title. The NIH determined that its policy to promote
public access to funded research results was not furthered when grantees
exercised their property rights only in the tangible materials that were not
publicly available. Under current regulations, the NIH will assume title to
those patentable research materials developed with federal funds if the
grantee institution does not elect title or agree to conditions of public ac-
cess, at least for research purposes.
Trade Secrets
Legally defined, a trade secret means information, including a formula,
pattern, compilation, program, device, method, technique, or process, that
(i) derives independent economic value, actual or potential, from not being
generally known and not being readily ascertainable by proper means by
other persons who can obtain economic value from its disclosure or use;
and (ii) is the subject of efforts that are reasonable under the circumstances
to maintain its secrecy.
In other words, a trade secret is information that is not publicly known
but that confers an economic value upon its owner and that its owner takes
reasonable steps to maintain as secret. The protection of trade secrets is
governed by individual state laws, not federal laws. Traditional legal pro-
tection of trade secrets is founded upon principles of contract law and civil
misappropriation but does not cover unauthorized use per se. However, le-
gal action can be taken against someone who fails to keep the secret as
obligated under contract or a fiduciary relationship or against someone
who obtains the secret illegally. A federal trade secrets act provides crimi-
nal penalties for a federal employee who discloses without permission in-
formation that concerns or relates to trade secrets provided to the U.S.
government.
For information to qualify as a trade secret, the courts, in actions
brought for infringement, have based their decisions on such issues as the
following: (i) the information was not readily available by independent re-
search, (ii) the information must have been used in business operations,
and (iii) the information provided a competitive advantage. Other issues
used by the courts in determining the status of a trade secret have included
the cost of developing or acquiring the trade secret, who within the busi-
ness knows the trade secret, and what the business has done to ensure that
the information remains secret. However, independent research and “re-
verse engineering” approaches have been determined to be legitimate
means to obtain trade secret information.
The Economic Espionage Act of 1996 (Public Law 112-269) is a federal
criminal statute enacted by the U.S. Congress that provides for monetary
penalties, incarceration, and forfeiture of property for the theft or
misappropriation of trade secrets. While this legislation was primarily in-

tended to prevent foreign governments and businesses from illegally ob-
taining trade secrets of U.S.-based commerce, its definition of trade secret
casts a wide net.
Unlike other forms of intellectual property, there is no expiration date
for a trade secret. It is in force as long as the information remains secret.
This imposes a significant burden on the owner to take reasonable precau-
tions to ensure that trade secrets do not become publicly known. For ex-
ample, the recipe for the Coca-Cola brand soft drink has been maintained
for more than 100 years as a trade secret. However, the moment the com-
pany fails to maintain the information as a secret and the information be-
comes public, the owners will lose the protection of the trade secret. Trade
secrets may be assigned or licensed to other parties in the same manner
that any other form of intellectual property may be sold or leased. Such
arrangements require that the recipient be legally bound to keep the infor-
mation secret.
Sophisticated and powerful chemical, physical, and biological analytic
procedures make the use of some trade secrets impractical, especially in
the biomedical and biotechnological industries. Today, it would be diffi-
cult, if not impossible, to maintain a genetic cell line, sequence, or other
biological composition as a trade secret. Unlike purely chemical composi-
tions, many biological materials have the unique ability to replicate faith-
fully in vivo (e.g., cell line propagation) or in vitro (PCR amplification of
DNA sequences), thus lending themselves to analysis in ways that can yield
secret information. In short, trade secret protection for most biotechno-
logical intellectual property is impractical because of the resolving power
of modern analytic technology.
A corporation may wish to reveal trade secrets in connection with a
contractual award to support research done at a university or an outside
research institution. Such entities may decline to accept trade secrets due
to the responsibilities that accompany the possession of such information.
More to the point, if such a trade secret were determined to have been re-
leased to others, the university or research institution would be in the un-
desirable position of having to defend itself—whether or not it was at
fault—and could be subject to legal action, financial liability, and large
fines.
Trademarks
Trademarks embody pictures, sounds, writings, devices, or objects that allow

the owner to identify and distinguish some idea, concept, service, or product
from those of a competitor. Trademarks protect an idea that conveys the
goodwill or reputation of a product or service of the owner. Consumers
298 Chapter 9
often rely on trademarks to know what they can expect if they buy the prod-
uct or service. This affords a degree of predictability in commerce that is
important to business. A related mark is the service mark, which serves the
same purpose as a trademark but denotes a service rather than a product.
Trademarks may be registered at both the state and federal levels. Alterna-
tively, a trademark can be used without any type of legal registration; how-
ever, enforcement against an infringer of the mark may then be limited.
Federal trademarks are issued by the U.S. Patent and Trademark Office
(PTO) for a fee upon the filing of an application by the applicant and a
search conducted by the PTO. Trademark registration lasts for 10 years
but can be renewed indefinitely for 10-year periods (with fees and the fil-
ing of an application). Foreign trademark protection must be sought sepa-
rately in the foreign jurisdiction in which protection is desired. The
unauthorized use in commerce of a mark (trademark or service mark)
owned by a first party may constitute infringement by a second party if the
latter’s use creates a likelihood of confusion as to the source of the goods
bearing the mark. The courts have considered various defenses to an ac-
tion against an infringer, including (i) whether or not there was a likeli-
hood of confusion, (ii) whether the mark was valid, (iii) whether the use
was authorized, and (iv) whether the mark was merely a descriptive term.
Copyrights
A copyright protects the expression or presentation of an idea, but it does not

protect the idea itself. Work to be copyrighted must be fixed in some type
of tangible medium. This includes material that must be accessed in some
way with the assistance of a machine (e.g., audio or video recordings—
analog or digital—and computer storage media). Anyone can use your
ideas even if the expression or presentation is protected by copyright.
A copyright comes into existence the instant the author’s words or ac-
tions are rendered into some tangible form. Although formal action be-
yond this is not needed, it is recommended that appropriate forms be filed
with the U.S. Copyright Office. In addition, payment of a small fee and
deposit of the work with the Copyright Office are necessary. Copyrighted
works produced after 1977 by individual authors are generally protected
for the life of the author plus an additional 70 years. Copyrighted works
created on a “work for hire” basis (employee’s creation, but assigned as
work by employer; see below) are protected for 95 years from the date of
publication or 120 years from the date of creation (whichever comes first).
Assuming a copyright has not lapsed and the work entered the public do-
main, a copyright on material created and published before January 1,
1978, was in force for 28 years after initial registration and was
automatically renewed for an additional 67 years. Similarly, for works cre-

ated but not published before January 1, 1978, the term of a copyright ex-
tends to 70 years after the death of the author. For works created by an
unknown author, the copyright term runs for 95 years from date of publi-
cation or 120 years from the date of creation, whichever is shorter.
What may be copyrighted falls into two categories: original works and
derivative works. Original works include all forms of tangible expression
created independently by the author and not copied from any previous work.
An original manuscript prepared on your research findings that contains
text, figures, and tables is a good example of an original work. Derivative
works include those created by the author while relying on other works but
does not include the mere copying of those works relied on. As an example,
consider a review article that contains numerous previously published tables
and figures from the literature, along with the derivative author’s original
text interpreting, explaining, or discussing the published literature. Copy-
right permission would have to be sought and granted to use the figures and
tables, but as expressed in your manuscript they would be covered by the
copyright protecting your review article. Similarly, your review might dis-
cuss the research findings of several papers of others by paraphrasing their
writings. This is not a copyright infringement. Moreover, your new written
expression of their ideas enjoys its own copyright protection.
It is important to distinguish the requirement of originality for copy-
right purposes from the requirement of novelty for patent purposes (dis-
cussed below). Work that comprises material that is entirely in the public
domain cannot be copyrighted (e.g., common mathematical tables, calen-
dars). The U.S. Constitution provides that only an author is entitled to
secure copyright protection. The courts have reasoned that authorship
conveys a requirement of originality. The copyright statute similarly pro-
vides protection only for original works of authorship. While originality
may appear to be the same as novelty, “originality means only that the
work owes its origin to the author, i.e., is independently created, and not
copied from other works.” This requirement is in contrast to the prereq-
uisite of novelty for the patenting of an invention. All inventions, to be
patentable, must be novel; that is, the invention must not have been
known or used by others nor have been patented or described in a printed
publication in this or a foreign country. The copyright originality require-
ment is not as difficult to satisfy as the patent requirement of novelty.
Because originality is easier to meet, the validity of a copyright based on a
work’s originality is easier to defend than the validity of the patent based
on an invention’s novelty. Conversely, the proof of copyright infringe-
ment is more arduous and requires evidentiary showing of not only sub-
stantial similarity but also the act of copying.
300 Chapter 9
Consider the following example, which invokes the principles of origi-

nality and novelty. Laboratory technician Smith creates a computer soft-
ware program that measures the activity and identity of a radioisotope. Ms.
Smith’s intellectual property could be patented and copyrighted. The copy-
right protection would cover the actual written program (not the idea). The
patent would protect the method of measuring the radioisotope’s activity by
using data from the electronic output of an ionization chamber. The origi-
nality of the software would be easily established, since the concept origi-
nated from Smith. The novelty of Smith’s invention may not be so easily
satisfied if another had published a similar (but not the same) invention that
used the same elements or components of Smith’s invention. If a copyright
and patent were each granted to Smith, the validity of the copyright would
be difficult to challenge unless the challenger provided evidence of Smith’s
having copied the work of another. However, the challenge to the validity of
the patent might not be as difficult if a challenger were to provide the writ-
ten description of another’s invention that used the same elements or com-
ponents as Smith used and claimed in her patent.
The owner of a copyright has exclusive rights over reproduction, distri-
bution, sale (or other transfer), and if appropriate, public performance of
the work. The copyright owner also may authorize others to do the same.
Copyright is explicitly indicated by the symbol © along with the year of
publication or creation. The word “copyright” can be substituted for or
used in addition to the © symbol. The author’s (or owner’s) name should
appear along with this indication if not obvious elsewhere on the work.
Indicating copyright in this manner is recommended (but not required)
even for unpublished work. Language indicating restrictions is frequently
included. Examples of such restrictive language include the following.
• Copyright © 2012 by Jane Smith. All rights, including the right of presen-
tation or reproduction in whole or in part in any form, are reserved. This
would have special meaning for a work of drama, for example. Even
one scene from the play could not be performed publicly without
permission from the author.
• Copyright © 2013 by Jane Smith. All rights reserved. No part of this pub-
lication may be reproduced, stored in a retrieval system, or transmitted in
any form or by any means, electronic, photocopying, recording, or otherwise,
without the prior written permission of the publisher and authors. This
language speaks to the prohibiting of electronic scanning (or retyp-
ing) of material into an electronic format that could be accessed by
computer.
Coauthors own the copyright on their part of the work. If partitioning
of this sort cannot be plausibly done, then the authors are equal co-owners
of the copyright. They must let each other use the work, but it cannot be
licensed to another party without the permission of all the owners. Of

course, as with any property right, the true owner(s) may assign his or her
rights to another. However, assignment may not be required if the work
constitutes a “work for hire.” A work for hire is work prepared by an em-
ployee within the scope of his or her employment. Where the employer is
the hiring party and the employee has created a specifically assigned work
within the scope of employment, the employer will own the copyright.
Alternatively, work may be prepared on a special order, commission, or
contractual basis, and such work is also considered work for hire. In this
case, certain requirements must be met. Specifically, a written agreement
must exist that provides that the copyright will vest in the hiring party.
Furthermore, the work must fall into one of nine categories. These include
works or writings prepared as (i) a contribution to a collective work, (ii) an
audiovisual work (e.g., a motion picture), (iii) a translation, (iv) a supple-
mental work (i.e., something written to accompany a primary work, such
as a book foreword), (v) a compilation, (vi) a textbook intended for instruc-
tional use, (vii) a test, (viii) answer material for a test, and (ix) an atlas.
If an employee is assigned to write an instruction manual for a company
instrument, then the copyright belongs to the employer. If, however, the
employee writes such a manual without being directly asked or specifically
assigned, then the employee owns the copyright. One academic institu-
tional intellectual properties policy affirms this in the following way:
Assigned duty is narrower than “scope of employment”, and is a task or un-
dertaking resulting from a specific request or direction. The general obliga-
tion to engage in research and scholarship which may result in publication is
not an assigned duty. A specific direction to prepare a particular article, lab-
oratory manual, computer program, etc., is an assigned duty.” (Intellectual
Properties Policy, Virginia Commonwealth University, Richmond, 2014)
Thus, in the context of this language, faculty who prepare original articles
on their research findings hold the copyright to such material. When an
article is accepted for publication, the author(s) usually—but not always—
assigns the copyright to the publisher of the journal in which it will appear.
The NIH and funding agencies in general encourage the publication of
research results. The NIH specifically provides that appropriate material
created under a grant may be copyrighted by the grantee. In practice, this
usually means the principal investigator (and any coauthors) hold the
copyright. However, as with ascertaining any legal right, competent legal
counsel should be sought in order to understand the effect of all applicable
laws and regulations.
Current copyright law provides that fair use of copyrighted material will
not constitute an act of infringement. An individual may copy from a pro-
tected work as long as the value of the work is not diminished and such ac-
tivity is nonprofit in nature. Fair use activities must be related to (i) criticism,
302 Chapter 9
(ii) news reporting, (iii) teaching, or (iv) research or scholarship. Other con-
siderations of fair use include the nature of the work, the quantity and sub-
stance of the material being copied as compared with the copyrighted work
as a whole, and the possible effect of such use on the potential market for the
copyrighted material. Photocopying an article from a scholarly journal for
your personal (nonprofit) use is generally recognized as a fair use practice.
On the other hand, preparing a compendium of photocopied chapters from
several textbooks for use in a graduate course and distributing these docu-
ments at a fee to cover the copying costs would likely represent copyright
infringement. Such use could be reasoned to diminish value (i.e., students
would not buy the books). Thus, the market for the books would be nega-
tively affected. Similar arguments can be made for the photocopying and use
of articles from serial publications. Indeed, court rulings have been clear in
finding copyright infringement in cases when a person who does not hold
the copyright distributes photocopied compendia of works without permis-
sion of the copyright holder and when a third party copies and distributes
serial publication articles. The interpretation of fair use under the above-
mentioned criteria holds that the copying and use must be of a personal
(nonprofit) nature; that is, articles are copied by the individual who intends
to use them under one of the categories related to fair use. Recent case law
has held that reproduction and use of copyrighted documents for litigation
or in connection with federal agency business (e.g., use in connection with
patent applications before the U.S. PTO) generally falls under the doctrine
of fair use.
Computer software applications usually are covered by copyright law.
Inspection of the narrative associated with software purchased on media or
downloaded will reveal program copyright information. Usually, commer-
cially available software is marketed under a so-called end user’s agree-
ment. This type of agreement between you and the software seller provides
that you observe copyright law as it pertains to the computer program. Its
language usually indicates that the software is being issued to you under a
limited, nonexclusive license. This always means you cannot electronically
copy the program and provide it to other individuals for their use under
any circumstances. Transfer of the software or documentation in whole or
in part to another party is often explicitly prohibited. In some cases, these
agreements specify the conditions for personal use of the software. For
example, you might be able to install the program on no more than one or
two of your personal computers. Wording associated with software pack-
ages often states that you agree to the terms of the software license when
you break the seal on the software package or open the envelope that holds
the electronic or optical media. In the case of downloaded software pro-
grams, this assertion is affirmed by the end user clicking an “I agree” field
presented before installation of the program. Thus far, courts have been
readily inclined to enforce licenses protected in these ways.
Some software is marketed under agreements called site licenses. This
commonly applies to educational and business institutions and involves the
authorization of multiple users for a software program. In this case, the li-
cense is made to the institution, and the individual agrees to honor the
copyright that protects the software. Site-licensed software can be used
only at the institution that holds the license. So-called copy-protected soft-
ware makes the unauthorized use of software difficult, if not impossible.
Copy protection may be part of the software system itself or may involve a
hardware device that is sold with the program. Such protection prevents
copying or use of the software on machines other than the one on which
initial installation took place. Copy protection is used by some manufac-
turers for specialized or costly programs. An increasing number of con-
temporary software packages come with significant copy protection and
upon installation may require that the installer enter a specific serial num-
ber that is provided under the license. Without the serial number, addi-
tional copies of the software may not be subsequently installed. Thus, users
of such software are entrusted with ensuring the appropriate legal opera-
tion of purchased programs. Transgressions of computer software copy-
rights are morally and legally wrong.
In the late 1990s, the U.S. Congress passed two major pieces of legisla-
tion aimed at strengthening enforcement of copyrights: the Digital Mil-
lennium Copyright Act (DMCA) and the Digital Theft Deterrence and
Copyright Damages Improvement Act (Copyright Damages Act). The
DMCA was enacted to bring U.S. copyright law into conformity with in-
ternational treaties pertaining to copyright protection. The DMCA does
not change the concept of copyright but adds legal provisions that relate to
electronic forms of expression. It is explicit in affirming that it has no effect
on the extant “rights, remedies, limitations, or defenses to copyright in-
fringement, including fair use.”
The DMCA takes a two-pronged approach to enforcing copyrights
on digital works. First, it provides for digital “fingerprints” or antipiracy
measures in the work. To protect these digital fingerprints or antipiracy
measures, the DMCA contains two specific prohibitions. It makes it a
crime to directly circumvent or “crack” any antipiracy measures built
into software or to do so indirectly by selling or distributing tools or
technology designed to defeat any such measures. While the DMCA
does permit bona fide research on encryption, product interoperability,
and computer security that would involve the cracking of copyright pro-
tection or antipiracy measures, some researchers have expressed concerns
that the threat of litigation under the DMCA has cast a chill over the
304 Chapter 9
encryption and software communities. The second prong of the DMCA

approach is a “carrot and stick” strategy aimed at the backbone of the
Internet—the Internet service providers (ISPs). The DMCA states that
ISPs are expected to remove from users’ websites materials that appear
to constitute copyright infringement. Each ISP must designate a
person—the DMCA agent—who facilitates the implementation of this
process. The name and contact information of the DMCA agent must be
available on the website of the service provider. The DMCA provides an
ISP “safe harbor” from liability under the DMCA if the ISP unknow-
ingly transmits or stores copyrighted material on its servers but removes
it promptly upon notice to its DMCA agent from the copyright owner.
Copyright owners are more frequently using the services of third parties
to send DMCA take-down notices to ISPs. Recent cases (under current
law) appear to hold that copyright owners can obtain under court-
ordered subpoena from an ISP the names and addresses of persons who
store (or temporarily cache) copyrighted works on the ISP’s servers, but
not the names of those persons who use the ISP only as a conduit for the
transfer of data without any storage on the ISP’s servers.
The typical website of a university contains enormous amounts of in-
formation including, in many cases, individual faculty and student Web
pages. In this context, the university is the ISP. Suppose a biotechnology
company found copyrighted images taken from its website stored on the
Web page of a faculty member. Further assume that the company had no
record of the faculty member seeking permission to use these images, nor
was there any attribution of their source on the faculty member’s Web
page, nor was there any arguable fair use. The company would contact the
DMCA agent of the university with a request that this material be removed
from the website. The DMCA agent would be responsible for investigat-
ing and resolving this problem. Removal of this material might satisfy the
company but would not necessarily preclude it from filing a copyright in-
fringement claim. In this regard, the DMCA does limit the liability of non-
profit institutions of higher education for copyright infringement involving
the actions of faculty and students.
The Copyright Damages Act significantly increased the statutory mon-
etary penalties that a court can impose upon a party found to infringe a
copyright.
Patents
The term “patent” is derived from the Latin patens, meaning “to be open.”
This term refers to the royal grants of the British monarchy that were “let-
ters open,” or litterae patentis. The early British patents granted during the
14th through 16th centuries were in fact royal grants of monopoly in a
specific field or for a specific product. A corrupt practice of selling royal

grants for tribute brought such patents into disrepute.
The modern patent is a grant by a national sovereign government to an
applicant for a specific and limited period of time. In the United States,
while the patent is in force, the grantee has a legal right to exclude others
from making, using, selling, offering to sell, or importing into the United
States (collectively referred to as practicing) the claimed invention. The
grant of a patent is made in exchange for the grantee’s providing a full dis-
closure as to how the invention may be made, may be used, or functions.
This is the classic example of the quid pro quo (“this for that”), a contractual
exchange between parties. One party is the sovereign, acting on behalf of
society, who provides this limited period of exclusivity to the second party,
the patentee, in exchange for the patentee’s providing a full disclosure of
novel, nonobvious, and useful inventions. This exchange is viewed as one
of the most powerful forces for advancing the technological basis of a na-
tion’s economy. All developed nations have national patent statutes and are
signatories to international patent treaties.
A patent is governed by explicit law. U.S. patent law can be traced to
legislation presented before the first session of the First Congress. The
U.S. patent statutes are the product of several major revisions and recent
amendments. Current patent statutes are codified at Title 35 United
States Code (Supp. 2012). A major revision to the patent statutes was
made by the Leahy-Smith America Invents Act of 2011 (AIA). Under
U.S. law, a patent conveys the grant to an individual, coinventor (or joint
inventor), or group of individuals (coinventors) the legal right (personal
property right) for a defined period of time to exclude all others from
practicing the invention as claimed. The term of a U.S. utility or plant
patent begins on the date the patent issues and continues for 20 years
from the filing date of the earliest filed application (e.g., the term of a
patent issuing on January 11, 1996, from an application filed July 11,
1995, expires on July 11, 2015; note that this is an enforceable term of 19
1/2 years). Previously, the term of a U.S. patent was 17 years from the
date of issue, but the term of a U.S. patent was changed effective June 8,
1995, to bring the United States’ patent statutes into conformity with
those of other nations. For those few patents currently in force that were
filed before June 8, 1995, the law provides a transition period during
which a patent term is the longer of the two terms. If a patent claims a
composition of matter or process for using a composition of matter that
has been subjected to a regulatory review by the Food and Drug Admin-
istration, the term of the patent may be extended up to 5 years beyond
the original 20-year term. Design patents have a term of 14 years.
In return for this property right, the inventor provides full and complete
instructions regarding the claimed invention: how to make or use it, its
306 Chapter 9
useful purposes, and to an extent, how it functions. So a patent is a reward

for disclosing something of social value to the public. The law states that
Whoever invents or discovers any new and useful process, machine, manu-
facture, or composition of matter, or any new and useful improvement
thereof, may obtain a patent therefore subject to the conditions and require-
ments of this title. (35 U.S.C. §101)
Patent law is specific to individual countries, but there is much interest in

“harmonizing” patent statutes to promote global uniformity. Patent protec-
tion is guaranteed only in the country where the patent has been issued. A
U.S. patent on a specific invention does not preclude others from making,
using, or selling the invention in Japan, for example. However, a U.S. patent
that claims a process for making a composition or product may be enforced
and preclude the importation into the United States of the composition or
product even if the actions that would otherwise infringe the patent if per-
formed in the United States were performed in another country.
Contrary to common thinking, under the patent statutes a patent does
not give someone the right to make, sell, or practice the invention. It sim-
ply permits the inventor to exclude others from making, selling, or using the
invention. However, common law provides a right to the inventor to prac-
tice his or her invention. This right may be dominated by patents held by
others. For example, a patent claiming the use of a recombinant plasmid
for the overexpression of a gene could dominate a patent claiming the use
of that vector for the isolation of large quantities of a novel enzyme. In
such a situation, the parties involved would need to cross-license with one
another to practice their own invention or risk an infringement action.
Because a patent is considered personal property, it can be sold or trans-
ferred (assigned) to another or it may be rented (licensed) in whole or in
part for the full or partial term of the patent.
For subject matter or invention to be patentable, it must be useful, new
or novel, nonobvious, and reduced to practice. Reduction to practice must
entail either the actual reduction to practice by the creation of a working
model (which is operable) or the constructive reduction to practice by the
filing of a patent application that provides a comprehensive description
enabling one “skilled in the art” to practice the claimed invention. Inven-
torship of patentable subject matter requires both the conception and the
act of reduction to practice. The inventor of an invention who applies for
and receives a patent is recognized as the patentee or patent owner; his or
her rights under a patent are considered personal property rights and are
assignable.
In the absence of a written agreement to the contrary, the patentee
owns the patented invention. The employer may obligate assignment of
invention rights if the employee is hired to specifically perform research
and invent. However, an employment agreement providing that an em-

ployee would assign his rights in the future does not constitute an actual
assignment, even if the research was supported by federal funding under
the Bayh-Dole Act, which permits universities to hold rights to federally
funded inventions. In the case of Board of Trustees of the Leland Stanford Ju-
nior University v. Roche Molecular Systems, Inc. (131 S. Ct. 2188 [2011]), the
U.S. Supreme Court held that a Stanford researcher who signed an agree-
ment to assign rights in future inventions, but left Stanford without having
made the assignment, did not make an assignment of rights in a PCR se-
quencing invention. The court held that the Bayh-Dole Act does not oper-
ate to assign patent rights to universities relating to inventions arising
under federally funded research.
On the other hand, under the “shop right” state laws, the employer may
own a personal, nontransferable, royalty-free nonexclusive license to the
patent if the employee used the employer’s time, materials, or facilities in
the course of inventing. The scope of the shop right is determined from
the nature of the employer’s business, character of invention, circum-
stances of its creation, and law of the specific state of jurisdiction.
The point in time to file a patent should be as soon as the invention is
actually reduced to practice or as soon as the inventor is able to provide the
full and complete disclosure that is required to achieve the constructive
reduction to practice. In the United States, the former patent law permit-
ted the applicant to file an application within 1 year of the first disclosure
(of subject matter to be later claimed in an application), whether the dis-
closure was made by the applicant or another (publication of a scientific
paper or, in many cases, presentation before a public meeting). However,
the disclosure of an invention before the filing of a patent application
would result in loss of foreign patent rights.
Under current law (AIA), the applicant can still file within 1 year of the
applicant’s disclosure and not lose any patent rights in the United States
(foreign patent rights would still be lost). However, the disclosure by an-
other of the same invention even 1 day before the applicant filed the ap-
plication could result in loss of the applicant’s patent rights in the United
States.
Changes to the U.S. patent system under the AIA move patent law
closer to a “first to file” regime that is followed by most other countries.
If an inventor delays her patent filing, she may lose her patent rights if a
second inventor files his application covering the same invention before
the first inventor files her application. In this case, the second inventor
was first to file. One exception to this rule is when the invention is de-
rived by someone who learns of the invention from the inventor. Then
the PTO conducts a derivation proceeding to determine who invented
the subject matter.
308 Chapter 9
The filing of a provisional or regular utility patent application could

protect an inventor’s patent rights from public disclosure by anyone. A fil-
ing in the U.S. PTO can also protect the foreign patent rights if a subse-
quent foreign patent application(s) is filed within 1 year of the U.S. filing.
A provisional patent application is not examined by the PTO and does
not issue as a patent, but the provisional patent application does not re-
quire the same degree of formality as the regular utility application. The
provisional patent application may merely consist of a copy of a scientific
manuscript prior to its publication. However, crafting a provisional appli-
cation with an eye toward filing a regular utility patent application pro-
vides a good foundation for continuing to seek protection. For example,
such a provisional application might contain claims drawn to the invention
or later claimed subject matter. Generally speaking, the inventor is best
served by a provisional patent application that is as complete as possible so
as to provide an enabling or full disclosure of the invention that is subse-
quently disclosed and claimed in a regular utility or plant patent applica-
tion. If a regular utility or plant patent application and any foreign patent
applications are filed within 1 year of the date that the provisional patent
application is filed, patent rights in the United States and internationally
may generally be preserved. In summary, the provisional patent applica-
tion provides a convenient and inexpensive way to maintain protection of
inventions in terms of U.S. and foreign patent rights.
Patent applications are maintained as confidential by the U.S. PTO, and
the contents of each are not made public until a patent issues or when ap-
plications are published 18 months from the patent application filing date.
The commercial use of a method, machine, or composition of matter at
least 1 year prior to the filing date of a patent application by another claim-
ing the same method, machine, or composition of matter serves as a de-
fense to infringement of another’s patent claiming that same method,
machine, or composition of matter. The prior commercial use defense is
not transferable to a second party, except as part of a sale of the entire en-
terprise or line of business. Also, the prior commercial use is not available
if the commercial use is abandoned. The prior use by nonprofit research
laboratories or other nonprofit entities such as hospitals or universities, for
which the public is the intended beneficiary, more than 1 year prior to the
filing of a patent application is considered commercial use for purposes of
an infringement defense.
The types of subject matter that can be patented include processes, ma-
chines, products, or composition of matter. Patents can also be sought and
may be obtained for modifications or improvements to any of the above.
Any new and distinctive variety of plant that is asexually produced (except-
ing plants of the tuber-propagated family or plants propagated by seed) is
considered patentable subject matter under a plant patent. Sexually
reproduced plants and tuber-or seed-propagated plants can be registered

by the U.S. Department of Agriculture under the Plant Variety Protection
Act. The U.S. Supreme Court affirmed a lower court ruling that held that
sexually reproducible plants are also patentable subject matter under 35
U.S.C. §101.
Patentable subject matter that was developed under federal funding is
an important part of technology developed through university research.
The Bayh-Dole Act provides that research sponsored under a federal
funding agreement (grant, cooperative agreement, or most contracts) that
gives rise to an invention can become the property of the funded non-
profit organization or small business (contractor) if the contractor elects
to take title to the subject invention and notifies the funding federal
agency. The organization can only elect title if rights in the invention
were first assigned by the inventor (see the discussion above concerning
Board of Trustees of the Leland Stanford Junior University v. Roche Molecular
Systems, Inc.). When the contractor elects title, it (i) is required to period-
ically report to the federal agency on the utilization of inventions; (ii) is
required to place a notice in the patent specification (written description)
identifying the federal support; and (iii) must, if the contractor is a non-
profit organization, provide a share of the royalties of any licensed subject
invention to the inventor and utilize its royalties for scientific research or
education. In the event that the contractor declines to elect title to the
subject invention, the federal agency determines whether it wishes to
elect to take title. If the federal agency declines to elect, the inventor may
elect to take title, subject to the federal agency’s approval.
Finally, moving from the discussion of utility and plant patents, there
remains one additional type of patent: design patents, which provide pro-
tection for any new, original, and nonobvious design for a product (e.g., a
new automobile body).
Patent Law in the Age of Biotechnology
Evolution in U.S. patent jurisprudence may have a significant effect on the

development of new technologies. A number of controversies have erupted
over the patenting of life forms or their components. For example, some
years ago one report described the filing of a patent application for a
method for making creatures that are part human and part animal by com-
bining embryos of both and implanting these hybrid, or chimeric, embryos
into surrogate mothers. While the report noted that the inventor did not
intend to make such creatures, his goal was principally to provoke public
debate and possibly initiate a case that could reach the U.S. Supreme Court
concerning the morality of patenting life forms and engineering human
beings. The PTO released a “media advisory” entitled “Facts on Patenting
310 Chapter 9
Life Forms Having a Relationship to Human.” This statement by the PTO

outlined the agency’s responsibilities to issue patents that meet the statu-
tory requirements, including the utility requirement. The PTO further
noted that inventions directed to human-nonhuman chimeras may, under
certain circumstances, not be patentable because they may fail to meet the
public policy and morality aspects of the utility requirement. Such a strong
view of public policy on morality grounds under the utility requirement is
not universally embraced among members of the patent bar.
This is understandably a highly charged political issue; however, the
PTO’s position is that it can distinguish a legitimate medical research ani-
mal from a monster. Research scientists and patent attorneys may not be so
sure. Numerous patents are issued that cover transgenic animals, cell lines,
and other compositions that contain human genes. It is by no means clear
what constitutes the threshold amount of human genetic material required
to trigger such a holding of lack of utility on moral grounds. The PTO’s
position is based on an 1817 court decision that states that an invention is
patentable unless the invention cannot be used for any honest and moral
purpose. In this connection, others have observed that the law requires
that the invention not be frivolous or injurious on either practical or ethi-
cal grounds. Current law provides a minimum threshold of the utility re-
quirement and gives little weight to any consideration of the morality of
the use of the invention. The AIA of 2011 specifically prohibits the issuing
of a patent with a “claim directed to or encompassing a human organism.”
Until this provision of the law is interpreted by the courts, it is not clear
whether “human organism” is narrowly defined as a complete human be-
ing or broadly defined as transgenic human cells, tissue, or organs.
In August 2004, the PTO issued U.S. Patent No. 6,781,030, on “Meth-
ods for cloning mammals using telophase oocytes,” to Baguisi et al. and
assigned it to Tufts College. Claim 1 is broadly drawn to a method of clon-
ing a mammal by activation of an unfertilized enucleated mammalian oo-
cyte through nuclear transfer from a somatic donor cell of the same species.
There are also claims drawn to similar methods for producing a transgenic
mammal and producing a mammalian fetus, but there are no claims to the
cloned mammalian organism. Since the written description discloses ap-
plicability of these methods to human mammals, those claims that are not
limited to nonhuman mammals may embrace methods for cloning hu-
mans. This patent appears to fall within the PTO’s policy. Fiscal year 2004
legislation funding the PTO included a provision that prohibited the PTO
from issuing a patent on claims directed to or encompassing a human or-
ganism. However, the author of this provision stated in the Congressional
Record that this did not preclude method claims.
Another aspect of patentable biotechnology research relates to gene
therapy of the human germ line. Both human and nonhuman animals are
made of somatic and germ line cells. The germ line cells—egg cells and
sperm cells—have reproductive capability, while somatic cells do not. The
combining of the germ line cells during fertilization results in the genetic
composition of the embryo. So the genetic sequences of the germ line cells
are inheritable, being passed from parent to offspring. Genetic therapy di-
rected to the germ line may in some instances be more technically effective
in replacing or repairing mutations that cause disease. However, modifica-
tions in the germ line may affect generations, while somatic cell modifica-
tions affect only the individual. A number of patents have issued with
claims drawn to methods of gene therapy of somatic cells, but only a very
few have issued that may encompass gene therapy involving germ line
cells. It appears that the PTO is being very cautious in allowing claims
drawn to gene therapy of the human germ line. One such patent that is-
sued, U.S. Patent No. 6,677,311 to Evans et al. and assigned to the Salk
Institute for Biological Studies, is drawn to methods of inhibiting growth
or causing death of a tissue type or cell line, including germ cell line, of an
intact organism into which is introduced a genetic construct selectively
operable in the tissue type or cell line and that upon induction converts a
latent toxin into a cell toxin, thereby selectively and negatively affecting
cell growth. It may be more difficult for the PTO to deny such inventions
on grounds of utility and morality, particularly in view of the potential
medical benefits to patients suffering from inheritable genetic diseases. On
the other hand, without the incentive provided by secure patent protection
to invest in the costly and time-consuming research to create new medical
treatments, development of vectors and other compositions useful in hu-
man germ line gene therapy might be discouraged. Critics of genetic ther-
apy could view this inhibition of development as a way to protect the
natural evolution of human genetics. Of course, the PTO continues to be
on a firmer legal footing in refusing to issue any patent claims drawn to
compositions that could include humans, since the Thirteenth Amend-
ment to the U.S. Constitution precludes ownership by one person of
another.
Along these related lines of public policy, there is concern over the pat-
enting of expressed sequence tags and single-nucleotide polymorphisms,
which are partial genetic sequences. Many critics of the patenting of ge-
netic sequences view patent protection of large numbers of partial genetic
sequences as interfering with scientific research by impeding the free ex-
change of materials and information, although many patent applicants also
make their genetic sequence databases accessible. Others have expressed
concerns that the commercialization of human genetic sequences raises
ethical issues. The U.S. Supreme Court in a recent decision (Association of
Molecular Pathology et al. v. Myriad Genetics, Inc. et al.; 133 S. Ct. 2107 [ June
13, 2013]) held that naturally existing segments of DNA are not patentable
312 Chapter 9
but that a laboratory creation of a genetic sequence not existing in nature

may be (e.g., cDNA sequences do not exist naturally).
Statutes providing property rights in intellectual property are a mecha-
nism to achieve social goals, such as promoting technological and com-
mercial development as well as international economic competitiveness.
Whether those goals should be restricted or left open to competitive en-
terprise continues to be debated.
On a more technical level, the patenting of genetic sequences, like the
patenting of any other composition of matter, requires that the invention
be a useful, novel, and nonobvious composition. Further, the applicant
must provide an adequate written description of the invention and provide
an enabling disclosure of how to make and use the invention. In 1991, the
NIH filed a patent application for 351 genetic fragments sequenced from
brain tissues. The PTO rejected the application in 1993, and the NIH
chose not to appeal the decision. The courts have clearly stated that an
applicant’s general disclosure of a genetic sequence that fails to provide an
adequate written description of the invention will not support the patent-
ing of specific genetic sequences. In Regents of the University of California v.
Eli Lilly (119 F.3d 1559, 43 USPQ2d 1398 [Fed. Cir. 1997]), the court
found that claims to a human DNA-encoding insulin were not adequately
described by the disclosure teaching a rat DNA-encoding insulin. There-
fore, an applicant’s written disclosure of a partial genetic sequence may not
be sufficient to support claims drawn to the complete gene sequence. In
1997, the PTO issued its first patent that claims expressed sequence tags
encoding portions of novel protein kinases. The issue of the utility of ex-
pressed sequence tags has been addressed by the PTO in its Utility Exam-
ination Guidelines, which provide that claimed subject matter is patentable
only if the applicant has disclosed credible, specific, and substantial utility
of the invention as claimed.
Beyond the legal requirements for the patenting of cell lines, genetic con-
structs, and transgenic animals and plants lie the cultural issues that seek to
analyze whether such materials should be patented, even if patentable. Inter-
national debate has been stimulated by the patenting of human cell lines
isolated from clinical samples of indigenous peoples; the patenting of plants
used in religious rituals and considered sacred by Amazonian people; the
patenting of new varieties of plants that have been considered cultural assets,
such as basmati rice of India; and the construction of transgenic animals and
plants used for medical research and agriculture. As the world evolves a more
integrated economy, many of these intercultural views raise religious, eco-
nomic, and sociological issues that require ethical as well as legal analyses.
In the United States and many developed countries, the biomedical re-
search community, government leaders, and others have considered
whether the commercialization of biotechnology may be hampering the
sharing of research tools. Some note that proprietary genetic constructs

are not accessible to the research community, while complex commercial
license arrangements may be needed for the distribution of gene chips or
cDNA library arrays. Others consider that increasing competition for re-
search funding and an increasingly competitive global economy may exert
undue pressure on universities and other nonprofit organizations to seek
patent protection and commercialize research inventions. Still, the patent
system appears to remain a grand experiment that provides incentive to
the inventor through the grant of a limited period of exclusivity, which in
turn has stimulated the development of exciting new technologies and
greatly advanced the quality of life for millions throughout the world. The
patenting of biotechnology inventions remains a challenge to scientists
and nonscientists alike, but one principle remains clear: new inventions
will always arise. This will inevitably result in the continued evolution of
patent laws, which must take into consideration new societal needs and
concerns by changing in some instances from traditional precepts to more
responsive policies.
A misconception of traditional patent lore has held that patents may not
be obtained for methods of conducting business. In fact, the PTO has is-
sued thousands of patents claiming methods or processes for conducting
business. The PTO has established specific procedures to review business
method patents. In addition, the AIA provides for a postgrant review of
business method patents, in which anyone may request that the PTO re-
view one or more specific patents to consider whether claims drawn to
business methods are valid.
Further, the patenting of computer software has been fraught with re-
quirements that the software, to be patentable, must involve the transfor-
mation or representation of a physical object. The U.S. Supreme Court
will hear oral arguments in 2014 in Alice Corporation Pty. Ltd. v. CLS Bank
International, which concerns whether claims to computer-implemented
inventions— including claims to systems and machines, processes, and
items of manufacture—are patentable subject matter.
As mentioned above, most software programs are now protected via
copyright, certain rights under which are licensed to the end user. A num-
ber of patents have issued protecting software and business methods, but
the extent to which patent protection will affect the software industry and
the use of software in the future remains to be seen. Another feature of the
AIA of 2011 is the prohibition of issuing patents claiming strategies for
reducing, avoiding, or deferring tax liability. The AIA also implemented
the prior commercial use defense, which is expected to reduce infringe-
ment liability to patents claiming business methods. From the many cases
in which software patents have been litigated, a common weakness of those
patents found invalid has been the failure during the prosecution process
314 Chapter 9
to carefully compare the invention with the prior art. This applies to pros-
ecution of any patent application drawn to new forms of technology, where
few, if any, issued patents constitute the prior art. Typically, scientific arti-
cles or conference presentations will serve as the best prior art until the
technology field matures to the point that issued patents serve as prior art
to future applications. Therefore, it is in the best interests of inventors or
applicants to disclose to the PTO during prosecution of their application
relevant printed publications (as well as any other considerations as to the
patentability of the claimed invention, including any offers for sale, public
use or descriptions, or patenting by others of the claimed invention) so
that any patent that issues will have been well examined over the best prior
art available.
The patent system in the United States balances disclosure of new
inventions to promote progress and innovation against the incentive of
reward to inventors. Several reports published in 2003 and 2004 called
for a number of changes in the patent system to improve on this “balanc-
ing act.” One report published in 2003, by the Federal Trade Commis-
sion (FTC), a federal agency responsible for promoting competition, is
entitled To Promote Innovation: The Proper Balance of Competition and Pat-
ent Law and Policy. This report examines ways to improve the patent sys-
tem. Competition policy and patent policy are two federal policies that
have a great influence on innovation. Innovation is also greatly influ-
enced by scientific research and development programs conducted in ac-
ademic, government, and private laboratories. The National Academy of
Sciences has also studied the effects of the patent system on the U.S. re-
search and development effort. In 2004, it published A Patent System for
the 21st Century. This report makes several recommendations to improve
patent quality and promote innovation. For example, one of the corner-
stones of the AIA is the postgrant review of patents, similar to the oppo-
sition proceeding in Europe. Anyone can file a request asking that the
patent office review one or more specific patents to ensure they each
meet the novelty, nonobviousness, and utility the law requires. A second
suggestion is the greater harmonization among the U.S., European, and
Japanese patent regimes. The AIA provides for a first-to-file system as is
used in the rest of the world.
The FTC published another study in 2011, The Evolving IP Marketplace:
Aligning Patent Notice and Remedies with Competition. This FTC report “rec-
ommends improvements to two areas of patent law: policies affecting how
well a patent gives notice to the public of what technology is protected and
remedies for patent infringement.” For instance, better notice to the pub-
lic follows claims that are drafted in clear terms and that are well supported
by the patent’s written description section. A claim should not fail to give
notice of what the invention is, much like a poorly lit traffic sign should
not fail to give clear directions to drivers.
There are several remedies available to a patentee who successfully sues
an infringer. These include royalties and injunctions. The former rep-
resents monetary payment to the patentee, while the latter is an order by
the court preventing the infringer from infringing in the future.
Seeking a Patent
To obtain a patent in the United States, one files a patent application with
the PTO in Washington, DC (the main office complex is physically lo-
cated in Alexandria, VA, with regional offices in Detroit, Dallas, Denver,
and Silicon Valley). Most patent applicants file and prosecute their appli-
cations electronically. Prosecution of a patent application generally takes
from 1 to several years. In some fields of technology, particularly biotech-
nology, it may take from 3 to 5 or more years before the patent is granted.
Patent applications may be prepared and prosecuted before the PTO by
registered patent attorneys or registered patent agents. While the inven-
tor is always entitled to prepare and prosecute on his or her own behalf,
no one else may represent the inventor before the PTO unless he or she
is admitted to practice before the PTO. The requirement for patent at-
torneys or agents to be registered by the PTO is to ensure that only qual-
ified practitioners represent inventors. Patent prosecution procedures are
highly regulated, with myriad rules, regulations, and deadlines. The fail-
ure to meet a deadline may cause the applicant to lose his or her right to
obtain a patent. Generally, in the field of biotechnology, an uncompli-
cated patent application (e.g., utility patent) prepared by a law firm may
cost from $10,000 to $15,000. In contrast, a provisional patent applica-
tion, similarly prepared, may cost significantly less. However, if a provi-
sional application is poorly prepared and not fully enabling for the
invention as claimed in the later filed regular utility application, the pro-
visional application may be a waste of time and money and result in the
loss of patent rights. Submission of a patent application is no guarantee
that a patent ultimately will be issued.
The usual first step in the preparation of filing a patent application is
for the inventor to file an invention disclosure with the inventor’s em-
ployer or patent attorney. This is key to securing protection of intellectual
property in a patent. Invention disclosure forms vary from institution to
institution. The scope of information required by these documents is ex-
emplified by the information required on the invention disclosure used at
Virginia Commonwealth University (Office of Vice President of Research,
316 Chapter 9
VCU Innovation Gateway, Virginia Commonwealth University, Rich-

mond, VA). The required information includes the following.
1. Title of the invention.

2. Give a concise description of the invention, which should be suffi-
ciently detailed to enable one skilled in the art to understand and
reproduce the invention, and should include construction, principles
involved, details of operation, and alternative methods of construc-
tion or operation. Attach drawings, photos, manuscripts, and sketches
that help describe the invention. Is it a new process, composition of
matter, a device, or one or more new products? Is it an improvement
to, or a new use of, an existing product or process?
3. What is novel or unusual about this invention? How does it differ
from present technology? What are its advantages?
4. What uses do you foresee for the invention, both now and in the
future?
5. What is the closest technology currently available, upon which this
invention improves?
6. What disadvantages does this invention have? How can they be
overcome?
7. Has any commercial interest been shown in the invention? Please
give company and individuals’ names, and addresses if available.
8. What other companies or industry groups might be interested in
this invention, and why?
9. Please prepare a brief summary (~2 sentences) of the invention
that can be publicly disclosed. This summary should describe the
invention and its advantages without giving specific details of the
invention.
10. Has the invention been described in a “publication” (journal arti-
cles, abstracts, news stories, and talks)? Please provide details in-
cluding dates and copies of written material.
11. Do you plan to publish within the next 6 months? Please provide
approximate date and any abstract, manuscript, etc., available.
12. Is the invention related to any prior works in the literature or in the
patent database (U.S. Patent and Trademark Office at http://patft
.uspto.gov, European Patent Office at http://worldwide.espacenet
.com/?locale=EN_ep, and Patent Cooperation Treaty [PCT] Of-
fice at http://www.wipo.org/)? If so, please attach the results of
your searches.
13. Dates of record, demonstrable from lab notebooks, correspon-
dence, etc.
• Earliest conception:
• First disclosure date:
• First disclosure to whom:

• First reduction to practice:
14. Use of proprietary materials. Please indicate below whether any as-
pect of the invention is predicated on, or was made possible by use
of, proprietary materials obtained from an outside company, insti-
tution, or individual. Please attach any relevant material transfer
agreements (MTAs).
15. Please list all sources of support contributing to this invention (give
account numbers).
• University funds (department, etc.):
• Sponsored funds:
Besides the above, information must be provided concerning the inven-
tor(s) (name, address, etc.). Some universities may further require provi-
sion of the percentage of the contribution of each inventor to the invention.
Patent law only requires that each listed joint inventor has made a contri-
bution to at least one claim.
It is essential that the inventor maintain a properly kept laboratory
notebook. In addition to being crucial to preparing an invention disclosure
or patent application, the research laboratory notebook is frequently used
in responding to challenges either during the prosecution of a patent or in
postpatent litigation.
In his book Writing the Laboratory Notebook, Howard Kanare lists im-
portant points of record keeping relating to invention disclosures and pat-
ent applications. The conception of an invention that follows from work
should be clearly stated. This should be done in a way that documents your
own work and compares it to prior work and knowledge in the field. Your
laboratory record keeping needs to document that you have worked dili-
gently to reduce your invention to practice. Having your work witnessed
by someone who understands it provides important evidence in both the
filing of a patent and in postgrant patent litigation.
Conclusion
Intellectual property law has always been relevant to scientific research. Un-
derstanding and honoring copyright is a major part of the culture of scien-
tific publication and other types of communication. Copyright law also has
significant implications in Internet use and in the protection of source code
and computer applications. The ability to protect intellectual property by
patenting has been a driving force in the application and commercialization
of basic research. In today’s global economy, no existing or new area of tech-
nology can truly prosper and have its maximum impact without the benefit
of intellectual property law. This is especially true for the biomedical and
318 Chapter 9
biotechnological sectors. We continue to reap the benefits of the biological

and digital information revolutions of the last quarter of the 20th century.
The commercialization of numerous discoveries in both these areas can be
traced to many small companies whose competitive position was made pos-
sible by the powerful use of intellectual property protection.
1. What reasons argue in favor of journal publishers holding the copy-

right to articles they publish? What reasons, if any, argue against this
practice (i.e., authors retaining copyright to their material)?
2. How would you go about deciding whether some aspect of your re-
search merited seeking patent protection?
3. What do you see as the advantages and the disadvantages of patent-
ing the sequences of human genes?
4. If a faculty member creates an online course and posts it on her uni-
versity’s website, what are the issues relevant to determination of
who holds the copyright?
Case Studies
9.1 Rose Huong is in medical school at State University. While taking a

course that required extensive memorization, Rose developed a
computer program that generates flash cards and quizzes from content pro-
vided by her instructor, the textbook, and the course website. This program
was very helpful to Rose and she decides to use it for other classes. She de-
velops a database to keep all her material organized. She maintains the data-
base on her personal computer. Rose tells some of her friends about her
program, and through word of mouth other students hear about her pro-
gram and want to use it. Rose sees this as a good way to make some extra
money to help pay for school. She expands her database and adds all her
computerized notes and definitions from her previous courses over her past
2 years in medical school. This includes information taken from her text-
books, previous exam questions, Web pages, and lecture notes. Rose is care-
ful to cite the appropriate sources for the information. She then charges
students $40 for the program and $15 for course information within the
database. Are there copyright issues that arise from this scenario? Would it
matter if Rose only charged for the program and not the database? Can
State University claim intellectual property rights to Rose’s program? Have
her activities infringed on the intellectual property of her professors?
9.2 During a federally funded, authorized archaeological dig on city

property, Dr. Dylan Moore, an assistant scientist at Western Re-
search Institute, recovers a 120-year-old diary that contains identifiable,
sensitive data that can potentially raise genealogical issues for descendants
who live in the area. Dr. Moore includes some of these data in the first
draft of a manuscript he is preparing for submission to a prestigious, peer-
reviewed archaeological journal. In addition, the city’s historical society
museum has found out about Dr. Moore’s discovery and has asked him to
display the artifacts from the dig, including some of the pages of the diary.
As he edits his draft and considers the museum’s request, he becomes both-
ered by certain aspects of his work and the direction it is going. Some of
the descendants of people mentioned in the diary are now significant con-
tributors to Western Research Institute. He is pondering several questions.
Who owns the diary? Should the discovery of the diary be disclosed to the
descendants? Is the decision to provide materials to the museum his alone?
Are there conflict-of-interest issues looming in this scenario? He comes to
you for advice. What do you tell him?
9.3 Theo Drakos is a first-year graduate student in the department of

electrical engineering enrolled in an advanced course in digital cir-
cuit design. The course director has announced a major assignment, which
accounts for a portion of the final grade. The assignment is due in 3 weeks
and requires a costly software application program that the students were
required to purchase for use in the course. At the time the assignment was
announced, Theo had not yet bought the software program. Although the
software package is available in the university bookstore, an online vendor
is selling the exact same software package at a 50% discount off the univer-
sity bookstore price. Ted is lured by the attractive price and places an order
online. Because the order processing and shipment take 10 to 14 days,
Theo convinces his classmate Lana Karim to let him load her copy of the
software onto his laptop so he can complete his assignment. He’s con-
cerned that the delay in getting his own copy of the software will compro-
mise his ability to successfully complete the assignment. Lana is fine with
this arrangement and allows Theo to use her diskette and serial number to
install a functional copy of the program. They both agree that he will de-
lete her copy of the software and replace it with his newly purchased ver-
sion as soon as it arrives. Comment on the legal and ethical implications of
this scenario in terms of both Theo’s and Lana’s actions. Did either do
anything wrong? Does this scenario involve either a copyright or academic
honor code violation?
9.4 A postdoctoral fellow and his mentor have coauthored a paper de-
scribing their research results. This paper appears as a preliminary
report in a copyrighted monograph. One of the figures in the paper is a
computer-generated graph that describes data on a series of cellular growth
curves. The postdoctoral fellow and mentor are now preparing a major
paper for submission to a peer-reviewed journal. They both agree that the
320 Chapter 9
growth curve data in the monograph article are crucial to the story they
are telling in the present manuscript. Accordingly, they decide that this
same figure must be included in their present writing. Because they are
aware of potential copyright violations, they generate the exact same figure
using different typeface fonts and different line thicknesses for the ordi-
nate and the abscissa. They have decided that since this is not the exact
same figure that appeared in their monograph article, the use of it will not
constitute a copyright infringement. They also plan to indicate in their
manuscript that this figure has been “adapted from” the one initially pub-
lished in the monograph article. Comment on what these authors are do-
ing. Do you view it as copyright infringement? If so, are there conditions
of modification of tables or figures that would sufficiently change them in
a way that avoids copyright infringement?
9.5 Dr. Sophia Mondello has been invited by Dr. Peter Cook to write a
chapter on protein structure. Dr. Cook is editing an introductory
biochemistry text to be published by the Dawson Publishing Company.
Dr. Mondello is paid a one-time honorarium of $750 for her chapter. She
signs a property transfer agreement assigning the copyright for her manu-
script to the publishing company. The book does exceptionally well in its
first edition, and Dr. Cook signs a contract with Dawson Publishing to edit
a second edition. Because Dr. Cook was not happy with Dr. Mondello’s
original chapter, he invites Dr. Hanah Saleem to write the protein struc-
ture chapter for the second edition. Dr. Saleem writes the chapter using
three illustrations taken from Dr. Mondello’s original chapter. She also in-
cludes several of the end-of-chapter problems written by Dr. Mondello.
Most of the text of the second edition chapter was written by Dr. Saleem,
but there are several instances where parts of paragraphs are verbatim cop-
ies of those from Dr. Mondello’s original chapter. Dr. Cook advises her
that this is acceptable because Dawson Publishing holds the chapter copy-
right and has given her explicit permission to use any and all of the original
content. When Dr. Mondello inspects a copy of the published second edi-
tion, she becomes incensed. She tells you she plans to file scientific mis-
conduct charges against Dr. Saleem. Comment on both the legal and
ethical issues of this case. What advice will you give Dr. Mondello?
9.6 Dr. Helen Hefner subscribes to a scientific journal that is published

monthly in print and online. To access articles online, she must log
on to the journal’s home page with her user name and password. Dr. Hef-
ner’s research group is composed of several pre-and postdoctoral trainees.
She makes her user name and password available to each of her lab train-
ees, claiming that this is no different from circulating her printed journals
using a routing list. She encourages her trainees to print copies of relevant
articles appearing in the online journal. She cautions them that they should
make copies only for their personal use in order to be consistent with the
fair use doctrine of copyright law. Some of Dr. Hefner’s trainees regularly
peruse the online journal and print papers for use in their research. Others
in her group refuse to use the online journal, arguing that such a practice is
different from using the printed journal to make a photocopy for their
personal use. Do you agree? Do you think that Dr. Hefner’s policy is legal?
Is it ethical? Explain the rationale for you conclusions.
9.7 Jim O’Brien is serving a 4-year term as a member of an NIH study

section. His service is a matter of public record, and his name ap-
pears on a roster distributed with all written critiques to grant applicants.
In preparing his own grant application, Dr. O’Brien reproduces a table and
a figure taken from the “Background” and “Significance” sections of two
applications he has reviewed. In both cases, these materials have been com-
piled by the applicant investigators from data in the public domain. They
are not composed of data generated by the investigators who authored the
two grant applications. O’Brien indicates the origin of both items in his
own grant and attributes them to their authors. Is this legal? Is it ethical?
As the scientific review administrator of the study section, you learn what
Dr. O’Brien has done. What, if anything, will you do?
9.8 Dr. Ruby Gopal, a new faculty member in the chemistry depart-
ment, is assigned the directorship of the laboratory safety course.
The course has no syllabus, and over the next 2 years Dr. Gopal writes a
complete syllabus containing useful reference material, well-documented
procedures, and problem sets. She publishes a website that contains all the
syllabus material in a useful format. During her fourth year as an assistant
professor, her chair, Dr. Brenda Latrell, tells her that her faculty contract
will not be renewed. Brenda explains that the department is losing a posi-
tion because of budgetary cutbacks and Ruby’s position must be eliminated
in order to balance the budget. Ruby is very upset but lands a new job at
another university. She removes the course syllabus from the university
computer and uses it in a comparable course at her new institution. The
next year, Dr. Latrell decides to teach the laboratory safety course and in-
tends to use Dr. Gopal’s electronic syllabus. She is surprised to find it miss-
ing from the university’s computer. She learns that Dr. Gopal has taken all
the files for the syllabus website. Dr. Gopal claims she holds the copyright
and that the university can license the site from her for a fee of $2,500 per
year. Dr. Latrell is angered by this and reminds Dr. Gopal that she assigned
her the course directorship; thus, she considers the website as being done
on a work-for-hire basis. Dr. Latrell affirms that her institution holds the
copyright on the laboratory safety course website. Comment on the legal
322 Chapter 9
aspects of this scenario. Regardless of legal interpretation, do you consider

Dr. Gopal’s actions to be ethical?
9.9 Rhonda Rico, a postdoctoral trainee whose work is funded by a

research grant on which her mentor is listed as principal investiga-
tor, develops a powerful computer algorithm using a commercially avail-
able spreadsheet program purchased with the grant funds. The particular
analysis routine that Rhonda has developed works completely within the
spreadsheet application software. It is a sophisticated routine that has re-
quired many hours of design and testing. Moreover, Rhonda has made it
available to all members of the mentor’s lab and, based on their comments
over several months, has introduced many refinements and improvements
to the routine. In short, the system can take raw data from enzyme assays
and, together with physiological measurements made in animals, statisti-
cally analyze data sets and present the results in multiple graphic formats.
The application software used for this project was purchased under an ac-
ademic institutional site license. The software package is copyrighted by
the manufacturer. Rhonda is considering protecting her algorithm as intel-
lectual property before she distributes it to anyone outside of the lab. Can
she legally copyright the algorithm? Can she patent the algorithm? Can
she do both? Will any of these strategies serve any useful purpose? What
advice would you give her?
9.10 Susan Barnes, a cell biologist working in a pharmacology depart-

ment of a university, has isolated a novel soil microorganism with
powerful apoptosis- inducing activity against eukaryotic cells. She tells
Jesse Packard, a colleague of hers at a biotechnology company, about her
discovery. In turn, Jesse tells the vice president for research at the com-
pany, who then invites Susan to give a seminar there. After her seminar, the
vice president asks Susan to prepare a five-page proposal and says that the
company should be able to provide a grant to support some of Susan’s
work. The anticancer implications of this agent have commercial impor-
tance to the company. Susan writes a proposal that aims to purify the ac-
tivity and test it against various cell lines. The grant application is
submitted, and an appropriate agreement about intellectual property is
executed. The company will have first right of refusal to license the com-
pound from Susan’s university, pending her results. The grant is paid as a
one-time $75,000 award. The grant provides that Susan should share re-
search materials with the company on a nonexclusive basis. About 1 month
into the project, Jesse asks Susan to send him a culture of the microorgan-
ism, and she honors this request. A team of scientists at the company have
come up with some predictions about enzymes that are likely to be
involved in the synthesis of this apoptosis-inducing agent. Over the course

of the next several months, they clone the corresponding genes and deter-
mine that the pathway for synthesis of the compound is composed of the
products of 19 linked genes. They determine the nucleotide sequence of
this 35-kb operon. Who owns patent rights for this important biosynthetic
operon? Based on your reading, do you think that the company and its
scientists acted legally? Did they act ethically?
Authors’ Note
This chapter does not purport, nor is it intended, to provide legal advice.
The reader is advised in all instances to seek advice from competent legal
counsel to ascertain his or her legal rights regarding intellectual
property.
Some of the cases in this chapter have solutions that impinge on intel-
lectual property law. Discussants are cautioned against assuming that
their proposed solutions to these cases— based on reading and class
dialogue—may be legally definitive. Typically, such cases that require le-
gal solutions would depend on the analysis of all facts and consideration
of current law. This is usually not possible in the scientific integrity class-
room. The cases present limited fact patterns designed to provoke dis-
cussion based on the general outline of intellectual property law discussed
in this chapter.
Resources
Print
Charmasson H, Buchaca J. 2008. Patents, Copyrights & Trademarks for Dummies,

2nd ed. Wiley Publishing, Inc, Hoboken, NJ.
Council on Governmental Relations. 2012. Access to and Retention of Research
Data: Rights and Responsibilities. Council on Governmental Relations, Washing-
ton, DC. http://www.cogr.edu/Pubs_ResearchAdmin.cfm.
Kanare HM. 1985. Writing the Laboratory Notebook. American Chemical Society,
Washington, DC.
Miller AR, Davis MH. 2012. Intellectual Property, Patents, Trademarks, and Copy-
right in a Nutshell, 5th ed. West Academic Publishing, St. Paul, MN.
National Research Council. 2003. Sharing Publication-Related Data and Materials:
Responsibilities of Authorship in the Life Sciences. National Academies Press, Wash-
National Research Council. 2004. A Patent System for the 21st Century. National
Academies Press, Washington, DC. http://www.nap.edu/catalog.php?record
_id=10976.
324 Chapter 9
Online
Copyrights
The website of the U.S. Copyright Office contains much general infor-
mation about copyrights as well as a search engine for finding copyright
registrations:
http://www.copyright.gov/
Data sharing
Data Sharing Regulations/Policy/Guidance Chart for NIH (National In-
stitutes of Health) Awards:
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_chart.doc
The NIH’s Frequently Asked Questions about Data Sharing Web page
includes the definition of “final research data” and other important contex-
tual information on research data and data sharing:
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm#898
The NIH Data Sharing Policy and Implementation Guidance Web page
includes sample data sharing plans:
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm
NIH Grants Policy Statement, which contains the data sharing policy
(Section 8.2.3.1):
http://grants.nih.gov/grants/policy/nihgps_2010/nihgps_ch8.htm#_Toc271264950
NIH Data Sharing Policy brochure:

http://grants.nih.gov/grants/policy/data_sharing/data_sharing_brochure.pdf
NIH Policy on the Sharing of Model Organisms for Biomedical Research

brochure:
http://grants.nih.gov/grants/policy/model_organism/model_organism_brochure
.pdf
National Science Foundation’s (NSF) Dissemination and Sharing of Re-

search Results Web page:
http://www.nsf.gov/bfa/dias/policy/dmp.jsp
NSF information on data management plans for grant applications to the

Directorate for Biological Sciences:
http://www.nsf.gov/bio/pubs/BIODMP061511.pdf
Federal Trade Commission resources

The 2004 report To Promote Innovation: the Proper Balance of Competition
and Patent Law and Policy can be accessed at
http://www.ftc.gov/reports/promote-i nnovation-p roper-b alance-c ompetition
-patent-law-policy
The 2011 report The Evolving IP Marketplace: Aligning Patent Notice and
Remedies with Competition can be accessed at
http://www.ftc.gov/reports/evolving-i p-m arketplace-a ligning-p atent-n otice
-remedies-competition
Freedom of information
The National Freedom of Information Coalition website is maintained by
“a nonpartisan alliance of citizen-driven nonprofit freedom of information
organizations, academic and First Amendment centers, journalistic socie
ties and attorneys.” This site contains current information on Freedom of
Information Act issues.
http://www.nfoic.org/
Genetic technology and intellectual property

National Human Genome Research Institute’s Intellectual Property and
Genomics Web page:
http://www.genome.gov/19016590
A 2013 article discussing the Supreme Court’s review of Myriad Genetics’

gene patents can be found at:
http://biotech.about.com/od/Biotech-and-society/a/The-Supreme-Court-Reviews
-Myriad-S-Gene-Patents.htm
For an analysis of the decision on SCOTUSblog, see:

http://www.scotusblog.com/2013/06/opinion-recap-no-patent-on-natural-gene
-work/
Intellectual property: general information

AIPLA (American Intellectual Property Law Association) is a bar associa-
tion of attorneys in private and corporate practice and government service
and offers a number of useful documents, specifically How To Protect and
Benefit From Your Ideas:
http://www.aipla.org/learningcenter/library/books/other-pubs/Documents/How
_To_Protect_and_Benefit_From_Ideas.pdf
326 Chapter 9
Patents
Information on patents and other forms of intellectual property can be
found at the website of the U.S. Patent and Trademark Office (PTO):
http://www.uspto.gov
Patent resources may be found at the site offered by the law firm of
Oppedahl and Larson:
http://patents.com/resources
Access to the U.S. PTO site is free and permits searching and downloading
of full-text (or image) copies of U.S. patents and published applications:
http://patft.uspto.gov/
Trademarks
A search engine for trademarks can be found on the U.S. PTO home page
under “Trademarks”:
http://www.uspto.gov/
Glossary
Civil misappropriation Taking and using the property of another without per-
mission for the sole purpose of capitalizing unfairly on the goodwill and reputation
of the property owner.
Common law Generally refers to principles of law developed through litigation
in the courts, rather than statutes enacted through the legislative process.
Contract law Subset body of law developed as common law and statute that re-
lates to agreements between parties, including rights and obligations of parties.
Copyright A property right over intangible intellectual property concerning orig-
inal works of authorship fixed in any tangible medium of expression.
Derivative work Work that is compiled by the author from preexisting works;
a copyright to a derivative work extends only to that material contributed by the
author and not to the preexisting work.
Fair use Statutory protected form of noncommercial use of work under copy-
right that includes use of work for purposes of criticism, comment, news reporting,
teaching, scholarship, and research.
Freedom of Information Act Statute requiring U.S. government agencies to
provide upon request documents in the possession of the agency and those whose
research is supported under a federal funding agreement and all research data pro-
duced therefrom, not otherwise exempted from release under statute (5 U.S.C.
§551 et seq. [1977 and Supp. 2002]). There are nine categories of exemptions that
are intended to protect the release of sensitive information.
Grantee Institution, organization, individual, or other person designated in
the grant; the legal entity to whom a grant is awarded. In the context of federal
funding, the party receiving a grant of financial assistance, as provided under 45

CFR Part 74, for grants from the U.S. Public Health Service.
Patent—Design Design patents provide a 14-year period of protection for the
ornamental features of an article of manufacture.
Patent—Plant Plant patents provide the same term as discussed below for utility
patents. Plant patents provide protection for those plants (and parts thereof) that
the inventor discovers and is able to reproduce asexually, other than tubers (e.g.,
potatoes).
Patent—Utility For those patent applications filed on or after June 8, 1995, the
term begins on the date the patent issues and continues for 20 years from the filing
date of the earliest filed application (e.g., the term of a patent issuing on January
11, 1996, from an application filed July 11, 1995, expires on July 11, 2015; note this
is an enforceable term of 19 1/2 years). Utility patents provide protection for those
inventions that are useful, novel, and nonobvious and that constitute a process, ma-
chine, manufacture, or composition of matter, or any new improvement thereof;
this includes the invention claimed as a drug or claimed as a use of a drug.
Principal investigator A single individual, designated by the grantee in the grant
application and approved by the Secretary of the U.S. Department of Health and
Human Services, who is responsible for the scientific and technical direction of the
project.
Provisional patent application An informal patent application filed with the
PTO that is less expensive to prepare than a regular utility application. The pro-
visional patent application is not considered by the PTO but remains on file for 1
year. Once filed, this document precludes a subsequent public disclosure of the ap-
plication’s subject matter from destroying the patentable novelty of the invention.
Disclosure without provisional patent application protection might otherwise re-
sult in forfeiture of patent rights. A regular patent application must be filed by the
end of the 1-year period of the provisional patent application, or the opportunity
to patent the invention will be lost.
Statute An act of the legislature declaring, commanding, or prohibiting some-
thing; a law.
Trade secret A formula, pattern, device, or compilation of information that is
used in one’s business and that gives one opportunity to obtain advantage over
competitors who do not know or use it.
Trademark A distinctive mark that indicates the source of a particular product or
service.
chapter 10
Scientific Record Keeping

Francis L. Macrina
Introduction • Why Do We Keep Records? •Defining Data • Data
Ownership • Data Storage and Retention • Tools of the Trade
• Laboratory Record-Keeping Policies • Record-Keeping Practices
• Electronic Record Keeping • Conclusion • Discussion Questions
• Case Studies • Resources
Introduction
P roper record keeping is crucial to scientific research. But the accepted

practices of record keeping and policies on custody and retention of
data are usually learned passively by most scientists. Informal surveys often
reveal that trainees receive little instruction in the principles of scientific
record keeping. When mentors do not communicate their expectations on
the subject, trainees learn the practice of record keeping by trial and error
and by having mentors correct their mistakes. Moreover, many of the
funding agencies that support graduate training in the biomedical sciences
fail to provide any guidance on record-keeping practices.
Discussions of scientific record keeping run the risk of implying some
uniform prescription for the process—a rigid method for the one correct
way to do things. However, there are multiple right ways to keep scientific
records. So, although this chapter will have much to say about keeping a
laboratory data book, its message is not an exact prescription or set of im-
mutable rules. On the other hand, there are important principles that cre-
ate a foundation for good record keeping. These are concisely presented in
Table 10.1.
The nature of the research, the form and amount of data generated, and
the preferences and experiences of individual scientists influence the
record-keeping process. Thus, there are many styles and permutations of
record keeping that are appropriate and effective. Equally important, there
are practices that are improper or even scientifically irresponsible.
doi:10.1128/9781555818487.ch10
329
330 Chapter 10
Table 10.1 Data book zen
Useful data books explain: Good data books:

• What you did • Are legible and written in ballpoint
• Why you did it pen ink
• How you did it • Are well organized and up-to-date
• When you did it • Are accurate and complete
• Where materials are • Include data output affixed to
• What happened (and what pages (e.g., photos)
did not) • Allow repetition of your
• Your interpretations experiments
• Contributions of others • Are compliant with relevant
• What’s next funding agency and institutional
requirements
• Are accessible to authorized
persons, stored properly, and
appropriately backed up
• Are properly witnessed when
necessary
• Are properly recognized as the
property of your institution
• Are the ultimate record of your
scientific contributions
Published works on the topic of scientific record keeping can aid the
seasoned investigator and trainee alike. Howard Kanare’s Writing the Lab-
oratory Notebook provides a thorough and technical presentation on this
subject. Although written in 1985, much of Kanare’s observations and ad-
vice hold true today. Kathy Barker’s At the Bench: A Laboratory Navigator
devotes an entire chapter to laboratory notebooks and record keeping. Ad-
ditionally, it contains chapters on laboratory setup and organization that
are relevant and useful. A monograph produced by the Howard Hughes
Medical Institute and the Burroughs Wellcome Fund titled Making the
Right Moves (2nd edition) also devotes a chapter to data management and
laboratory notebook keeping. Finally, Internet searches can be used to lo-
cate both university and research institute guidelines and policies that deal
with scientific record keeping.
Why Do We Keep Records?
Kanare defines and describes the laboratory data book as “a bound collec-
tion of serially numbered pages used to record the progress of scientific
investigations. . . . It contains a written record of the researcher’s mental
and physical activities from experiment and observation, to the ultimate
understanding of physical phenomena.” Such records provide the platform
for analysis and interpretation of results obtained in the field or the labora-
tory. They are the basis for scholarly writings, including reports, grant and
patent applications, journal articles, and theses and dissertations. Labora-
Scientific Record Keeping 331
tory data books are the definitive source of facts and details. Good record
keeping fosters the scientific norms of accuracy, replication, and reliability.
Corroboration and verification of scientific results using primary data con-
tained in a laboratory data book may involve individuals other than the
primary data book keeper. A scientist or scientist-trainee may take over a
project, and it will be necessary for him or her to understand precisely the
laboratory data book contents in order to continue the work. Thus, a spe-
cific data book may become a key research tool for someone else in the
laboratory group, or even someone outside the laboratory or the institu-
tion. This makes clarity and completeness of the laboratory data book es-
sential to its usefulness. A properly kept data book can be a teaching tool as
well. In reviewing the pages of a data book with an experienced investiga-
tor, a trainee may learn how that scientist formulates questions, designs
experiments, and troubleshoots problems.
Proper data book keeping also has legal implications. Funding agencies
like the National Institutes of Health (NIH) may audit and examine rec
ords that are relevant to any research grant award. It follows that recipients
of research grants have an obligation to keep appropriate records of exper-
imental activities even though funding agencies seldom impose require-
ments or provide guidance about this. Providing primary research data is
often a component of the approval process for new drugs or medical appli-
cations (e.g., data submitted to the U.S. Food and Drug Administration
[FDA]). And record-keeping requirements for this type of research are
usually explicit. Failure to conform to such specifications can compromise
the validity of the data and the utility of the research. Finally, scientific re-
cord keeping is critical to proprietary matters arising from the research. As
one seeks the protection of intellectual property by applying for a patent
(see chapter 9), it may become necessary to disclose data book contents to
the patent examiner. This disclosure might be related to requests for addi-
tional supporting data, dates of experiments or discoveries, verification
that the records have been properly witnessed, or proof of reduction to
practice. Properly kept data books continue to be important after a patent
is issued. Patents can be legally challenged once they are issued. Litigation
involving these challenges may require that original data books be in-
spected as part of the legal proceedings. Patents in whole or in part can be
nullified as the result of such legal activities.
Finally, scientific records play a role in the investigation of allegations
of research misconduct. In conducting investigations into allegations of
research misconduct, the National Science Foundation Office of Inspector
General considers the following in assessing laboratory data books and
records.
Completeness. The record should describe all the activities of the re-
searcher, not just the “successful” ones.
332 Chapter 10
Linkage. A written laboratory notebook should reference electronic rec

ords by name and location in detail sufficient to locate the electronic
records.
Review. A regular (weekly or monthly) documented review of laboratory
notebooks by a supervisor or a faculty advisor can help ensure the
quality of laboratory records.
Accuracy. Records should be a contemporaneous chronology of all perti-
nent laboratory activity and results, whether successful or not, and be
sufficient to support the reconstruction of activities by another com-
petent researcher.
Safekeeping. All laboratory records should be maintained in a secure
manner and backed up with copies stored in an alternate location.
Convictions or exonerations in high-profile investigations of scientific
misconduct have been strongly influenced or even decided on the basis of
the scientific record. Typically, misconduct investigations begin with the
investigative team taking custody of or sequestering the data books of the
accused. Clearly, properly kept scientific records provide a strong position
from which to defend research results that have been called into question
on the grounds of alleged misconduct.
Defining Data
What do we mean by data? Simply stated, data are any form of factual in-
formation used for reasoning. Data take many forms. Scientific data are
not limited to the contents of data books. Much of what we would call data
contained in data books is commonly classified as being intangible. That is,
data books may contain hand script or affixed typescript that records and
reports measurements, observations, calculations, interpretations, and
conclusions. The term “tangible data,” on the other hand, is used to de-
scribe materials such as cells, tissues or tissue sections, biological speci-
mens, gels, photographs and micrographs, and other physical manifestations
of research.
Data are said to have authenticity and integrity. Authentic data repre-
sent the true results of work and observations. When data deviate from this
standard because of carelessness, self-deception, or deliberate misrepre-
sentation, they lose their authenticity. Integrity of data is dependent on
results being collected using well- chosen methods carried out in the
proper manner.
During the course of experimentation, some kinds of data evolve into
different forms. Let’s say you set out to do an electrophoretic analysis of a
protein mixture. Your experiment results in a polyacrylamide gel slab in
which a mixture of several proteins has been electrophoretically separated
in a single lane. One lane of the gel contains reference proteins of known
molecular weight and concentration. You visualize the protein components
by staining with Coomassie blue dye. Then you desiccate the gel and seal
it in a clear plastic envelope. You photograph the gel, and the resulting
print and negative are placed in plastic sleeves and taped into your data
book; the desiccated gel is also taped to a data book page. Next, you calcu-
late the apparent molecular weights of the proteins by comparing their
migration relative to the standards. You do this by making measurements
on both the gel and the photograph. In both of these cases, the data be-
come transformed into handwriting in the data book. Then you enter your
measurements into a computer, which generates a numerical data set that
is fixed as a printed copy; it is also maintained as an electronic file. You use
a computer algorithm to determine the apparent molecular weights, and
you compare the results obtained by the different methods. Can you as-
cribe value to the various forms of the data that have come from this work?
Is the gel itself the most important piece of data? Or could the gel be dis-
carded once it is recorded photographically? This scenario can be made
more complex. For example, you scan the photographic negative using a
digital scanner, resulting in its image being captured in an electronic file,
which can then be printed. You use these electronic data to quantitate the
proteins by comparing them with the concentrations of the proteins pres-
ent in a control lane on the gel. You also use these data to make measure-
ments electronically, enabling the program to compute the molecular sizes
of the proteins.
All the forms of the data being considered—desiccated gel, photo-
graphic, electronic, and written or printed formats—are legitimate. Elec-
tronic technologies continue to change how data are acquired, handled,
and stored. The questions of identifying legitimate data strongly affect
data analysis. Some forms of data may be better used for measurements
and calculations than others. In the example given, it can be argued that
measurements made from an optically or electronically generated image
are more uniform from experiment to experiment than are those taken
directly from the gel. This example also raises issues about data storage. Is
it better to emphasize the long-term storage of desiccated gels or to rely
exclusively on a photographic or electronically derived image?
Terms like “raw data,” “original data,” and “primary data” are often used
by scientists, but their definitions are elusive and their use can be confus-
ing. The changing face of data collection, now strongly affected by elec-
tronic technology, requires careful consideration of what constitutes
legitimate and valid data. Thus far, definitions of scientific data have been
of limited scope and usefulness. Yet the definition of data is central to sci-
entific integrity. Scientists need to recognize the importance of multiple
data forms and to strive to clarify and define their importance. When
334 Chapter 10
doing sponsored research, scientists should be aware of and comply with

all agency and institutional requirements concerning data custody and
storage, removal and duplication, and disposal.
Data Ownership
Let’s revisit the topic of data ownership, which was discussed in chapter 9.
It’s safe to say that the details and implications of data ownership are not
foremost in the minds of most researchers when they are writing grant
applications or doing experiments. However, many funding agencies that
sponsor research are clear on the issue of data ownership. As the primary
and largest funding agency for biomedical research in the United States,
the NIH, under the aegis of the U.S. Public Health Service, provides guid-
ance on data ownership related to work supported by its research grants.
As a matter of both policy and practice, the Public Health Service recog-
nizes the grantee institution as the owner of the data generated by the
NIH-funded research. Most NIH research grants are made to institutions,
not to individuals. The individual who submits the grant on behalf of the
institution is called the principal investigator. In practice, the principal in-
vestigator is the steward of the federal funds and of all aspects of the re-
search that are sponsored by that support. The principal investigator
assumes the primary responsibilities for data collection, recording, storage,
retention, and disposal. Grantee institutions (e.g., universities) usually op-
erate so as to give maximum latitude and discretion to principal investiga-
tors. However, the discharge of these duties does not impinge upon, nor
should it cloud, the issue of data ownership. For example, if the principal
investigator resigns his or her position to take another one at a different
university, the grant award, the equipment purchased from the grant funds,
and all of the data are required to remain at the institution that initially
received the award. However, permission may be sought to transfer the
grant award, some or all of the equipment, and the data to the principal
investigator’s new institution. The process to do this is formal and requires
mutual consent of the involved parties: the granting agency, the current
grantee institution, and the proposed grantee institution. If for some rea-
son an agreement is not reached, the initial grantee institution can keep
the award, assuming it identifies a new principal investigator who is ac-
ceptable to the granting agency. The principal investigator as an individual
never legally has ownership of the data. The transfer of data ownership,
when it occurs, is between grantee institutions.
In summary, neither the principal investigator nor any member of the
laboratory research team owns the data generated under an NIH research
grant. This is generally true for awards from federal agencies. Informing
trainees and staff about practical issues of record keeping is the responsi-
bility of the principal investigator.
Data Storage and Retention
The NIH requires that data obtained under the aegis of an NIH grant be
retained for 3 years beyond the date of the final financial expenditure re-
port. Requirements for the amount of time research data must be retained
may vary for various public and private funding agencies. Because of this, it
would be impractical, if not impossible, for a major research university to
organize, implement, and maintain a uniform data storage system for all of
its research projects. Such logistical problems at most universities and re-
search institutions place the responsibility for the storage of data squarely
on the principal investigator. Therefore, it is essential that investigators
have a clear understanding of their granting agency’s policies governing
data ownership issues and data retention. Furthermore, investigators need
to be aware of relevant state laws regarding the retention of data, because
they usually override federal ones. For example, the Commonwealth of
Virginia mandates that data gathered by state agencies be retained for 5
years, thus extending the NIH requirement for scientists at state-supported
universities.
Tools of the Trade
Keeping original results and observations for significant periods of time

requires the selection of appropriate materials for recording and storing
data. An entire chapter of the Kanare book is devoted to “The Hardware
of Notekeeping.”
Paper
Kanare’s discussions on the quality of data book paper are thorough and
technical and may be summarized as follows. Make sure your data are re-
corded on acid-free paper as the best insurance for permanence. Selection
of data books composed of paper that is considered permanent can be
aided by consulting data book suppliers or manufacturers. Often, paper
composition is printed on the bound data book cover. The longevity of
laboratory data books is facilitated by proper storage. Strong light sources
(especially sunlight), high humidity, chemical fumes (in exhaust hoods), ex-
tremes in temperature, and excessive dust can have unwanted and undesir-
able effects on stored laboratory records.
Ink and pen type

Kanare’s recommendations on instruments for writing in data books are
simple. Never use pencil. Do not use pens with aqueous- based inks.
Graphite smudges over time, and even a little water can obliterate the inks
in many popular pens (e.g., felt-tip, fountain, rollerball [gel-based inks]).
Kanare’s testing of various inks and pens led him to conclude that a
336 Chapter 10
ballpoint pen with black ink is best for scientific note keeping. Colored
inks are not desirable, because their decomposition promoted by light is
significant compared with black ink. However, varying the color of inks
when drawing diagrams, for example, may be essential in some types of
work. Inventories of pens for laboratory use should be sufficient for short-
term (a few months) use. Long-term storage of ballpoint pens is undesir-
able because of ink component partitioning within the ink cartridge, which
can result in problems of ink flow.
Bound versus loose-leaf data books

Most, if not all, industrial research laboratories mandate the use of bound
(preferably a sewn binding) data books with serially numbered pages.
Variations on this theme include bound data books with duplicate num-
bered carbon pages, which may be detached and stored separately as
backup. Any other type of binding—plastic comb, wire spiral, or ring
binder—is considered unacceptable because pages can be intentionally
inserted, removed, or accidentally ripped out or lost. This could damage
the integrity of the records, compromising, for example, the ability to
gain patent protection. Outside of industry, however, the use of loose-leaf
notebooks is seen along with bound data books. Although the typical
three-ring loose-leaf binder offers the advantages of being able to logi-
cally organize ongoing and completed experiments, the above-mentioned
drawbacks should be kept in mind.
Bound, page-numbered data books have features that argue compel-
lingly for their use. Their integral construction is consistent with preserva-
tion of data authenticity because intentional page deletion or insertion
becomes immediately obvious. Quality control of paper composition is
easier compared with the vast array of papers available for loose-leaf books.
Data books of uniform size and shape also are more amenable to efficient
and organized storage. Numbered volumes, with serially numbered pages,
may be readily indexed, making the task of locating stored data relatively
easy. In sum, bound data books provide organization and ease of use that
makes sense for the responsible custody of scientific data. As a practical
matter, the use of a bound data book with chronological ordering of exper-
imental protocols and results, with each page dated, serves the purpose of
most academic research laboratories.
Laboratory Record-Keeping Policies
Principal investigators and laboratory leaders are well advised to develop

policies for record keeping. No guidance on scientific record keeping
amounts to a tacit approval of slipshod practices that threaten the authen-
ticity and integrity of scientific data. Ideas for developing data-keeping
policies and practices can be obtained from a variety of sources. Printed

material (including this chapter) may be used (see the “Resources” section
at the end of this chapter), or websites for universities and research insti-
tutes may be consulted. Increasingly, academic institutions have such
guidelines or policies, which are typically published on their websites, but
the challenge of covering widely divergent research areas makes the devel-
opment of uniform policies difficult. Record-keeping policies and data
book management tend to be the rule rather than the exception in indus-
trial research laboratories. But procuring these policies for outside use or
adaptation is often impossible, as they are treated as proprietary materials.
The record-keeping guidelines of one biotechnology company may be
found in Appendix VI.
Policy documents need not be complex or lengthy. They may reflect the
experiences, training, and personal preferences of the principal investiga-
tor or group of principal investigators who write them. Group efforts are
useful in writing guidelines. The experience and wisdom of several investi-
gators will give a valuable perspective to your guidelines. Once in place,
such documents should be regularly reviewed and modified as necessary. A
clear statement about data ownership and retention should be part of these
documents.
Record-Keeping Practices
Drawing from references of the types cited previously, experience, and ob-
servation, the following is an overview of laboratory record-keeping prac-
tices useful in developing record-keeping policies.
Data books
The case for using permanently bound laboratory data books with con-
secutively numbered pages has been made previously, but the discretion
of the principal investigator should prevail in selecting specific data book
types and mandating their use. Hereafter in these discussions, use of
bound data books will be assumed. Some investigators like to control the
distribution of data books. For example, data books are given out as
needed by the principal investigator or the lab manager. At the time of
distribution, a record is made of the date, data book user, and project; at
this point, the data book can be coded with a designation (e.g., a volume
number), which will allow for its tracking while in use or storage. This
strategy has merit in laboratories where there are multiple trainees and
staff working on a variety of projects, funded from different sources.
Data book users should clearly understand the lab policy for data book
storage, retention in the lab, and any requirements for duplicating data
book pages and other forms of data.
338 Chapter 10
Organization
The first several pages of an individual’s data book should be reserved for a
table of contents. The first entry before beginning the table of contents
should consist of the name of the data book user and other relevant infor-
mation; especially for work with potential proprietary implications, the
location (room, building, institution) of the laboratory in which the exper-
iments are being performed is recommended. Financial sponsorship
should be identified by stating the title of the grant proposal, its agency
identification number, dates of support, and the name of the principal in-
vestigator. Experiments listed in the table of contents should have concise
but descriptive titles. The numbering of experiments chronologically facil-
itates cross-referencing experiments. A glossary of abbreviations, symbols,
or common designations may be included after the table of contents or,
alternatively, can be listed at the end of the data book. Leave enough space
for this information in order to be able to make additions to the glossary
throughout the project.
The maintenance of a master data book log may be desirable. This cen-
tral record (essentially a standard data book or perhaps even a computer-
based word-processing or database algorithm) contains a listing of all
experiments performed by the research team. Individuals are responsible
for maintaining the log by entering experiment titles, dates, investigators’
names, and the location of relevant data. A second type of laboratory-based
reference resource is the methodology notebook. These notebooks are a
compendium of all standard laboratory methodology. Compilation of
these books works best when it involves all laboratory members. Experi-
mental methods should be described in sufficient detail to be useful even
to the novice investigator. A printed copy of the complete book (in this
case, loose-leaf or comparable binders are acceptable) can be kept in a cen-
tral location, or duplicated copies can be distributed to lab members. Alter-
natively, copies of the methods notebook can be distributed in electronic
format for the use of lab members. If a laboratory methods notebook is to
be kept, it is critically important that the master copy, controlled by the
principal investigator or lab manager, be updated regularly—perhaps on a
yearly basis. Again, this can be done as a group effort, benefiting from im-
provements and refinements made by individuals using the techniques.
Updated copies of new methodology notebooks should be distributed to
replace old versions. The previous version of the master methodology log
should be stored in an unaltered state. This allows for methods that have
been updated or discontinued to be saved; referring back to methods, even
discontinued ones, is sometimes necessary. These methods should be ar-
chived so that the date of revision or replacement of the method is obvi-
ous. Even if a central methodology book is maintained in the laboratory, it
is a good idea that the data books of individual investigators describe
regularly used procedures. These can be transcribed into the data book.
Alternatively, typed copies can be prepared on high-quality paper and at-
tached to the pages of the data book using archival-quality tape or glue.
Obviously, any specialized techniques or methods used in research projects
(which might not be appropriate for a central methodology book) should
be recorded in the individual’s data book.
Finally, consider a methods book kept separately by each member of the
laboratory. In other words, investigators compile their own methods books
and modify them as needed, leaving the original copy with the rest of their
data books when they leave the lab. This might be practical in a laboratory
where strikingly different methods are used in various projects. All of the
above considerations apply to the maintenance of such a methods book.
Decisions relating to whether to use centralized or decentralized record
keeping should be made by the laboratory leader. Modern biomedical re-
search frequently involves methodologies and interdisciplinary research
that require the centralized organization of methods commonly used by
the group. Such organization and maintenance facilitate the teaching of
novice trainees and staff, ensure quality control, and help in the trouble-
shooting of technical problems. Reference manuals describing common
methodologies and reagents have been published and are likely to be use-
ful to researchers in the biomedical and life sciences. A growing number of
published laboratory manuals are entering the marketplace each year. Cold
Spring Harbor Laboratory Press publishes a large number of specialized
laboratory manuals that cover topics from molecular cloning to cell imag-
ing to bioinformatics. These titles can be found by searching its website
(http://www.cshlpress.com/) using “laboratory manual” as the keyword
phrase. Finally, the Nature Publishing Group publishes an online journal
called Nature Protocols (http://www.nature.com/nprot/index.html). This
journal publishes protocols in what is termed a “recipe style,” providing a
source of information allowing the direct use of methods by readers. Pub-
lished protocols cover a wide range of topics in the biomedical and life
sciences.
Tangible data and the data book

Tangible forms of data such as photographs, negatives, autoradiograms,
and printouts should be included in the data book when this is physically
possible. The use of archival-quality glues and tapes is suggested for affix-
ing these materials into data books. Materials that cannot be glued or taped
directly into the book should be inserted into plastic sleeves, which are
then fixed in the data book. Printed material, especially that produced by
photocopying or laser printing, should not come in contact with plastic
material of any type. Over time the ink will transfer its image to the plastic,
and this will obscure, if not ruin, the printed data. Information that is
340 Chapter 10
collected on tape, printouts, thermo fax paper, or any paper stock of low
quality should be photocopied onto high-quality paper before being glued
or taped into the data book. Alternatively, such outputs can be digitally
scanned, printed, and affixed to the data book page. A record of the name
and location of the digital file also should be described in your data book,
as mentioned in the next paragraph.
Certain materials that contain or represent data cannot be practically
included in the laboratory data book. These include, for example, oversize
photographic or autoradiographic material, magnetic media, embedded
specimens or tissues, and some data obtained by light or electron micros-
copy. For proper storage of these materials, one should consider such fac-
tors as humidity, temperature, light, security, and ease of accessibility. For
example, oversize X-ray films contained in protective sleeves that are ap-
propriately coded can be stored in metal cabinets of some type. Pressed-
board boxes also are useful for storage. Such containers come in varied
sizes and shapes, but only those composed of acid-free materials should be
used. Ordinary cardboard boxes, even those commercially sold for storage
purposes, are inferior and can release damaging acids over time. When
using remote-site storage, it is important that a description of the data
storage system, the storage location, and the coding scheme be described
in your laboratory data book. As a rule, an individual who inspects the data
book should be able to locate all forms of data relevant to the experiments
presented simply by reading its pages. For example, if centrally stored elec-
tron microscope grids or tissue sections cannot be located from reading
the data book, then repeating certain experiments or observations may not
be possible.
For maximum longevity, prolonged storage of data books and related
materials such as photographs, negatives, or oversized documents should
ideally occur under conditions of controlled temperature (65 to 71°F) and
relative humidity (50%). Basements, attics, and poorly ventilated storage
rooms are notoriously bad places for long-term storage of data and data
books.
Format
Investigators should plan how experiments will be recorded in the data
book. Some argue that writing should be concise. Although this is a rea-
sonable guiding principle in data book writing, it should never compro-
mise capturing any part of the experiment. For example, if an observation
requires an explanation that is complex and must be described at extraordi-
nary length, then this should be done without reservation. The same is
true for interpretations and for thoughts on plans for additional work. Pre-
sentation and detail must be complete and comprehensible. All entries in
the laboratory data book should be made legibly.
Purpose. Each experiment should begin with a brief but instructive

statement of the purpose of the experiment. This is done no matter how
routine the experiment. Whether the experiment is to test some elegant
hypothesis or simply to isolate cellular DNA, its purpose should be re-
corded. No experiment is too trivial to be deprived of a written purpose.
An investigator might want to know how many independently isolated
preparations of a plasmid DNA were used in performing genetic mapping
studies. His or her job will be easier if each preparative run can be traced
to a clearly recorded experiment that begins with a statement of purpose.
Materials and methods. A description of any methods not found in

the laboratory central methods manual should be included in the data
book. The appropriate literature from which methods are derived should
be cited. Assuming a central methods book exists, as described previously,
methods used may be cited by referring back to the central laboratory
source book. Specific reference to the exact book (likely designated by
date) should be made so that the precise method may be located in the fu-
ture. If there are deviations from referenced procedure, such changes must
be precisely indicated. To eliminate any confusion, it may be necessary to
write the modified method in the data book.
The materials and methods section of the experiment should also doc-
ument materials being used. The grade, sources, and lot numbers of spe-
cialized chemicals, reagents, and enzymes should all be recorded. If there is
any question about the name recognition of the supplier (e.g., the supplier
of a rare chemical or unusual enzyme), the name, address, and phone num-
ber of the supplier should be included. In the case of biological materials
such as cell lines, bacterial strains, or animals, specific information on
properties (e.g., genotypes and phenotypes) and source should be recorded.
If working laboratory designations have been used for convenience, a full
explanation of the material’s original designation should be included. If
methodology has involved an outside vendor or shared resource (internal
multiuser core facility), details of that service should be thorough. Include
names of individuals you dealt with, the dates of order submission and re-
ceipt of data or materials requested, and a description of the nature and
location of the storage. Consider a situation where you have employed the
services of an outside vendor to perform high-throughput DNA sequenc-
ing location. The data have been returned to you on portable hard drives.
Where you store these drives that contain the originally received data and
the location of the server drives to which you have copied any or all of the
data should be explicitly described in your data book.
Each repeat of an experiment should be written up separately in the
data book. In the case of materials and methods, it is acceptable to record
this section with appropriate detail and completeness the first time the
342 Chapter 10
experiment is performed. Assuming no changes in methodology are imple-

mented in future runs, it is acceptable to refer back to the materials and
methods section recorded in the first experiment of the series. If changes
are made, reference to the original methods can be made and the modifica-
tions noted. When recording changes made to established or previously
tried protocols, it is a good idea to present the rationale for the change.
If an experiment requires the use of specialized equipment, relevant in-
formation should be recorded in the data book. For example, if several
electron microscopes are available for the work, which one (type, location)
was used in the experiment? If calibration of a piece of hardware is re-
quired, information on the calibration process should be recorded.
Observations and results. Data should be recorded directly into the

data book as soon as they become available. Original data recorded in hand
script are always entered directly into the data book. Data should never be
written on loose sheets of paper and then transcribed later into the data
book. This practice risks the incorporation of errors during transcription
and threatens the authenticity of the data. Direct recording of data re-
quires organization at two levels. First, any writing that will facilitate data
entry should be planned and carried out in advance of doing the experi-
ment. For example, a matrix drawn and labeled to receive written data
from instrument readings or direct observations greatly assists data collec-
tion. The second organizational consideration involves the physical avail-
ability of the data book to the investigator while the experiment is being
performed. The data book should always be conveniently accessible to the
investigator. This may mean arranging bench work space ahead of time so
as to accommodate the physical tools of the experiment, including the data
book itself.
In addition to recorded data, the observations and results section should
contain all renderings of the data, including calculations and organized
presentations such as tables and graphs created using the data. Calcula-
tions should be explained. Tables and graphs should be clearly labeled.
Photographic materials should be affixed to the page using archival-quality
glue or tape. Any related materials not included in the data book should be
catalogued and their storage location identified. For example, photographs
attached to the data book may have their corresponding negatives stored
in an appropriate file (see below). If the photographic system being used
creates a negative, these should be contained in glassine envelopes and
stored at room temperature away from sources of high humidity, excessive
light, and temperature swings (i.e., avoid proximity to windows, water
baths, incubators, ovens, or autoclaves). If you are using an imaging system
in which a digital photograph is generated, a hard copy of the photograph
should be affixed to the data book page along with a notation of the name
of the electronic image file and its storage location.
Discussion. Each experiment should be discussed following the record-

ing of observations and calculations. It may be necessary to enter discus-
sion comments at various places in the experimental write-up. In other
words, the discussion for a single experiment need not be organized to
appear at the conclusion of the write-up. It is appropriate to include com-
ments that capture impressions and present interpretations at various
places in the written experiment. This is convenient and ensures the most
effective use of space in the data book. The standard formal presentation
usually required by scientific journals, with its clear separation of the actual
results and their discussion, is not usually applied to data book keeping.
The last entry in the completed write-up of the experiment should state
the conclusions of the work. This should be done even if it repeats com-
ments previously written into the data book. Conclusions logically belong
at the end of the experiment. Just as we look to the beginning of the
write-up of an experiment to find a purpose, conclusions are logically
sought at the end of the write-up. A conclusion should be written, no mat-
ter how trivial or routine it is thought to be. Future reference to the data
book is aided by written experiments that have a clear beginning and a
clear end.
There is no consensus about the style of the discussion section. For ex-
ample, making comments that editorialize on the results has been debated.
Some investigators urge refraining from this on the grounds that it may
create confusion and mislead others at a later time. Moreover, editorializ-
ing is generally inconsistent with the overall recommendation of recording
notes in as concise a fashion as possible. Others argue that the data book
should record all of the mental and physical activities of the investigator.
Accordingly, if something is important enough to record, a note of it
should be made. Interestingly, some industrial research data book policies
admonish investigators never to make comments that could be subject to
misinterpretation by others. Specifically, investigators are cautioned
against using phrases like “the experiment failed” or describing a yield of
some biological material as “no good.” This is argued on the theoretical
grounds that the interpretation of a single experiment is usually not
enough on which to base a far-reaching conclusion. Repetition and confir-
mation are always necessary, and hence subjective statements about indi-
vidual experiments are considered ill- advised and are vulnerable to
incorrect interpretation. On practical grounds, such statements are poten-
tially damaging to a planned or existing intellectual property position (e.g.,
a patent application).
344 Chapter 10
Format and corrections

For single projects (e.g., a dissertation research project), data books should
be used consecutively; do not start multiple data books. Once appropriate
pages are reserved for a table of contents and abbreviation list (if neces-
sary), make entries in the data book in a continuous and chronological
fashion. Do not skip pages. Date each experiment, and date the entry of all
recorded data and your comments. Many suggest writing each page in
such a way that minimal margin space is left available for after-the-fact
note taking. The perceived importance of such ancillary notations may
create confusion, and frequently the limited space available for them com-
promises their legibility. If an alternative explanation of the data becomes
apparent, begin a new entry at the next available point in the data book.
Then cross-reference the new entry with the original experiment (page
and experiment number). Unused portions of any data book pages should
be marked through with a pen stroke or a large “X.”
Mistakes in the data book should be marked through with a single line
and a full explanation of the error provided. For mistakes that can be cor-
rected instantly, this practice presents no problem with available page
space. For mistakes discovered at a later date, there may not be enough
space to provide an explanation. Thus, an investigator marks a line through
the error and writes: “see page XX for explanation.” Never obliterate mis-
takes with ink or cover them with any type of correcting fluid. First, their
legibility may be important to you in the future, as the incorrect entries
may provide needed information. Second, to the casual observer, practices
that appear to remove data from the data book may suggest that such ac-
tions were taken for improper reasons.
Witnessing data and interactions with other people

Witnessing of data is a required procedure in the industrial research labo-
ratory. The need to protect inventions and potentially patentable ideas ne-
cessitates this practice. Witnessing of data is less common in the academic
research laboratory. A funding agency might require this for certain types
of contract work, for example, clinical testing. However, little thought is
given to witnessing the data books produced during the course of most
basic research projects that constitute thesis or dissertation research. In-
vestigators performing fundamental experiments often do not think about
their work leading directly or indirectly to a discovery of a commercial
application, requiring the protection of a patent. However, the unexpected
bridging of basic and applied research is becoming commonplace today in
the biomedical sciences. Witnessing of data is necessary if the work may
lead to a patentable discovery or invention. In the academic or research
institute setting, where rules for witnessing do not usually exist, establish-
ment and enforcement of such a policy reside with the laboratory director.
In deciding to put a policy in place, the investigator must consider the re-
quirements (if any) of funding agencies and the possibility that applied sci-
ence may emerge from the research.
Where it is a standard practice or required in research laboratories (e.g.,
certain types of corporate-sponsored research or FDA-required good lab-
oratory practices), each and every page of the data book is witnessed. The
witness signs and dates the page of the data book being examined. The
witness must be able to understand the work. The signature may be ac-
companied by a declaration that says “witnessed and understood.” Some
commercially available data books have this declaration and a line or box
for signature and date printed on each page. The witness must not be a
coinventor. In patent prosecution, coinventors are not allowed to corrobo-
rate each other’s work. Thus, selection of a neutral party who is able to
understand the work is needed for appropriate witnessing of scientific data.
Consider, for example, a discovery that grew from a predoctoral research
project. The trainee’s mentor would likely be considered a coinventor and,
thus, should not sign as a witness to the data. Another worker in the same
lab could sign, assuming he or she understood the work but was not in-
volved in it.
It is desirable to record in the data book discussions with others about
the research. These notes should list the times, names of the individuals
talked to, and relevant points of the discussion. This is a good record-
keeping habit that will help trace the investigator’s thinking processes and
provide a prompt when it is time to attribute credit. In addition, should
corroboration of data be needed at some point, tracking down individuals
who can talk about certain experiments is the next best thing to a wit-
nessed data book page. Correspondence to and from colleagues about your
experiments should be recorded in the data book as well. Letters can be
photocopied on high-quality paper and then fixed in the data book using
archival tape or glue. Alternatively, it may be appropriate to make notes
from such correspondence in the data book and then refer to the location
of the letter in a file (print or electronic) that can be easily found by some-
one reading the data book.
Finally, names of individuals who have played any role in your research
need to be entered in the data book along with a description of their contri-
butions. Collaborative researchers fall into this category. Agreements with
collaborators pertaining to research contributions, expenditures on grants,
personnel involvement, and perhaps most important, authorship on papers
should be recorded in the data book. People who have participated in your
research, even on a fee-for-service basis, should be noted in your writing.
Personnel working in institutional core facilities are especially important.
Who was the statistician or bioinformatician who provided needed analyses
of your data, or the core lab technician who did the mass spectroscopy on
346 Chapter 10
your samples? These notations represent a record of quality control. They

can help you in troubleshooting problems and can provide a source of inde-
pendent corroboration in matters of intellectual property.
Pages 348 and 349 show data book pages that exemplify good scientific
record keeping.
Electronic Record Keeping
Computer-assisted record keeping

The advent of widespread personal computer use in the early 1980s marked
the beginning of digital record keeping in research. Such practices—
described in this section as computer-assisted record keeping—involve the
use of commercial software programs (e.g., word-processing, spreadsheet,
or database software) to record data electronically and, in doing so, aug-
ment writing data into the conventional paper laboratory notebook. The
malleability of such off-the-shelf programs readily accommodates the needs
of the experimentalist and improves the efficiency of record keeping. Data
handling using spreadsheet algorithms, search functions, and the clarity
provided by keyboard input can add power to record keeping. Scanners,
drawing programs, and instruments that create digital data are also part of
this landscape, producing an array of output files that can be appended to
the electronic research record. As its ultimate step, computer-assisted rec
ord keeping should involve printing all electronic files and affixing them to
the pages of a traditional data book. This is done in addition to electronic
storage of the computer files.
Using extant software and hardware in this fashion to assist in record
keeping has become commonplace in the research laboratory. But there
are certain planning and operational elements that need attention, and
these should be approved by the principal investigator or the laboratory
director. These include the following.
• An official procedure for the lab’s electronic record-keeping process

should be developed and communicated to all users. This should in-
clude the name(s) and responsibilities of the custodian of the process
and of the electronic records themselves.
• The principal investigator or the laboratory director should define
the nature of what electronic record keeping means in the context of
this practice. Is the practice required by all in the lab, or does it de-
pend on the individual or the nature of his or her research project?
• The storage location and organization of electronic records should
be clearly defined. Ideally, storage should be on servers that are pass-
word protected. Enterprise backup systems for stored records are
preferable.
• Stored files should be encrypted using appropriate software pro-

grams or by using encryption functions that may reside in the oper-
ating system.
• Electronic files should be write protected, using read-only permis-
sion for anyone accessing research data files. This may be accom-
plished by write-protection features of the software program being
used (e.g., word-processing software), by third-party software, or by
write-protection mechanisms resident in the computer’s operating
system.
• To ensure authenticity, all electronic files should be time stamped.
Depending on needs, this could be done with time-stamping fea-
tures resident in the software program being used or by third-party
time-stamping programs that generate a so-called hash function,
which is a digital fingerprint of the file. Any alteration to the file will
change the value of the hash function. The date and content of elec-
tronic records should never be altered. Furthermore, all electronic
files used for dissemination of research results should be seques-
tered into a single file storage system (folder or directory) that is
time stamped with the date and time created, captures all time
stamps for individual files, and incorporates access protections using
both password protection and read-only permission to preserve data
provenance.
• Regular (daily) backup of all electronic records should be mandated,
and the process and oversight of this should be clearly prescribed and
regularly monitored for compliance.
• Access to the stored electronic data of researchers in the lab should
be authorized by the principal investigator as needed, with full
knowledge of all involved parties.
• There should be an explicit policy describing what kinds of elec-
tronic data must be printed and affixed to the paper pages of a data
book. It may be necessary to have such pages witnessed and dated as
evidence of authentication. This is especially true for records that
may be needed for pursuing intellectual property protection.
• Files on the primary computer (e.g., researcher’s laptop) being used
to enter data should be encrypted. The same goes for data files resi-
dent on portable hard drives and portable media like thumb drives,
flash cards, and the like. Any portable computer or storage device
should never leave the lab unless the data on it have been encrypted.
• All electronic records should be retained for the appropriate time as
prescribed by funding agencies or government mandates. Beyond
that period, there should be clear policy on whether files should be
archived (and the process for doing this) or destroyed (and the pro-
cess for doing this).
348 Chapter 10
xamples of laboratory data book pages. These illustrate the style of a single per-
E
son but exemplify a number of features important to good record keeping. Each
numbered page in the bound data book is dated. The experiment is titled (title and
page are also recorded in the book’s table of contents) and begins with a statement
of the objective. The opening remarks contain a literature citation for reference.
DNA oligonucleotide primers being used in this experiment are not described at
the sequence level, but the data book page on which this information may be found
is noted. A digitized, computer-labeled image of an ethidium bromide-stained aga-
rose gel has been printed and taped to the page. A series of conclusions are listed,
and modifications for a future experiment are proposed.
350 Chapter 10
Electronic laboratory notebooks

ELN is an acronym frequently used to denote the electronic laboratory
notebook, and it is commonly used in marketing commercially available
software packages. The validity of ELNs can be traced to laws that were
enacted in the United States and other countries in 2000. In effect, these
laws made ELNs and paper data books equivalent forms of record keeping
in terms of validity and rules of evidence. This seeded commercial efforts
aimed at providing stand-alone electronic laboratory notebooks that would
provide full record-keeping functionality, as opposed to using computer
technology to augment the paper data book methodology as discussed in
the previous section. ELNs are designed to totally replace paper in research
record keeping. The MEDRAD Electronic Lab Notebook Project, released in
2006, reported ELN products being marketed by 28 vendors. This number
reached nearly three dozen by 2011 and is continuing to grow at a signifi-
cant pace. In 2011, Michael Rubacha, Anil Rattan, and Stephen Hosselet
published a useful review of ELNs. To qualify for review in their paper, an
ELN had to meet the definition established by the Collaborative Electronic
Notebook Systems Association: “a system to create, store, retrieve and share
fully electronic records in ways that meet all legal, regulatory, technical, and
scientific requirements.” Twenty-eight of the 35 vendor products mentioned
in their study met this definition. The authors categorized the products of
their studies according to the primary market audience. These five classifi-
cations were Research and Development, Biology, Chemistry, Quality As-
surance and Quality Control, and Multidiscipline. Their paper provides
narrative on each product, providing readers with facts and observations
that can be used to inform the selection of an ELN program suitable for
their needs. ELNs reported in these groups share common features, includ-
ing offering the ability to be in compliance with the FDA’s guidance under
21 CFR 11. This part of the Code of Federal Regulations details criteria
bearing on keeping electronic records and using electronic signatures.
Compliance with 21 CFR 11 enables researchers to affirm the trustworthi-
ness and reliability of the electronic research records. In short, this compli-
ance establishes the equivalence of electronic and paper record keeping.
It is reasonable to expect that the market penetration of ELNs will in-
crease over time. Growing use will lead to a specific appreciation of ELN
capability and performance, helping scientists who want to use ELNs to
select the most appropriate platform for their research.
Conclusion
The laboratory data book may not always be the central repository for raw
data, but it must be the center of the research data record. No matter what
form the data are in or where the data may be stored, locating and
understanding the data must ultimately begin with the data book. Research
record keeping requires above-average organizational skills and the disci-
pline to implement them consistently. It’s easy to cut corners or pay little
attention to details of annotation and storage. Failing to record observa-
tions in a timely fashion may lead to inaccuracies. Improperly organized
data may become meaningless to you and to others.
Speaker’s notes provide a useful metaphor for record keeping. Such
notes generally fit into two categories. The first includes short phrases,
words, or occasional sentences that provide triggers for the speaker. The
second category is a verbatim text of the speaker’s remarks—a script of
every word to be spoken during the presentation. There are no abbrevia-
tions, cryptic reminders, or shorthand notations. If the speaker were sud-
denly taken ill, a colleague could easily give the speech. However, it is
doubtful that a colleague could successfully deliver the speech using only
the abbreviated notes. Think about your record keeping in similar terms. A
laboratory data book is inherently more useful as the “verbatim text” of
experimental work. In his book The Cuckoo’s Egg (Doubleday, New York,
NY, 1989), Clifford Stoll lauds the value of a carefully documented data
book. His advice rings true as an axiom of scientific record keeping: “If you
don’t document it, you might as well not have observed it.”
1. Do you think that electronic record keeping will either increase or
decrease our ability to detect scientific misconduct? Why or why
not?
2. If an NIH-funded principal investigator takes a new position, does
he have the right to take all of his data and data books with him to
his new institution? If not, what policies or ethical issues apply to
such a situation?
3. What characteristics do you consider essential to the functionality of
an electronic laboratory notebook?
4. Could sloppy and incomplete record keeping ever qualify as scien-
tific misconduct? Explain.
Case Studies
10.1 Dr. Oliver Dickerson directs a highly productive, federally funded

research program in the neurobiology department of a private uni-
versity. Over the past 18 months, two of his predoctoral trainees have suc-
cessfully petitioned the department’s graduate committee to leave his lab
and join groups directed by other faculty. In addition, a postdoctoral
trainee just left Dickerson’s group after only 1 year to take a new
352 Chapter 10
postdoctoral fellowship at another university. Professor Sandra Sarkar, a

faculty member in Dickerson’s department, approaches you, the university
research integrity officer, shortly following the departure of the postdoc-
toral trainee. She tells you that the “hallway conversation” in the depart-
ment suggests that the personnel departures from Dickerson’s group are
likely due to his aggressive style of pressuring trainees. It includes placing
unreasonable expectations on trainee productivity to the point of condon-
ing questionable scientific conduct. Professor Sarkar relates that the post-
doc who left the lab was rumored to have refused Dickerson’s demand to
electronically modify a digital radiograph that was intended for use in a
poster presentation. Sarkar declares that a forensic examination of the
Dickerson group’s data books would uncover blatant falsification when
compared with results being published by the lab. Upon hearing this, you
ask Professor Sarkar if she is making an allegation of misconduct against
Dickerson, but she responds that she is not. As the institutional research
integrity officer, are you obligated to do anything? What, if anything, will
you do?
10.2 The research laboratory of a faculty investigator has begun using a

new electrophoresis technique. The technique works well in the
hands of the laboratory investigators. A field service representative from
the company that manufactures the apparatus asks several of the workers
in the laboratory if she may borrow some of the photographs of their re-
sults to show them to potential clients. In return, she offers to take the
whole lab to dinner at an expensive restaurant. The lab members comply,
and the whole group goes to dinner. You, as laboratory director, are told of
these events after the fact. Comment on the implications of this scenario
for data ownership and laboratory record keeping. What action, if any, will
you take?
10.3 Joshua Hanani is preparing his first major paper as an indepen-

dent investigator. His faculty colleague Dr. Ellen Fang reviews
the manuscript and they meet over coffee to discuss her critique. She has
some questions about the image of a DNA gel analysis in the paper. She
says part of the gel image appears deliberately altered. Joshua admits this
to be true and offers the following explanation. The gel contains the
products of PCR-amplified whole-cell DNA. The amplified DNA frag-
ments are arrayed linearly from largest to smallest on the gel. The exper-
iment produced the expected results but also contained some unexpected,
exciting findings. Specifically, two small DNA fragments suggest an ex-
citing hypothesis that will likely take 6 to 8 months to test. Worried that
readers would recognize this and “scoop” him, Joshua used an image ed-
itor to “underexpose” those fragments so they were no longer visible. He
mentions to Ellen that he included an explanation of this in the figure

legend, writing: “Minor signals of unexplained origin were present in the
lower molecular size range in this experiment, but they are not visible in
the photograph.” This, he claims, will protect him from the competition
of major labs working in the field. Ellen cautions him that his reasoning
is flawed and he is deliberately falsifying data. She offers an alternative
solution, saying he should just electronically crop the image so that it
includes just the expected DNA fragments and not the unexpected ones.
She says this can be easily done since the unexpected fragments are at the
edge of the image. Then, she argues, no explanation about the image will
be needed. Comment on Joshua’s actions and Ellen’s alternative solution.
If they came to you for your opinion and advice, what would you tell
them?
10.4 Professor Astrid Mueller and her postdoc, Dr. Jonathan Rao, have
coauthored a major paper in a prestigious international journal.
After the paper was published, Jonathan left the lab to take a position as a
biotechnology investment analyst. Two years after the paper was pub-
lished, Mueller’s university, a public institution, receives a Freedom of
Information Act (FOIA) request from a national watchdog group, the
Public RCR Institute. The Institute is collecting information to study
“the degree to which researchers adhere to the important scientific stan-
dards of keeping complete and accurate data books and other investiga-
tory records.” The FOIA request contains a list of 10 recently published
papers authored or coauthored by faculty at Mueller’s university. The
Rao and Mueller paper is on the list. The FOIA request asks for copies of
10 randomly selected data book pages associated with each of the listed
publications. The office of the university counsel initiates coordination of
the FOIA request and instructs Dr. Mueller to begin identifying the rele-
vant data book pages. The two relevant data books for the publication
were created by Jonathan. As Mueller reviews the data in the books, she
discovers some major inconsistencies between raw data book records and
the formal presentation of data in one of the tables in the published pa-
per. In fact, she is unable to reconstruct the table to her satisfaction. Rel-
evant data are scattered throughout one of the data books, reflecting their
collection at different times. Some data have been excluded in the con-
struction of the table, but there is no explanation provided as to why. Al-
though she is concerned about the implications this has on the FOIA
request, these concerns pale in comparison to those she has about the
published paper. If someone tries to reproduce results based on the table
in question, how will she be able to defend their data? She comes to you
for advice on how to proceed in addressing this dilemma. What guidance
and advice do you have to offer?
354 Chapter 10
10.5 Bob, your fellow graduate student, comes to you for advice. Bob’s
mentor recently has noticed that he keeps his stained, desiccated
polyacrylamide gels in sealed plastic bags that are taped to the pages of his
data book. Bob considers such gels to be primary data that must be re-
tained in their original form. Bob’s mentor has ordered him to stop doing
this. Moreover, he tells Bob to remove the gels already in his data book.
Bob’s mentor says that polyacrylamide is a neurotoxin and should be dis-
posed of properly. Further, he tells Bob to make black-and-white photo-
graphs of all his previous gels and to retain both the print and negative for
each gel. He says that in the future this practice should be followed for all
acrylamide gel data storage. He says the photographs are to be considered
the primary data and retained in Bob’s data book. Bob disagrees with his
mentor and argues that photographs can be altered and that a desiccated
gel is an accurate representation of the original data. He also argues that
once the acrylamide is sealed in plastic, there is no danger of exposure to
toxic material. Bob’s mentor dismisses these arguments and gives him 1
month to photograph the existing gels and to dispose of them. Bob is very
upset. He thinks his mentor is acting irresponsibly with respect to data
retention. He also feels his mentor is being a bully, by forcing Bob to adopt
his personal preferences. What advice do you give Bob?
10.6 Dr. Isabelle Amos is a physiologist studying ligand-gated ion chan-

nels in smooth muscle. Matt Pinfield, one of Dr. Amos’s postdoc-
toral trainees, is finishing up his work in the lab. He has completed a series
of experiments designed to investigate the modulation of ion channel
function by angiotensin II. The results of the study are exciting and appear
to shed new light on how angiotensin II affects ion channel function in
vascular smooth muscle. The findings may eventually lead to treatments
for hypertension. Matt has submitted a manuscript describing the experi-
ments to the prestigious journal Molecular Physiology, with himself as the
first author and Dr. Amos as the second author. While the paper is under
review, Dr. Amos receives a manuscript for ad hoc review that suggests a key
finding of Matt’s work is incorrect. Without specifically mentioning the
manuscript she is reviewing, Dr. Amos questions Matt about his experi-
ments. Matt insists that his results are correct. But when Dr. Amos inspects
the data books from the relevant experiments, she finds the records incom-
plete and sloppy. Dr. Amos suggests that Matt perform some new experi-
ments that would confirm his original findings, but Matt responds that he
does not have time to do any more experiments since he has accepted a
faculty position at another institution. Shortly after Matt leaves to begin
his faculty position, he informs Dr. Amos that the paper has been accepted
for publication. Dr. Amos insists that Matt withdraw the paper because she
is unsure of the results, but Matt refuses. Thus, Dr. Amos insists that her
name be removed from the author’s byline and reference to her grant be
removed from the acknowledgments. Matt agrees, and the paper is pub-
lished with him as the sole author. The relationship between Matt and Dr.
Amos subsequently deteriorates. Meantime, Dr. Amos enlists her new
postdoctoral trainee, Dr. Juanita Gomez, to repeat the relevant experi-
ments, and her results clearly support that the findings in question are in-
correct. Drs. Amos and Gomez prepare a manuscript reporting this and
ultimately publish their results in Molecular Physiology. Comment on Dr.
Amos’s handling of this situation. What, if anything, would you have done
differently? Does anything described in this scenario meet the definition
of scientific misconduct? Explain.
10.7 A predoctoral trainee under your supervision has had several diffi-
cult years finishing up his dissertation research. He has needed
continual guidance, and his attitude has not been positive. He does not
seem motivated about the work, but you press him almost daily until the
work is completed and the dissertation is finally written. The student turns
in an average defense and informs you that he is leaving science to take a
job in biomedical supply sales. Several areas of the student’s dissertation
need additional work before the research can be written up in manuscripts
for publication. You turn several portions of the dissertation work over to a
competent postdoctoral trainee in your laboratory. Over the course of the
next several weeks, the postdoctoral trainee pursues these new lines of ex-
perimentation. In the process, however, she uncovers several problems
with the data in the dissertation. In fact, a number of experiments cannot
be repeated. Moreover, some of the results obtained are opposite to those
reported in the student’s dissertation. You review the student’s data books
and are unable to find entries that could have been used to construct some
of the tables included in the dissertation. Moreover, other data sets written
into the data book have been used selectively to construct some tables in
the dissertation; i.e., critical points that would have confused analysis were
omitted in the dissertation. After considerable analysis and discussion with
the postdoctoral trainee, you decide that the student has at least falsified
data and possibly fabricated data presented in his dissertation. You have
not yet published any of the work of the student’s dissertation in manu-
script form. However, one published abstract contains accurate informa-
tion that has been authenticated by your postdoctoral trainee. All of the
student’s work was supported by your NIH grant. What actions, if any, will
you take in this situation?
10.8 Alvin Dunning, a fifth-year Ph.D. student, was in the process of

rerunning some analyses for a revised manuscript submission. This
publication is the remaining hurdle between Alvin and his dissertation
356 Chapter 10
defense. Alvin’s research has involved analysis of survey items. In preparing

his data for analysis, he has been careful to document all of the variables
and their codes (i.e., 1 = strongly disagree, 2 = somewhat disagree, 3 =
somewhat agree, 4 = agree, 5 = strongly agree) in a code book. Now, as he
looks at the raw data prior to analysis, he sees that one variable’s responses
include several 0’s. This is unexpected because the range of responses
should have been from 1 to 5. He now realizes that the 0’s actually repre-
sent missing data. Instead of considering the data “missing,” his initial
analysis had included the 0’s as real values. This erroneous analysis was
used for the original submission. In a slight panic, Alvin deletes all of the
0’s from the database and reruns the analysis. He breathes a sigh of relief
because his results are still significant, though somewhat different (P =
0.048 compared with a previously reported P = 0.011). Alvin is concerned
that if he makes public his error, it could cast doubt on the integrity of his
analyses; this could delay or even preclude publication. He decides that
because the results are still significant, he will erase all evidence of the pre-
vious 0’s and the earlier analyses. He also plans simply to report “P  0.05.”
As you are the senior postdoc in the lab, Alvin runs his plan by you and asks
your advice. What do you tell him?
10.9 Dr. Megan Hennessey has collected blood samples from 100 hu-
man patient volunteers to test antibody levels against two differ-
ent viruses. Relevant clinical histories of these patients, corresponding to
the individual samples, are noted in her data book. She has carefully
tagged the tubes with self-adhesive labels and stored them in racks of 20
in the freezer. She assays the samples in three of the five racks and obtains
interesting results. She records her results meticulously in her lab data
book, cross-referencing the antibody values to the clinical patient data.
Megan asks you to witness these data book pages because the results have
implications for the development of an important diagnostic test. You
sign her data book pages as requested. When she opens the freezer to
retrieve the sera in the fourth rack, she makes a disturbing discovery. All
the labels have fallen off the tubes in racks 1 and 2. (She later finds out
she used the wrong kind of self-sticking labels on these tubes, resulting in
their failure to adhere at –70°C.) Megan proceeds to number all the tubes
in racks 1 and 2 by order of their rack location. Then she repeats the an-
tibody assays on these samples. She arranges her resulting data into a
summary table that she compares with her original assays of these sam-
ples. She is relieved that the data compare favorably, and she relabels the
tubes consistent with their original designations. She comes to you for
advice on her actions and asks how, if at all, she should record these events
in her data book. What do you tell her?
10.10 Dr. Raja Rastami’s research group recently published an important

paper in a leading physiology journal. Four months after the publi-
cation of the manuscript, Dr. Rastami is contacted by a colleague who has
been unable to reproduce the results presented in two figures of the paper.
Dr. Rastami sends copies of the pertinent laboratory protocols and recipes
to her colleague and thinks no more of the discrepancy. Two months later,
a graduate student in a competitor’s laboratory contacts Dr. Rastami and
reports that he, too, was unable to reproduce the results. After this second
call, Dr. Rastami meets with Adam Green, the postdoctoral fellow who did
the experiments in question. She asks Adam to bring his data book to the
meeting so they can review the results together. Once in Dr. Rastami’s of-
fice, Adam confesses that he has been remiss in keeping his data book. He
says that all of his electrophysiology experiments observations were digi-
tally recorded. Adam then transcribed these observations into his data
book. However, there was a period of several days when his microphone
was not working properly. Although Adam replaced the microphone as
soon as he found that it was not working, he relied on his memory to tran-
scribe the results of those particular experiments. After completing the fig-
ures for the manuscript, Adam was pleased to find that his data supported
Dr. Rastami’s hypothesis. Dr. Rastami comes to you for advice on how to
handle this situation. What do you suggest?
Resources
Print
Barker K. 2005. At the Bench: A Laboratory Navigator, updated ed. Cold Spring
Harbor Laboratory Press, Cold Spring Harbor, NY.
Making the Right Moves: A Practical Guide to Scientific Management for Postdocs
and New Faculty, 2nd ed, p 143–152. Burroughs Wellcome Fund, Research Tri-
angle Park, NC, and Howard Hughes Medical Institute, Chevy Chase, MD.
Canfield MR (ed). 2011. Field Notes on Science and Nature. Harvard University
Press, Cambridge, MA.
Kanare HM. 1985. Writing the Laboratory Notebook. American Chemical Society,
Washington, DC.
Mellick AS, Rodgers L (ed). 2006. Lab Ref: A Handbook of Recipes, Reagents, and
Other Reference Tools for Use at the Bench, vol 2. Cold Spring Harbor Laboratory
Press, Cold Spring Harbor, NY.
Menzel J, Weil P, Bittihn P, Hornung D, Mathieu N, Demiroglu SY. 2013.
Requirement analysis for an electronic laboratory notebook for sustainable data
management in biomedical research. Stud Health Technol Inform 192:1108.
358 Chapter 10
Milsted AJ, Hale JR, Frey JG, Neylon C. 2013. LabTrove: a lightweight, web
based, laboratory “blog” as a route towards a marked up record of work in a
bioscience research laboratory. PLoS One 8:e67460.
doi: 10.1371/journal.pone.0067460. http://www.plosone.org/article/info%3A
doi%2F10.1371%2Fjournal.pone.0067460.
Roskams J, Rodgers L (ed). 2002. Lab Ref: A Handbook of Recipes, Reagents, and
Other Reference Tools for Use at the Bench, vol 1. Cold Spring Harbor Laboratory
Press, Cold Spring Harbor, NY.
Rubacha M, Rattan AK, Hosselet SC. 2011. A review of electronic laboratory
notebooks available in the market today. J Lab Autom 16:90–98. http://jla
.sagepub.com/content/16/1/90.long.
Voegele C, Bouchereau B, Robinot N, McKay J, Damiecki P, Alteyrac L. 2013.
A universal open-
source Electronic Laboratory Notebook. Bioinformatics
29:1710–1712.
Online
Resources from federal agencies
National Cancer Institute Technology Transfer Center’s 2009 Guide for
Keeping Laboratory Records brochure:
http://ttc.nci.nih.gov/pdfs/brochures/Keeping_Lab_Records.pdf
National Institutes of Health’s (NIH) 2008 Guidelines for Scientific Rec

ord Keeping in the Intramural Research Program at the NIH:
http://sourcebook.od.nih.gov/ethic-conduct/RECORDKEEPING.pdf
In the National Science Foundation Office of Inspector General’s Semian-

nual Report to Congress of March 2009, discussion of meaningful labora-
tory records can be found on p 51:
http://www.nsf.gov/pubs/2009/oig0902/oig0902.pdf
The NSF’s Proposal and Award Policies and Procedures Guide, released in
2013, contains information on data sharing, record retention, and other
topics relevant to this chapter. It is available at
http://www.nsf.gov/pubs/policydocs/pappguide/nsf13001/gpgprint.pdf
The NIH Grants Policy Statement contains information on data sharing,

record retention, and other topics relevant to this chapter. It is available at
http://www.nih.gov/grants/policy/nihgps_2013/
Paper laboratory data books

University bookstores and office supply companies typically sell bound
data books suitable for laboratory record keeping. Such data books come
in several standard formats. The paper contained in these products may

not be acid free.
Some companies specialize in data book manufacturing. Products mar-
keted by these companies contain acid-free paper and come in standard or
custom-designed formats. These companies sell directly to individual cus-
tomers but usually require a minimum order. Some of their data books are
carried by university bookstores.
For standard-format data books of various styles:

Scientific Notebook Company
http://www.snco.com/
For custom-manufactured data books:

Eureka Lab Book, Inc
http://www.eurekalabbook.com
Laboratory Notebook Company

http://www.lab-notebook.com/about.html
For materials for archiving, including acid-free glue, archival mending

tape, and acid-free boxes of varying styles and sizes:
University Products, Inc
http://www.universityproducts.com/
Electronic laboratory notebooks and related information

The Food and Drug Administration’s 2003 Guidance for Industry: Part
11, Electronic Records; Electronic Signatures—Scope and Application:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm125125.pdf
MEDRAD, Inc’s 2006 Electronic Lab Notebook Project—Final

Report—8/04/06:
http://www.hcii.cmu.edu/M-H CI/2006/MEDRADProject/deliverables
/MEDRAD-FinalPaper-080406.pdf
chapter 11
Science, Technology, and Society

Cindy L. Munro and Francis L. Macrina
Responsibilities of Scientists to Society • rDNA Technology • Genetic
Technology • DURC • Conclusion • Discussion Questions
• Resources
Responsibilities of Scientists to Society
Creating and translating new knowledge

Scientists have responsibilities to the scientific community and to society.
These include the carrying out of research with honesty and integrity,
compliant and compassionate use of research subjects, accurate and re-
sponsible reporting of results, disclosure and management of competing
interests, and management of resources prudently and with accountability.
These resources are almost always public funds representing taxpayer or
philanthropic dollars. The investment of these resources is accompanied
by an implicit trust that the scientist will conduct the research in an ethical
and responsible manner. That the scientist is accountable for his or her
research is a reasonable expectation that flows from this trust.
The public support of research gives rise to other aspects of responsibil-
ity and accountability. Most would argue that the scientist has an obliga-
tion to recognize and act on new knowledge created by his or her research.
Such actions might involve seeking intellectual property protection of a
discovery and working with institutional offices to ensure that the discov-
ery is moved toward practical application to benefit society. These kinds of
activities are captured in the phrase “translational research.” In the par-
lance of biomedical research this is commonly expressed as taking research
from “the bench to the bedside.” The importance of translating new
knowledge into practical applications that may be commercialized has
been affirmed strongly by federal funding agencies in recent times. This is
doi:10.1128/9781555818487.ch11
361
362 Chapter 11
exemplified in the National Institutes of Health (NIH) infrastructure

grants—Clinical and Translational Science Awards, discussed in chapter
8—to support translational research and in the creation of a new NIH
center, the National Center for Advancing Translational Sciences. If a dis-
covery can be applied to benefit society, then publicly funded scientists
have an obligation to originate this process. At a minimum, this would in-
volve filing an invention disclosure with their institutional technology
transfer office. If appropriate, this would be followed by the filing of a
provisional patent or nonprovisional patent application (see chapter 9 and
Appendix V). Once filed, such an application would provide at least tempo-
rary protection of the discovery that would position the institution to pur-
sue subsequent steps aimed at its commercialization.
Contemplating and communicating the

implications of research
Some research may cause concerns on the parts of both the scientific com-
munity and the public. Such concerns may center on the specific nature of
the work being done as well as on the potential use of the results of the re-
search. At the crux of this issue is the scientist who proposes and conducts
the research. To what extent should scientists be obligated to explain the
purposes and implications of their research? If the implications of their pro-
posed research are potentially harmful to man, animals, or the environment,
must scientists consider such harm in deciding whether to do the research?
To what degree, if any, should scientists be responsible and accountable for
harmful consequences that result from the application of their research?
This topic has been discussed and debated for decades, if not centuries. Tra-
ditionally, science has been characterized as being value free or value neu-
tral. That is, scientists are objective in their collection of facts, and these
facts are not laden with values, good or bad. But since the middle of the 20th
century, scientists and others have opened the door to thinking that there
are obligations on the part of scientists to articulate risks associated with
certain types of research and to accept the responsibility to ensure the ap-
propriate use of knowledge derived from their research.
On the role of the scientist

Writing in the wake of World War II, Ward Pigman and Emmett Carmi-
chael commented that the war “demonstrated to the public in general and to
legislators and businessmen in particular that science, especially basic sci-
ence, is much more than a scholarly pursuit—that it is a vital force for the
advancement or destruction of society.” In their thoughtful article in Science
magazine, these authors wrote about the need for a written ethical code for
scientists. One of the first elements contemplated for such a code was that
It should state the scientist’s obligation to explain the nature and purposes of
science, and the policies in dealing directly with the public. It should clarify
Science, Technology, and Society 363
the scientist’s attitudes toward patents and secrecy restrictions. It should af-
firm the scientist’s obligations to individuals—to his employer, his associates,
other scientists, and his assistants and graduates—and scientists’ obligations
as a group to other professions.
Writing on the social and ethical responsibilities of scientists, the late H.

Bentley Glass proclaimed: “It is the social duty and function of the scientist
in this arena of discussion to inform and to demand of the people, and of
their leaders too, a discussion and consideration of all those impending
problems that grow out of scientific discovery and the amplification of hu-
man power.” Published in 1965, this quote and its supporting arguments
were reprinted in 2002 in the second edition of The Ethical Dimensions of the
Biological and Health Sciences. Glass enjoyed a productive scientific career as a
geneticist, but also wrote prolifically as a newspaper columnist and essayist
about issues of social relevance, including the application of genetic tech-
nology and the dangers of radioactivity. The need for and virtues of this
kind of social activism by scientists are extolled by Jon Beckwith in his book
Making Genes, Making Waves: A Social Activist in Science.
Stanley Reiser and Ruth Bulger have promoted the notion that scien-
tists have responsibilities to society. Society’s funding of research is a key
element in their discourse. This, they argue, creates an “intellectual war-
rant” given by society to scientists, enabling them to apply their specialized
training and skills to create new knowledge. They acknowledge extant
mechanisms of societal oversight like the regulatory boards that review
and approve research involving humans or animals. These formalized
mechanisms provide safeguards for specific kinds of research activities.
Reiser and Bulger’s point is that if research subjects are afforded protec-
tions in this fashion, then “society itself should receive a similar protec-
tion.” Science is recognized as a profession (see chapter 2), and social
responsibilities of scientists are connected to their professional role and
duties. This is summarized in the following two passages from their 1997
Science and Engineering in Ethics paper.
Yet, when a person has special knowledge about and responsibility for a par-
ticular discovery and the discovery becomes the basis for a consequential
outcome, as scientists have when they discover and interpret natural phe-
nomena, their responsibility flows not from a general commitment to serve
one’s fellow citizens, but from a direct commitment to take account of effects
which their own actions revealed. . . .
Whoever makes the effort and succeeds in the discovery receives the ku-
dos, but must also accept the responsibility for having done it: not the re-
sponsibility that carries blame for unanticipated consequences, but the
responsibility to be there, to participate, to follow the path the discovery
takes and to help society use it appropriately.
In this chapter, we will discuss a few topic areas that bear on scientific
research with potential or emerging social agendas. We will begin with a
discussion of the development and use of recombinant DNA (rDNA)
364 Chapter 11
technology, a unique example of social activism by scientists. Next, we will

discuss some topics focusing on modern genetic technology that loom at
the interface of technology and society. We will conclude with a review of
dual use research of concern (DURC), a topic of growing interest, and one
that is already having an impact on proposing and reporting research.
rDNA Technology
Background
In chapters 5 and 6, we discussed oversight mechanisms that ensure the eth-
ical use of humans and animals in research. The Nuremberg Code and the
Declaration of Helsinki provided the prevailing international standards for
human subjects research in the 1950s and 1960s. The Nuremberg Code was
created in response to the atrocities committed by Nazi doctors under the
guise of “experimentation.” Physicians helped write the Code, which pro-
vided critical guidance for the court in the prosecution of the trial. The
Declaration of Helsinki, first promulgated in 1964 by the World Medical
Association, built on the authority of the Code. Both the Nuremberg Code
and the Declaration of Helsinki strongly influenced the U.S. federal laws
that now govern human subjects research. This history featured seminal
events that created public awareness and mobilized scientists, legal infra-
structure, governments, government agencies, and international scientific
organizations. Formal guidance and codes for the use of animals in research
further illustrate the effect of convergence of multiple factors to create a
new ethical culture. The initial passage of the Animal Welfare Act in 1966
followed just months after a Life magazine article described horrific condi-
tions under which commercial breeders maintained their dogs. The public
outcry, together with the speed at which the U.S. Congress acted, was stun-
ning, and the impact on the use of animals in research was lasting. Clearly,
the need to conduct research with human and animal subjects in ethical and
responsible ways emerged as a mandate from both inside and outside of the
research community. In the end, science and society became engaged in an
agenda aimed at ensuring the responsible conduct of research.
The development of rDNA technology and the debate about risks asso-
ciated with its use provide a powerful example of the intersection of sci-
ence and society. Its uniqueness lies in two separate characteristics. The
first is that the discovery of rDNA technology and the ensuing concerns
about the use of this technology were brought into the public domain by
scientists who had a vested interest in its use and success as a research tool.
Second, debate about the use of rDNA technology was robust and wide-
spread, involving scientists, the government and government funding
agencies, and the public. The upshot of the dialogue and debate about the
technology was a regulatory infrastructure designed to monitor certain
kinds of rDNA experiments, which continues to this day. The impact of

rDNA technology on the biomedical and life sciences turned out to be
enormous and far-reaching. It made possible the ready isolation and ma-
nipulation of genes, creating powerful new ways to explore gene structure,
organization, and expression. It enabled the practical and efficient se-
quencing of DNA molecules. This was aptly expressed by Nobel laureate
Paul Berg in 2004 when he wrote: “Without the tools of recombinant
DNA there would be no human or any other genome sequence.” The
practical and commercial applications of rDNA research launched the
modern biotechnology industry.
Pre-rDNA concerns about genetic engineering:

isolating the lactose operon
rDNA technology readily allowed the isolation and purification of DNA
fragments. Beginning in the 1970s, rDNA technology rapidly became the
dominant, if not exclusive, method for capturing and working with specific
genes. However, in 1969, a few years prior to the publication of the paper
that laid the foundation for rDNA technology, a report was published in
Nature describing the isolation of a genetic determinant using molecular
biological techniques that did not involve the basic elements of rDNA. This
work reported the successful isolation of purified DNA consisting of only
the lactose operon from the intestinal bacterium Escherichia coli. This se-
quence is the genetic determinant that enables E. coli to use the sugar lac-
tose as a carbon source. The paper was authored by a team of scientists led
by Jonathan Beckwith. This accomplishment demonstrated the power of
the relatively new field of molecular biology in genetic research. But in
publishing the work, Beckwith and his colleagues expressed concerns about
the possible misuse of such information. A New York Times article about the
paper was titled “Scientists Isolate a Gene; Step in Heredity Control.” The
Times writer invoked the term “genetic engineering,” mentioning the po-
tential to add desirable genetic traits or to eliminate undesirable ones. In
comments made during a press conference leading to the New York Times
article as well as in quotes in the article itself, Beckwith and his colleagues
expressed caution about the negative consequences of genetic manipulation
and its misuse. These publicly stated concerns were a harbinger for the so-
cial activism that would accompany the advent of rDNA technology a few
years later.
Discovery, debate, and decision

The key events of rDNA technology development, the ongoing dialogue
about its potential, and the various outcomes of the debate affecting its use
and regulation provide an exemplar of engagement of the scientific enter-
prise with society. The definitive book on the subject is the memoir of
366 Chapter 11
Donald S. Frederickson, The Recombinant DNA Controversy, published by

ASM Press in 2002. Frederickson served as director of the NIH from 1975
to 1981, a period during which the seminal events of the rDNA debate
played out. As NIH director, he participated in an unprecedented series of
meetings involving scientists and others who discussed the implications of
rDNA research and contemplated the need for its oversight. Frederickson
served as the chair of the inaugural NIH Recombinant DNA Advisory
Committee from 1975 to 1978; this committee continues to play an im-
portant role in policy development and oversight of rDNA experimenta-
tion. During his tenure as NIH director, the first and second versions of
the NIH Guidelines for Research Involving Recombinant DNA Mole-
cules were written and implemented (1976 and 1979).
The history of the advent of rDNA technology began in 1971 with
Richard Pollack, a microbiologist at the Cold Spring Harbor Laboratory
on Long Island in New York, challenging Stanford University biochemist
Paul Berg. In a phone conversation between the two scientists, Pollack
expressed concerns about experiments underway in Berg’s laboratory to
enzymatically splice together the genome of an animal virus, simian virus
40 (SV40), with sequences of a bacterial virus called dvgal. The resultant
hybrid molecule could conceivably be introduced into E. coli, where it
would replicate itself inside the bacterial cell. Pollack cautioned that SV40,
a known animal tumor virus, was able to infect human cells growing in
tissue culture, transforming them to a state that resembled tumor cells.
Propagating SV40 in a bacterium that naturally lives in the human colon
might present health risks if such “genetically engineered” organisms
found their way into this ecological niche.
The conversation with Pollack gave Berg pause and caused him to alter
his research plans. First, he sought and contemplated opinions from other
scientists about the implications of this work, and he postponed the exper-
iment to introduce the SV40-dvgal “recombinant molecule” into E. coli.
Later, in 1972, he published, with David Jackson and Robert Symons, the
method for linking the two molecules, noting in the “Discussion” section
of the paper that experiments to evaluate the biological activity of the
SV40-dvgal molecule were in progress (e.g., testing the ability of the mol-
ecule to replicate in E. coli). Second, he engaged Pollack and others in or-
ganizing a conference on the hazards of working with tumor viruses, which
was held in 1972 at the Asilomar Conference Grounds in Pacific Grove,
CA. A subsequent meeting in 1975 at this site would make the Asilomar
name emblematic of the scientific and public discourse that surrounded
the emergence of rDNA technology.
A number of scientific meetings in 1972 and 1973 featured discussions
of creating hybrid DNA molecules along with reports on the tools and
methodologies that accompanied such research. A seminal paper by
Stanley Cohen and collaborators in November 1973 described the con-

struction of functional rDNA molecules consisting of two different bacte-
rial plasmids. These are small circular DNA molecules that exist and
replicate independently of the bacterial chromosome. This paper reported
the use of enzymes called restriction endonucleases to prepare DNA se-
quences to be spliced together. The use of such enzymes—which cleave
DNA at specific sites, typically yielding cohesive termini, commonly called
“sticky ends”—quickly predominated as the methodology for constructing
recombinant molecules. Also termed “bacterial restriction enzymes” (they
are of bacterial origin), these enzymes were a major topic of discussion at
the Gordon Research Conference on Nucleic Acids in 1973. This discus-
sion included consideration of the potential hazards that might come from
the construction of certain types of rDNA molecules. The upshot of this
concern was the decision by the majority of those in attendance at the
meeting to ask the president of the National Academy of Sciences and the
president of the Institute of Medicine to establish a study committee to
evaluate the concerns and recommend specific actions or guidelines for
doing rDNA research. The cochairs of the meeting, Maxine Singer and
Dieter Soll, were signatories to the letter that made this request.
The action of the Gordon conferees represented an unprecedented
event. Scientists had identified a nascent area of research about which
there was significant concern that included a potential impact on society.
Accordingly, they proposed that the academies study the issue with an eye
toward outcomes that would address the concerns in an informed way. The
president of the National Academy of Sciences, Philip Handler, appointed
Paul Berg to head the effort. Berg convened a small group to consider the
potential dangers and benefits of rDNA research, and the recommenda-
tions of this group were published in a letter to Science on July 26, 1974,
titled “Potential Biohazards of Recombinant DNA Molecules.” There
were four recommendations in the letter, which was also published in the
Proceedings of the National Academy of Sciences of the United States of America.
1. Implement a moratorium on the construction of new bacterial plas-

mids carrying genes that could have an untoward impact on human
health (specific examples involved certain antibiotic resistance genes
or gene combinations, bacterial toxins, and DNA sequences from
oncogenic or other animal viruses).
2. Mandate careful consideration of rDNA construction involving ani-
mal DNA fragments, weighing the possibility that animal DNA fre-
quently contains sequences common to RNA tumor viruses.
3. Request that the NIH director consider (i) establishing a program to
evaluate potential biological and ecological hazards from the above-
mentioned types of rDNA molecules; (ii) developing procedures to
368 Chapter 11
minimize the spread of rDNA molecules within human and other

populations; and (iii) devising guidelines for research that uses
rDNA technology.
4. Convene an international meeting in early 1975 to review scientific
progress and discuss ways to deal with the potential biohazards of
rDNA.
Shortly after the letter in Science appeared, a committee to organize the

recommended international meeting was established, chaired by Berg.
The NIH would provide most of the funds to support the three-and-a-
half-
day meeting, which was to be held at the Asilomar Conference
Grounds in early 1975. In attendance, by invitation, were some 150 molec-
ular biologists from 13 countries. Sixteen members of the press were also
invited and attended under the condition that they not file any stories until
the conference was over. A provisional statement of meeting proceedings
was issued at its conclusion, and a summary statement of the report of the
meeting to the National Academy of Sciences was published in Science and
the Proceedings of the National Academy of Sciences in mid-1975. The newly
formed NIH Recombinant DNA Molecule Program Advisory Committee
immediately adopted the Asilomar meeting provisional statement as in-
terim rules for federally supported laboratories in the United States. This
effectively lifted the voluntary moratorium recommended in 1974 in the
Berg et al. letter published in Science. The Asilomar report also provided
strong guidance for the crafting of the NIH Guidelines for Research In-
volving Recombinant DNA Molecules published in 1976. The report set
out guiding principles for recommendations that were aimed at ensuring
safety and minimizing potential risks associated with the performance of
experiments involving rDNA technology. It defined levels of containment
that were matched to an assessment of the potential for biohazards associ-
ated with the proposed experiment. It detailed types of experiments, com-
menting on perceived biohazard issues. It also recommended that certain
experiments, although feasible, were too dangerous to be undertaken at
that time with the available genetic tools and containment capability. Fi-
nally, it called on the scientific community (i) to develop safer vectors and
hosts for rDNA work; (ii) to embrace laboratory safety training and ap-
propriate heath surveillance of lab workers; and (iii) to engage in continu-
ing reassessment of the field, coupling new knowledge to training and
educational efforts.
The infrastructure that was born of the Asilomar meeting is in strong
evidence today. The NIH guidelines have been revised several times since
they first appeared in 1976. They are now called the NIH Guidelines for
Research Involving Recombinant or Synthetic DNA Molecules, and the
most recent revision was published in November 2013. Recombinant
DNA oversight is located in the NIH Office of Biotechnology Activities,

and the oversight process has been enhanced by the direct involvement of
locally based institutional biohazard committees.
“Asilomar and Recombinant DNA”

Paul Berg was awarded the 1980 Nobel Prize in chemistry “for his funda-
mental studies of the biochemistry of nucleic acids, with particular regard
to recombinant-DNA.” In 2004, he published an article titled “Asilomar
and Recombinant DNA” on the Nobel Prize website. Writing in the year
of its 30th anniversary, Berg recounted the circumstances that spawned the
1975 Asilomar Conference and how the outcomes of this meeting allowed
rDNA technology to have its profound impact on research in a diversity of
scientific fields.
He affirmed that the conference was “the beginning of an exceptional
era for science and the public discussion of science policy.” As mentioned
earlier, the origins of that discussion are unique in that societal engage-
ment was instigated by scientists who were doing or knew about the re-
search. Berg declared that the Asilomar Conference gained the public’s
trust when he wrote that “it was the very scientists who were most involved
in the work and had every incentive to be left free to pursue their dream
that called attention to the risks inherent in the experiments they were
doing.” Berg attributed the actions by scientists (and ultimately govern-
ments) throughout the 1973 to 1976 period to be motivated by the need to
protect researchers, the public, and the environment from hazards that
might emanate from experiments using rDNA technology. Although the
conference has been criticized for its failure to consider the implications of
genetic engineering, gene therapy, genetic screening, and the like, Berg
defended the Asilomar agenda of risk assessment, reduction, and elimina-
tion. The discussion of risk was urgent, while the deeper issues of applica-
tion were “far in the future.” Berg stated: “We accepted that the other
issues would be dealt with as they became imminent and estimable.” The
debate about the possible hazards of rDNA research often featured ex-
tremes in opinion that ranged from the accidental creation of an “Androm-
eda strain” to a dismissal of any concern that rDNA technology and its
component biological elements posed any risk to health or the environ-
ment. Berg asserted that “hundreds of millions of experiments” using
rDNA technology were performed in the 30 years since the Asilomar
Conference without any documented incident or hazard to public health.
Berg concluded his article by asking whether the model established by
the Asilomar Conference would be appropriate for addressing contempo-
rary controversial research issues. Examples offered included fetal tissue
and embryonic stem cell research, somatic and germ line gene therapy, and
genetic modification of food crops. Berg posited that the Asilomar model
370 Chapter 11
would not succeed today in contributing to the resolution of such topics.

He cited four elements that worked together in allowing the Asilomar
Conference to achieve its successful outcomes regarding rDNA research.
First, public awareness of rDNA was “sudden and unanticipated,” and the
advance carried with it potential public health hazards. Second, the con-
cerns of risk were not made public by an investigative reporter or by a
disaffected scientist. Instead, scientists doing the research brought their
case to the public, an event Berg called “historic.” Third, action was
prompt, being viewed by the public “to have been achieved by transparent
deliberations and with considerable cost to their own scientific interests.”
Finally, Berg noted that this progression of events resulted in a resolution
before the development of an “entrenched, intransigent and chronic
opposition.”
Berg discussed his analysis of the Asilomar Conference in the context of
some modern-day research challenges, noting that the latter are qualita-
tively different from those faced by the conference participants in 1975.
Research topics of the type cited above “are often beset with economic
self-interest and increasingly by nearly irreconcilable ethical and religious
conflicts and challenges to deeply held social values.” This, he argued,
would doom the use of an Asilomar Conference model to “acrimony and
policy stagnation.” Berg ended his article with the following paragraph.
The Asilomar decisions emerged from a consensus of opposing views. Al-
though the recommendations were clearly “inconvenient,” the participants
had a stake in having the science move forward and not in leaving the rules
for conducting the research to be set by others. By contrast, there is little
prospect for consensus in our society on the ethical issues concerning fetal
tissue and embryonic stem cell research, genetic testing, somatic and germ-
line gene therapy, and engineered plant and animal species and hence little
incentive to seek a compromise. Compromise in those instances may only be
achievable by political means, where majority rule prevails.
At first blush, one might interpret this passage as ceding the resolution
of challenging research dilemmas to political process. But Berg’s message
does not rule out or dismiss activism on the part of scientists and the scien-
tific community. In fact, the complexity of the issues associated with a
number of modern-day research areas demands the input and involvement
of scientists in whatever means seems appropriate to seek understanding
and resolution. The Asilomar Conference stands as a shining example of
social activism in science. The outcomes of the conference should con-
vince scientists of the importance of public engagement and inspire their
sense of social responsibility, which is, in fact, an obligation. Beckwith and
Franklin Huang point out that the scope of the scientific research enter-
prise today exceeds that at any other time, and that the societal conse-
quences of such research are correspondingly expansive. Echoing earlier
comments made in this chapter, these authors declared: “It is more neces-
sary than ever that scientists be part of the public conversation that fosters
both an understanding of science and shapes the impact science will have
on society.”
Genetic Technology
Although rDNA and other genetic technologies began as research tools,

the translation from bench to bedside has been rapid. DNA-based reagents
have emerged as tools with unprecedented power in predicting suscepti-
bility to disease, providing precision in disease diagnosis, and guiding indi-
vidualized treatment. Data also move from “bedside to bench,” as biological
specimens and genetic information from patients become material for re-
search. The engagement of scientists, research funders, health care provid-
ers, patients, and the broader public in dialogue is critical in understanding
and addressing the complex issues posed by the intersection of science and
health care.
The Human Genome Project

The Human Genome Project, completed in April 2003, provided genetic
mapping and DNA sequence information on the 3 billion base pairs of the
human genome. The initial and continuing impact of the field of human
genomics is having an enormous impact on advancing both DNA diagnos-
tics and therapeutics. In recognition of the magnitude of issues related to
the science, from its initiation the Human Genome Project included plans
to consider ethical, social, and legal implications of the work. An early
commitment was made to devote 5% of the project budget to consider-
ation of ethical issues related to the project. The Ethical, Legal and Social
Implications (ELSI) Working Group was established in 1989 as a subgroup
of the Program Advisory Committee on the Human Genome. It was sup-
ported by the two major sponsors of the Human Genome Project, the
NIH National Human Genome Research Institute and the Department of
Energy (DOE). The ELSI Working Group quickly set about to inform
and influence public policy related to genetics and genomics. Each of the
two task forces formed under the ELSI Working Group, the Task Force on
Genetic Information and Insurance and the Task Force on Genetic Test-
ing, had substantial influence on the development of societal norms and
national policy.
The Task Force on Genetic Information and Insurance, whose final
report was issued in 1994, provided the foundation for subsequent health
care reform legislation. The task force recommended that genetic infor-
mation (as well as other information about past, present, or future health
status) should not be used to deny health care coverage or service, and
372 Chapter 11
further recommended that genetic services should be offered comparably

to other health care services. These recommendations directly addressed
alarming reports of discrimination based on genetic information. Con-
gress passed The Health Insurance Portability and Accountability Act
(HIPAA) in 1996. HIPAA, which is discussed in chapter 5, prohibited
group health insurance plans from excluding individuals based on genetic
information and established that genetic information without a current
diagnosis of illness could not be defined as a preexisting condition. A 13-
year debate in Congress that centered on more comprehensive genetic
legislation culminated in the 2008 passage of the Genetic Information
Nondiscrimination Act (GINA), which ensured protection against dis-
crimination in health insurance underwriting and in employment based
on genetic information. Under GINA, genetic information cannot be
used by insurers to make eligibility, coverage, underwriting, or premium-
setting decisions. However, neither HIPAA nor GINA provided protec-
tion for individuals with existing genetic illness (in contrast to protections
provided for those who had genetic predisposition without diagnosis of
illness). The Affordable Care Act of 2010 extended protections further by
requiring insurers in either the group or individual health insurance mar-
ket to provide coverage (and set premiums) without consideration of pre-
existing conditions.
The ELSI Task Force on Genetic Testing was charged with reviewing
genetic testing in the United States and making recommendations to en-
sure the development of safe and effective genetic tests. The task force re-
leased its final report (Promoting Safe and Effective Genetic Testing in the
United States) in 1997. Recommendations were organized into several
broad areas, including (i) principles to ensure the safety and effectiveness
of genetic tests (focused on clinical sensitivity, specificity, and predictive
value in order for providers and patients to understand risk and benefits);
(ii) standards to ensure high quality in laboratories performing genetic
tests, including recommendations to enhance Clinical Laboratory Im-
provement Amendments regulations for genetic tests and explicit opposi-
tion to direct marketing of predictive genetic tests to the public; (iii)
strategies to improve understanding and appropriate use of genetic testing
among consumers and health care providers, focusing in particular on
health care professionals who are not genetic specialists; and (iv) continued
development of genetic testing for rare inherited disorders.
The original ELSI Working Group concluded its work in 1997, but
ELSI activities continue to be central to both NIH and DOE research
initiatives. At the NIH, the National Human Genome Research Institute
maintains an ELSI Research Program, which funds research grants and
trainees. The DOE sustains an ELSI program of its own. The NIH and
DOE ELSI programs have collaborated closely since the initiation of the
Human Genome Project. Since 2003, they have jointly supported interdis-
ciplinary Centers of Excellence in ELSI Research.
Genetic testing
The development of new techniques in molecular biology has fueled a rev-
olution in genetic testing, and testing is now available from preconception
through adulthood. In addition to tests performed by and interpreted by
health care providers, direct-to-consumer testing has also become avail-
able. There has been controversy regarding whether individuals should
have direct access to their own genetic data. Invoking the principle of au-
tonomy, it can be argued that individuals have a right to their own genetic
data. Based on beneficence, others argue that provision of genetic infor-
mation directly to individuals, without the assistance of a health care pro-
vider to interpret the implications, should be prohibited because it has
high risk of harm. These discordant views were exemplified in November
2013, when the U.S. Food and Drug Administration (FDA) issued a warn-
ing letter to the personal genomics company 23andMe that the company’s
Personal Genome Service (PGS) was classified as a medical device, and
that the company “must immediately discontinue marketing the PGS until
such time as it receives FDA marketing authorization for the device.”
23andMe complied, but stated on its website, “We remain firmly com-
mitted to fulfilling our long-term mission to help people everywhere have
access to their own genetic data and have the ability to use that informa-
tion to improve their lives.”
Genetic tests can pose difficult dilemmas that may not be readily appre-
ciated by scientists designing such screening tools or the consumers who
use them. The FDA cited such concerns in the November 2013 warning
letter to 23andMe:
Most of the intended uses for PGS listed on your website, a list that has
grown over time, are medical device uses under section 201(h) of the F[ood],
D[rug], &C[osmetic] Act. Most of these uses have not been classified and
thus require premarket approval or de novo classification, as FDA has ex-
plained to you on numerous occasions.
Some of the uses for which PGS is intended are particularly concerning,
such as assessments for BRCA-related genetic risk and drug responses (e.g.,
warfarin sensitivity, clopidogrel response, and 5-fluorouracil toxicity) be-
cause of the potential health consequences that could result from false posi-
tive or false negative assessments for high-risk indications such as these. For
instance, if the BRCA-related risk assessment for breast or ovarian cancer
reports a false positive, it could lead a patient to undergo prophylactic sur-
gery, chemoprevention, intensive screening, or other morbidity-inducing
actions, while a false negative could result in a failure to recognize an actual
risk that may exist. Assessments for drug responses carry the risks that pa-
tients relying on such tests may begin to self- manage their treatments
through dose changes or even abandon certain therapies depending on the
374 Chapter 11
outcome of the assessment. For example, false genotype results for your
warfarin drug response test could have significant unreasonable risk of ill-
ness, injury, or death to the patient due to thrombosis or bleeding events that
occur from treatment with a drug at a dose that does not provide the appro-
priately calibrated anticoagulant effect. These risks are typically mitigated
by International Normalized Ratio (INR) management under a physician’s
care. The risk of serious injury or death is known to be high when patients
are either non-compliant or not properly dosed; combined with the risk that
a direct-to-consumer test result may be used by a patient to self-manage,
serious concerns are raised if test results are not adequately understood by
patients or if incorrect test results are reported.
In most cases, the ability to identify risks associated with particular gen-
otypes precedes understanding of how the genotype informs effective
treatment. It might be argued that providing individuals with knowledge
of the potential for disease promotes autonomy; however, a person’s wel-
fare may or may not be enhanced by knowing that he or she has a predis-
position to a disease for which there is currently no preventive therapy and
no cure. It is also not possible to predict what future therapies for manage-
ment or cure of disease may be developed or when these therapies will be
available to patients. Among individuals with the same genotype, quality of
life, disease course, and severity can vary substantially. Genetic informa-
tion is often erroneously applied, and there have been ongoing concerns
related to discrimination based on genetic information. As described
above, GINA, HIPAA, and the Affordable Care Act contain specific pro-
tections related to the use of individual genetic information.
Valuable data can be obtained by collection and analysis of DNA from
large cohorts. Genome-wide association studies scan the genomes from
many different people to identify genetic markers that can be used to pre-
dict the presence of a disease. NIH-funded genome-wide association stud-
ies are required to submit these data to a repository at the NIH in order
that the information can be made available for additional research. At the
February 2012 inauguration of the NIH-sponsored Alzheimer’s Disease
Sequencing Project (ADSP), NIH director Francis S. Collins said, “Pro-
viding raw DNA sequence data to a wide range of researchers proves a
powerful crowd-sourced way to find genomic changes that put us at in-
creased risk for this devastating disease. The ADSP is designed to identify
genetic risks for late-onset of Alzheimer’s disease, but it could also discover
versions of genes that protect us. These insights could lead to a new era in
prevention and treatment.”
Confidentiality and use of genetic information

Concerns exist about the confidentiality and use of genetic information
and results of genetic tests. Unlike many other specimens, genetic infor-
mation can be stored for long periods and can be analyzed for factors other
than that for which it was originally intended and at a time removed from
the collection and consent process. Concerns regarding subsequent re-
search use of supposedly deidentified biological specimens are exemplified
in Rebecca Skloot’s book The Immortal Life of Henrietta Lacks. HeLa cells, a
prominent cell line in research, were derived from a sample of cervical
cancer cells taken from Henrietta Lacks, who died of cervical cancer in
1951. The cells were obtained without her knowledge or permission. HeLa
cells have been a cornerstone of cell and biomedical research for decades
and are the most widely used cell line in the research community. Henri-
etta Lacks was publicly identified in the research community as the
source of the cells in 1971, although her family did not learn about the
existence of the cell line derived from her cervical sample until 1973. In
March 2013, a German group posted full sequence data from a HeLa cell
line on two open-access databases (at the European Bioinformatics Insti-
tute and the NIH’s National Center for Biotechnology Information); se-
quence data from another HeLa cell line by an American group were
simultaneously in press. Such public sharing of scientific data is widely
viewed as a public good that advances science and is required by many
prominent funders and prestigious journals. Henrietta Lacks’s family ex-
pressed concern that sharing the full HeLa sequence also could reveal ge-
netic information about the family; some members of the public agreed
with their concerns. Both groups of investigators agreed to withholding of
the data from open access while the issue was discussed over a 4-month
period among scientists (led by NIH director Collins) and members of the
Lacks family. The matter was resolved by mutual agreement. DNA se-
quences derived from HeLa cells will be deposited into a controlled-access
(rather than open-access) NIH database. The HeLa Genome Data Access
Working Group, an advisory committee to the NIH director, was formed
to evaluate requests from researchers for access to the data. The working
group includes two members of the Lacks family. As part of the agreement,
researchers who use or derive genomic data from HeLa cells are asked to
acknowledge the contribution of Henrietta Lacks and her family in their
publications. However, in describing the agreement, NIH officials Kathy
Hudson and Francis Collins stated, “It is important to note, however, that
we are responding to an extraordinary situation here, not setting a prece-
dent for research with previously stored, de-identified specimens. The ap-
proach we have developed through working with the Lacks family is
unique because HeLa cells were taken and used without consent, and gave
rise to the most widely used human cell line in the world, and because the
family members are known by name to millions of people.”
Early on, it was believed that deidentification of specimens might obvi-
ate the need for robust consent for future use. However, a small number of
genetic variants can uniquely identify a single individual. Even in data
376 Chapter 11
pooled from several hundred subjects, it is possible to determine if an indi-

vidual with a specific genetic profile was included in the aggregate genomic
data. It is now clear that true deidentification is difficult and may well be
impossible.
It is vital that informed consent be elicited from patients in health care
settings and subjects in research settings; those from whom specimens are
collected should give express permission for subsequent sharing for re-
search purposes and should be made aware of confidentiality safeguards in
the storage and future use of the material.
Public discourse that involves multiple stakeholders is essential in build-
ing consensus about critical issues related to “bench to bedside to bench”
interactions. In answering the newest questions, it will be necessary to look
beyond the scientific expediencies of research to address broader societal
implications of scientists’ and clinicians’ behaviors.
DURC
In chapter 4, we defined “dual use research of concern” and discussed its

emerging impact on peer review and publication. The results of DURC
may have the potential to be misapplied or deliberately used to threaten or
harm humans, animals, crops or plants, or the environment. As mentioned
at the beginning of this chapter, the long-standing notion that the results of
scientific research do not inherently carry value has now given way to the
thinking that scientists have an obligation to consider the implications of
their research and to act responsibly in ensuring their appropriate applica-
tion. The bioterrorism attacks of 2001 focused attention on the deliberate
misuse of scientific knowledge, as was the case in preparing anthrax spores
by standard bacteriological methods and delivering these agents to individ-
uals so as to infect them. These attacks prompted new discussion about the
possible use of scientific knowledge for evil purposes and caused some jour-
nals to implement new publication policies. Not only did such policies re-
quire researchers to contemplate the possible dual use concerns of their
research, they afforded specific means to address dual use issues during the
peer review process, reserving the right to use appropriate experts to evalu-
ate the appropriateness of the work for publication (see chapter 4).
In 2004, the National Academies Press published a report by the Com-
mittee on Research Standards and Practices to Prevent the Destructive Ap-
plication of Biotechnology of the National Research Council. The charge to
this committee by the U.S. National Academies was to “minimize threats
from biological warfare and bioterrorism without hindering the progress of
biotechnology.” The committee was chaired by Gerald R. Fink, and the
published report was titled Biotechnology Research in an Age of Bioterrorism.
The report was commonly known as the “Fink Report,” and it was the first
report of the National Academies to deal specifically with national security

and the life sciences. Noteworthy among the seven recommendations of the
report were the following. One recommendation described seven classes of
experiments that were identified as “experiments of concern.” Such experi-
ments exemplified those that would require review and discussion before
they were performed and/or published. These were experiments that would
(i) demonstrate how to render a vaccine ineffective, (ii) confer resistance to
therapeutically useful antibiotics and antiviral agents, (iii) enhance the viru-
lence of a pathogen or render a nonpathogen virulent, (iv) increase the
transmissibility of a pathogen, (v) alter the host range of a pathogen, (vi)
enable the evasion of diagnostic/detection modalities, and (vii) enable the
weaponization of a biological agent or toxin.
Another recommendation called for enhanced manuscript review prior
to publication for potential national security risks associated with the re-
search findings. This recommendation was in keeping with the 2003 posi-
tion paper published in Nature (and other journals) by Ronald Atlas et al.,
previously discussed in chapter 4. The Fink Report also called for the for-
mation of a national science advisory board for biodefense. This board was
to be created by the Department of Health and Human Services (HHS) to
provide “advice, guidance, and leadership for the system of review and
oversight” that was proposed in the report. In fact, both of these recom-
mendations were implemented following the publication of the Fink Re-
port. First, the seven experiments of concern presented in the Fink Report
have provided a framework for the closer evaluation of a number of high-
profile manuscripts, under journal policies that address the handling of
biosecurity concerns. Second, in early 2004, the U.S. Secretary of Health
and Human Services (HHS) signed the charter creating the National Sci-
ence Advisory Board for Biosecurity (NSABB). The duration of the Board’s
existence is described as “continuing,” with no specific end date, but its
charter has been modified and renewed at approximately 2-year intervals
since its inception. As described in its currently active charter, the Board
consists of 25 voting members, including a chair, who are appointed by the
secretary of HHS. The Board also includes nonvoting ex officio members
from 15 federal agencies and departments. The NSABB operates as part of
the NIH Office of Biotechnology Activities. The NASBB is charged spe-
cifically to
• Recommend strategies and guidance for enhancing personnel reli-

ability among individuals with access to biological select agents and
toxins
• Provide recommendations on the development of programs for out-
reach, education, and training in dual use research issues for scien-
tists, laboratory workers, students, and trainees in relevant disciplines
378 Chapter 11
• Advise on policies governing publication, public communication,

and dissemination of dual use research methodologies and results
• Recommend strategies for fostering international engagement on
dual use biological research issues
• Advise on the development, utilization, and promotion of codes of
conduct to interdisciplinary life scientists and relevant professional
groups
• Advise on policies regarding the conduct, communication, and over-
sight of dual use research and results, as requested
• Advise on the Federal Select Agent Program, as requested
• Address any other issues as directed by the secretary of HHS
The NSABB’s inaugural meeting was held in mid-2005. The charter

prescribes that the Board meet approximately twice per year, although it
may be convened on an as-needed basis. During its history the NSABB has
produced a number of documents that have addressed DURC and related
topics. These are all available on the NSABB Web page and include topics
such as synthetic biology, biologic select agents and toxins, and educational
strategies and content. Of note among these documents is the 2007 NS-
ABB report Proposed Framework for the Oversight of Dual Use Life Sciences
Research: Strategies for Minimizing the Potential Misuse of Research Informa-
tion. The NSABB’s use of the word “Framework” in the title was meant to
convey the document as one that could be used by the federal government
to develop a system for the responsible “identification, review, conduct,
and communication of dual use research.” The report envisions seven key
elements of the proposed oversight system: federal guidelines, enhancing
the culture of awareness, education, local evaluation and review of research
for dual use potential, risk assessment and risk management, periodic eval-
uation, and compliance.
The NSABB also has been involved in the evaluation of manuscripts
that were identified as reporting DURC. Arguably, the highest-profile case
to date has involved genetic engineering of the so-called bird flu virus
(H5N1 avian influenza virus). Work done independently by research
groups on two continents demonstrated that a small assortment of muta-
tions could enable the virus to be communicable by airborne transmission
in mammals. Manuscripts submitted by both groups to prominent journals
stirred controversy, and the NSABB was asked by the NIH to provide a
recommendation on whether the work should be published. In addition to
the NSABB review, the World Health Organization convened an interna-
tional group of public health experts to review and make a recommenda-
tion on whether the work should be published. This process began in the
fall of 2011. Initially, the NSABB recommended that the papers not be
published as written but that they be revised and redacted to eliminate
certain details of the research on the mutations the H5N1 viruses acquired
that allowed their airborne transmission in animals. A few months later,
the NSABB reviewed revised manuscripts and reversed its decision, rec-
ommending full publication of both. The NSABB recommendations to
fully publish the work were announced in March 2012, a few weeks after
the World Health Organization recommendation to publish them without
redaction was announced. The papers appeared in print in May and June
of 2012.
The external review of the manuscripts and the broad discussion that
accompanied the biosecurity implications of the work prompted a group of
about 40 researchers to declare a voluntary moratorium on work aimed at
H5N1 transmissibility. The moratorium was implemented to create more
time for discussions about this research and measures to minimize its risk.
Further, the moratorium was expected to afford time for organizations and
governments around the world to develop “the best solutions for opportu-
nities and challenges that stem from the work.” A 60-day voluntary mora-
torium on such research was announced in a letter to the editor of Science
and was titled “Pause on Avian Flu Transmission Research.” In fact, the
moratorium lasted approximately 1 year instead of the planned 2 months.
In its statement on recommending the publication of the H5N1 manu-
scripts, the NSABB said:
As a general principle, the NSABB strongly supports the unrestricted com-
munication of research information unless that information could be directly
misused to pose a significant and immediate risk to public health and safety.
While the communication of the information in these revised manuscripts
still presents dual use concerns, the additional information changed the
Board’s risk/benefit calculation.
• The data described in the revised manuscripts do not appear to pro-
vide information that would immediately enable misuse of the re-
search in ways that would endanger public health or national
security.
• New evidence has emerged that underscores the fact that under-
standing specific mutations may improve international surveillance
and public health and safety. Global cooperation, critical for pan-
demic influenza preparedness efforts, is predicated upon the free
sharing of information and was a fundamental principle in evaluat-
ing these manuscripts.
In late March 2012, the U.S. federal government issued the United
States Government Policy for the Oversight of Life Sciences Dual Use
Research of Concern. The plan is available on the NSABB website, and its
central purpose is “to establish regular review of United States Govern-
ment funded or conducted research with certain high-consequence patho-
gens and toxins for its potential to be dual use research of concern” in
order to mitigate risks associated with such research. The policy’s
380 Chapter 11
implementation is also intended to collect information that will aide in the

development of updated versions of it. The policy’s guiding principles in-
clude affirmations of the importance of life sciences research balanced
against the reality of misuse of new knowledge coming from such research,
as well as the need for some degree of federal and institutional oversight of
DURC. Where DURC-associated risks are identified, the policy mandates
the development of risk mitigation plans and offers a list of examples in-
cluding measures such as the use of specific or enhanced biosecurity or
biosafety measures, research design modification, ongoing institutional re-
view of DURC for emerging research findings that fit the definition of
DURC, and voluntary redaction of manuscripts for publication that report
the results of such research.
The policy focuses on work identified as DURC that uses any agents or
toxins included in a subset of the list regulated by the Federal Select Agent
Program, which is administered under federal law. These regulated agents
and toxins are considered those “which pose the greatest risk of deliberate
misuse with most significant potential for mass casualties or devastating
effects to the economy, critical infrastructure, or public confidence.” The
policy requires biannual reporting by all federal departments and agencies
to the Assistant to the President for Homeland Security and Counterter-
rorism. Such reporting is to include the number of current and proposed
unclassified, intramural, and extramural research projects that include
DURC involving one or more of the toxins and agents. As an example, the
NIH has established a Policy on Mitigating Risks of Life Sciences Dual
Use Research of Concern. The NIH conducts administrative review of
awards to identify those deemed to involve DURC. When projects are
identified as involving DURC, the NIH will work collaboratively with the
institution and investigator to prepare a risk mitigation plan that must be
implemented for the duration of the grant award. The NIH also may re-
quest that a grantee institution make periodic reviews of its projects for
potential DURC. Further, the institution may be asked to share any result-
ing manuscripts reporting the results of such research with the relevant
NIH program officer prior to submitting the manuscript for consideration
for publication by a journal.
The events surrounding the emergence of rDNA technology in the
1970s and focus on DURC in the opening decades of the 21st century
have some similar characteristics. Both are examples of engagement that,
to a greater or lesser degree, involved the scientific community, govern-
ment, scientific organizations, funding agencies, lay public, and media. A
principal difference is that in the case of rDNA, scientists brought their
concerns about new knowledge from within the research community to
the attention of the public. This became the seminal event from which all
else followed in the discussion, debate, and policy development as regards
rDNA technology and its use. Although the concept of dual use research
had been discussed for decades, the bioterrorism attacks of 2001 focused
attention on the need to address DURC especially as it applies to life sci-
ences research. Public events provided the stimulus for action, and the
U.S. National Academy of Sciences and the U.S. Center for Strategic In-
ternational Studies sponsored a meeting of scientists, editors, and other
stakeholders to discuss national security and scientific publication. The
discussions of the so-called Journal Editors and Authors Group were artic-
ulated in its 2003 published statement in Nature (“Statement on the Con-
sideration of Biodefence and Biosecurity”). This statement catalyzed more
proactivity, most notably the publication of the Fink Report and the im-
plementation of biosecurity review policies by some journals. Both rDNA
and DURC involved moratoriums that were self-imposed by the scientists
involved in the work. But the rDNA moratorium generally applied to the
experimental technology, while the moratorium that was imposed in the
case of DURC specifically involved research on the transmission of influ-
enza virus.
DURC process and policy development in the life sciences is still na-
scent, as reflected in the U.S. government’s policy that contemplates “up-
dating as needed, following domestic dialogue, engagement with our
international partners, and input from interested communities.” So a full
and rigorous comparison of the rDNA debate and DURC must await fur-
ther development and implementation of policies, guidelines, and codes
that take DURC into account. In the meantime, both the rDNA debate
and policy development and the ongoing discussions and policy develop-
ment related to DURC remain as worthy examples of the scientific enter-
prise engaging in dialogue and action in matters regarding the broad
impact of scientific research on society.
Conclusion
Much research that takes place in universities, research institutes, hospi-

tals, and other organizations is supported by public funds in the form of
either taxpayer or philanthropic dollars. Scientists are expected to do this
research responsibly and with integrity. This engenders a relationship in
which the scientist must continually strive to earn the trust of the agen-
cies and individuals who support their research, as well as the public trust.
The long-standing elements of responsible research conduct upon which
this implicit covenant is based are manifold. These include unfailing
compliance with policies and codes that govern such things as subjects’
protections, disclosure and management of conflicts, responsible report-
ing, maintenance of confidentiality as appropriate in peer review and
other activities, appropriate management of resources, and acceptance of
382 Chapter 11
accountability for the research. Prudent investment of research resources

also carries with it an obligation to be cognizant of and proactive in ap-
plying new knowledge to benefit society. Scientists should become en-
gaged in the translation of their research findings whenever possible and
as appropriate. Scientists should recognize that they have a duty to com-
municate their research to society and to address concerns that may be
raised about it. Similarly, scientists need to embrace activism in matters
pertaining to the conduct of research with societal or environmental im-
pact; participate in conversations involving the scientific, government,
organizational, and public communities to appreciate and evaluate re-
search impact; and develop appropriate policies, measures, or codes to
mitigate concerns or dangers.
1. Should the genome sequence data of dangerous pathogenic agents
be restricted or placed in the public domain? Why?
2. The prospects of genetic screening raise interesting and sometimes
controversial issues when applied to the family setting. Disclosing
information may violate a sibling’s right to privacy, but withholding
it may cause harm, too. How should information discovered by ge-
netic technology in one family member be treated if it could affect
other family members?
3. What do you see as the issues surrounding the production and mar-
keting of genetically engineered foods? What roles can and should
scientists play in the discussion of genetically modified foods?
4. Frozen human embryos that have been stored for 7 years or longer
(and are not considered usable for in vitro fertilization) have been
suggested as sources to create human embryonic stem cell lines for
research. Do you favor this idea? Why or why not?
5. Should federal proposals that involve research on human genetic di-
agnostics and therapeutics be subjected to a review of their ethical
implications? Why? If you favor this, what weight should such a re-
view have relative to the review of scientific merit? Who should con-
duct the review?
6. Although safeguards may be in place, it is still possible that published
research findings or a new discovery may be used for evil purposes.
Does the scientist who created and published this new knowledge
bear any responsibility to help prevent inappropriate use of his or
her research findings? Is there any obligation for scientists to ensure
that new knowledge they create and publish is put only to good use?
Conversely, are there obligations for scientists to rectify wrongs or
harm done by inappropriate use of their research?
7. Assuming an obligation to do so, what do you see as the means and

process for scientists to explain the purposes and implications of
their research?
8. What do you view as the pros and cons of a universal Ethical Code
for Scientists?
Resources
Print
Atlas R, Campbell P, Cozzarelli NR, Curfman G, Enquist L, Fink G, Flanagin
A, Fletcher J, George E, Hammes G, Heyman D, Inglesby T, Kaplan S,
Kennedy D, Krug J, Levinson R, Marcus E, Metzger H, Morse SS, O’Brien
A, Onderdonk A, Poste G, Renault B, Rich R, Rosengard A, Salzberg S,
Scanlan M, Shenk T, Tabor H, Varmus H, Wimmer E, Yamamoto K; Jour-
nal Editors and Authors Group. 2003. Statement on the consideration of bio-
defence and biosecurity. Nature 421:771.
Beckwith J. 2002. Making Genes, Making Waves: A Social Activist in Science. Harvard
University Press, Cambridge, MA.
Beckwith J, Huang F. 2005. Should we make a fuss? A case for social responsibil-
ity in science. Nat Biotechnol 23:1479–1480.
Berg P, Baltimore D, Boyer HW, Cohen SN, Davis RW, Hogness DS, Na-
thans D, Roblin R, Watson JD, Weissman S, Zinder ND. 1974. Letter: Po-
tential biohazards of recombinant DNA molecules. Science 185:303. (Also pub-
lished in Proc Natl Acad Sci USA 71:2593–2594 [1974].)
Berg P, Baltimore D, Brenner S, Roblin RO III, Singer MF. 1975. Asilomar
conference on recombinant DNA molecules. Science 188:991–994. (Also pub-
lished in Proc Natl Acad Sci USA 72:1981–1984 [1975].)
and Health Sciences, 2nd ed. Cambridge University Press. Cambridge, United
Kingdom.
Cohen SN, Chang AC, Boyer HW, Helling RB. 1973. Constructions of biologi-
cally functional bacterial plasmids in vitro. Proc Natl Acad Sci USA 70:3240–3244.
Elward C. 2013. Dual use research of concern: practical policy approaches to best
avoid misuse in the life sciences. The Spectra (the Virginia Engineering and Sci-
ence Research Journal) IV, Spring 2013, p 11–20. http://www.seas
.virginia.edu/pubs/spectra/pdfs/journal.pdf.
Fouchier RA, García-Sastre A, Kawaoka Y, Barclay WS, Bouvier NM, Brown
IH, Capua I, Chen H, Compans RW, Couch RB, Cox NJ, Doherty PC,
Donis RO, Feldmann H, Guan Y, Katz J, Klenk HD, Kobinger G, Liu J,
Liu X, Lowen A, Mettenleiter TC, Osterhaus AD, Palese P, Peiris JS, Perez
DR, Richt JA, Schultz- Cherry S, Steel J, Subbarao K, Swayne DE,
Takimoto T, Tashiro M, Taubenberger JK, Thomas PG, Tripp RA, Tumpey
TM, Webby RJ, Webster RG. 2012. Pause on avian flu transmission research.
Science 335:400–401.
Frederickson D. 2001. The Recombinant DNA Controversy—A Memoir. ASM Press,
Washington, DC.
384 Chapter 11
Holtzman NA, Watson MS. 1998. Promoting Safe and Effective Genetic Testing in
the United States: Final Report of the Task Force on Genetic Testing. Johns Hopkins
University Press, Baltimore, MD.
Hudson KL, Collins FS. 2013. Biospecimen policy: family matters. Nature
500:141–142.
Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, Zhong G, Han-
son A, Katsura H, Watanabe S, Li C, Kawakami E, Yamada S, Kiso M, Su-
zuki Y, Maher EA, Neumann G, Kawaoka Y. 2012. Experimental adaptation
of an influenza H5 HA confers respiratory droplet transmission to a reassortant
H5 HA/H1N1 virus in ferrets. Nature 486:420–428.
Jackson DA, Symons RH, Berg P. 1972. Biochemical method for inserting new
genetic information into DNA of simian virus 40: circular SV40 DNA mole-
cules containing lambda phage genes and the galactose operon of Escherichia
coli. Proc Natl Acad Sci USA 69:2904–2909.
Lander ES. 2011. Initial impact of the sequencing of the human genome. Nature
470:187–197.
National Research Council. 2004. Biotechnology Research in an Age of Bioterrorism.
National Academies Press, Washington, DC. http://www.nap.edu/openbook
.php?isbn=0309089778.
Pigman W, Carmichael EB. 1950. An ethical code for scientists. Science 111:643–
647.
Reinhold R. 1969. Scientists isolate a gene; step in heredity control. The New York
Times, November 23, 1969, p 1, 72.
Reiser SJ, Bulger RE. 1997. The social responsibilities of biological scientists. Sci
Eng Ethics 3:137–143.
Rodriguez LL, Brooks LD, Greenberg JH, Green ED. 2013. Research ethics.
The complexities of genomic identifiability. Science 339:275–276.
Science. 2012. Special issue: H5N1. http://www.sciencemag.org/site/special/h5n1/.
Shapiro J, Machattie L, Eron L, Ihler G, Ippen K, Beckwith J. 1969. Isolation
of pure lac operon DNA. Nature 224:768–774.
Shuster E. 1997. Fifty years later: the significance of the Nuremberg Code. N Engl
J Med 337:1436–1440.
Online
Paul Berg’s 2004 article “Asilomar and Recombinant DNA” is available on
the Nobel Prize website:
http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1980/berg-article
.html
“Statement by NIH Director Francis Collins, M.D., Ph.D., on the NSABB

Review of Revised H5N1 Manuscripts,” from 2012, can be accessed on the
National Institutes of Health (NIH) website:
http://www.nih.gov/about/director/04202012_NSABB.htm
The Ethical, Legal and Social Implications (ELSI) Research Program, Na-
tional Human Genome Research Institute (NHGRI)
http://www.genome.gov/elsi/
Information on the Genetic Information Nondiscrimination Act (GINA)

of 2008 can be found on the NHGRI website at:
http://www.genome.gov/24519851
HeLa Genome Data Access Working Group (with link to HeLa data shar-
ing agreement):
http://acd.od.nih.gov/hlgda.htm
For a HeLa cell-Henrietta Lacks story timeline, derived from Rebecca

Skloot’s research for The Immortal Life of Henrietta Lacks, see:
http://rebeccaskloot.com/wp-content/uploads/2011/03/HenriettaLacks_RGG_
timeline.pdf
National Select Agent Registry (Centers for Disease Control and the Ani-
mal and Plant Health Inspection Services/Agricultural Select Agent
Program):
http://www.selectagents.gov/
NIH Office of Biotechnology Activities (Office of Science Policy): the re-

combinant DNA program overseen by the NIH, which includes the NIH
Guidelines, the Institutional Biosafety Committee registration site, the
Recombinant DNA Advisory Committee, and other items, may be ac-
cessed online at
http://osp.od.nih.gov/office-biotechnology-activities/rdna/rdna.html
NIH Office of Biotechnology Activities (Office of Science Policy): the Na-

tional Science Advisory Board for Biosecurity website is located at
http://osp.od.nih.gov/office-biotechnology-activities/biosecurity/biosecurity.html
National Science Advisory Board for Biosecurity Recommendations and

Reports on manuscripts reporting the transmissibility of influenza A/
H5N1 virus:
http://osp.od.nih.gov/office-biotechnology-activities/biosecurity/biosecurity_docu
ments.html
386 Chapter 11
NIH Policy on Mitigating Risks of Life Sciences Dual Use Research of

Concern. Notice Number: NOT-OD-13-107 (released in 2013):
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-13-107.htmlNational
Science Advisory Board for Biosecurity (NSABB) Proposed Framework for the Over-
sight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of
Research Information (2007):
http://osp.od.nih.gov/sites/default/files/resources/Framework%20for%20transmit
tal%20duplex%209-10-07.pdf
United States Government Policy for the Oversight of Life Sciences Dual
Use Research of Concern (2012):
http://oba.od.nih.gov/oba/biosecurity/pdf/united_states_government_policy_for_
oversight_of_durc_final_version_032812.pdf
The following organizations promote social activism in science.
Council for Responsible Genetics

http://www.councilforresponsiblegenetics.org/
Union of Concerned Scientists

http://www.ucsusa.org/
Physicians for Social Responsibility

http://www.psr.org/
appendix I
Surveys as a Tool for Training

in Scientific Integrity
Michael W. Kalichman
S cientific integrity is about more than rules, regulation, and compliance.

Much of what we do as scientists requires decisions that must be made
in the absence of clear guidelines. Questions about topics such as data
management, publication, and the use of animal or human subjects often
represent difficult ethical challenges. To learn about such concepts, which
are frequently complex and nuanced, it is essential to have the chance to
think actively rather than merely listen to a lecture or read some text.
Grappling with tough cases through discussion is one common approach
to stimulate an active learning process. One excellent way to generate dis-
cussion is to survey attitudes, perceptions, and experience of course
participants.
Surveys, like the scenarios used for case study discussion, require train-
ees to examine their own perceptions and assumptions. Through the pro-
cess of this reflection, it is possible to refine existing standards, identify
new standards, and develop strategies for responding to difficult questions.
The characteristic that distinguishes surveys from case study discussions is
that answers are not typically open-ended. Instead, the respondents are
asked to answer forced-choice questions that are either categorical (e.g.,
yes/no) or quantitative (e.g., the degree of agreement or disagreement).
These answers then can be reduced and summarized for discussion of pat-
terns and correlations within a particular group (e.g., this year’s students)
or between groups (e.g., those who have had versus those who have not
had training in scientific integrity). Although the subtleties in complex
cases may not always emerge in discussion, it is often possible with surveys
doi:10.1128/9781555818487.AppI
387
388 Appendix I
to elicit information about common trends and attitudes that would other-
wise be lost. The following includes both general observations about the
use of the sample surveys and some specific comments about the use of
each.
The surveys included below parallel the topic areas of this text. The
following points should be kept in mind when employing them as teaching
tools. First, because some surveys overlap, their selection is at the discre-
tion of the instructor. Further, not all surveys will be appropriate to meet
the needs of a specific course, instructor, or group of students. Second,
these surveys should not be viewed as definitive; instructors may want to
develop new surveys to meet specific instructional objectives. Third, nearly
all of these surveys are suitable for administration during class or a work-
shop, but some may be more appropriate as homework assignments. For
purposes of homework or distribution, these forms can be found as PDF
files at this book’s website, www.scientificintegrity.net, and printed for con-
venient use, or suitable response sheets may be prepared by the instructor.
Fourth, simply completing these surveys can have value in stimulating re-
flection on personal values and the normative conduct of science. How-
ever, analysis and discussion of survey results are a key part of this exercise.
The instructor could do the analyses, but it may be even more valuable to
have trainees summarize the data, select results of interest, present their
findings, and lead class discussion about interesting results. Usually, it is
not necessary for the survey discussants to focus on the responses to each
and every item in the survey. Instead, identifying questions that reveal dif-
fering attitudes and perceptions on the part of the respondents is desirable.
These should be used to stimulate class discussion, allowing the discus-
sants to state their positions and the rationales underlying their responses.
Such discussions allow students to invoke their critical thinking skills in
articulating their arguments. Equally important, these discussions fre-
quently uncover multiple points of view, many of which have merit and can
be appropriately defended.
Author’s note
Using surveys to collect information may fall into the category of human
subjects research. In such cases, institutional review board (IRB) approval
must be sought before any work is begun (see chapter 5). The definition of
human subjects research centers on the fulfillment of criteria related to the
subjects and to the investigational process and goals. Human subjects are
defined as living individuals about whom an investigator obtains (i) infor-
mation, specimens, or other data through intervention or interaction with
the individual or (ii) identifiable private information. The word “research”
is meant to encompass systematic investigation designed to develop or
contribute to generalizable knowledge. If you use the surveys in this
Surveys as a Tool for Training in Scientific Integrity 389
appendix as tools for stimulating class discussion, and nothing more, your
actions do not constitute contributing to generalizable knowledge. Under
these conditions, administering these surveys and presenting the resulting
data for purposes of discussion do not constitute research. However, the
authors of this appendix and this book encourage users to check with their
institutions’ review boards to verify whether such use is exempt, can be
expedited for review, or requires full IRB review. If your use of these sur-
veys extends beyond the immediate purpose of classroom instruction, it is
likely that IRB review and approval would be needed.
Survey Descriptions
Survey 1: Overview (chapters 1 and 2)

This survey is modified from one originally used to study perceptions
about research misconduct at the University of California, San Diego (2).
This survey has potential value as an introductory exercise for a course in
scientific integrity. Ideally, students would be asked to complete the ques-
tionnaire immediately before or at the beginning of a workshop or the first
meeting of the course. In addition to the raw data being of interest (e.g.,
what percentage of respondents believe they have firsthand knowledge of
plagiarism), secondary analyses and discussion about the meaning of the
answers are at least as important. Examples of specific analyses that might
be of interest are (i) the correlation between position (question #1), years
of experience (#2), or experience as an author (#3) and the answers to ques-
tions about misconduct experience (#4 to 13) and (ii) discussion of the var-
ious possible interpretations of, for example, 10% of respondents reporting
firsthand knowledge of data fabrication or falsification. It can also be of
interest to compare results of this survey to those that are published (1, 2).
Survey 2: Research misconduct (chapters 1 and 2)

The primary focus of this survey is research misconduct as defined by fed-
eral regulatory agencies to include fabrication, falsification, and plagiarism.
Some areas that may lend themselves to fruitful discussion include differ-
ent types of plagiarism (#1 to 3), distinctions between different kinds of
data falsification (#5 versus 6), personal willingness to commit possible
misconduct (#4 to 8), responsibilities for whistle-blowing (#10 to 12), and
allocation of blame versus punishment (#13 and 14).
Survey 3: Mentoring (chapter 3)

The results of this survey can provide the basis for discussions on the re-
sponsibilities of mentoring. All of these questions address potential roles
for mentors, heads of research groups, and/or thesis supervisors. One pos-
sible use of this survey is to have it completed by both students and their
390 Appendix I
thesis supervisors, followed by a presentation and discussion of the results

in class.
Survey 4: Publication (chapter 4)

The initial two questions are based on a brief scenario to distinguish be-
tween knowing what one should do and one’s willingness to do so. The
following questions address two key areas: (i) the reasons for publishing a
paper (#3 to 7) and (ii) a variety of publication practices that may be viewed
as more or less acceptable (#8 to 13). For both sets of questions, interesting
discussions can result from identifying relative differences and considering
possible rationales for those differences. A concluding set of questions (#14
to 17) address criteria for retracting a published manuscript.
Survey 5: Authorship (chapter 4)

This is the second of three surveys on the topic of publication. The open-
ing questions focus on a junior scientist’s dilemma about adding a senior
scientist’s name to the list of authors on a forthcoming publication. The
remaining questions highlight both what should be criteria for authorship
(#3 to 9) and what should not be criteria for authorship (#10 to 15). Typi-
cally, these questions will readily reveal a wide range of views about how
authorship should be defined.
Survey 6: Peer review (chapter 4)

This survey is specifically designed as a homework assignment. The goals
are 3-fold. First, trainees are asked to think about the practice of a manu-
script reviewer asking that one of her or his postdocs review a manuscript
(#1 and 2). Second, trainees are asked to discuss related questions with at
least one active investigator (#3 to 6) as well as offer their own views (#7 to
10). Third, several questions (#11 to 14) focus on the trainee’s responsibil-
ity if asked to participate in a review assigned to someone else. Finally, the
trainees are asked to think about when it would not be appropriate to ac-
cept an assignment for manuscript review (#15 to 17).
Survey 7: Human subjects (chapter 5)

Research with human subjects is distinguished by the obligation to con-
sider and protect the interests of those who have volunteered to be in a
research study. The initial questions in this survey (#1 to 7) focus on the
role and domain of the IRB. The remaining questions address the circum-
stances under which potential research subjects might enroll in a research
study (#8 to 12) as well as whether a study should be approved (#13) or
stopped early (#14). Discussions of these questions are likely to reveal per-
ceptions and attitudes that are mutually incompatible, even though all are
potentially acceptable under current regulations.
Survey 8: Animal subjects (chapter 6)

Although there are many specific regulatory controls for the use of animals
in research, this remains an area about which the public and even the bio-
medical science community are sharply divided. The initial questions (#1
to 4) consider the role of the Institutional Animal Care and Use Commit-
tee in reviewing research with animal subjects. The remainder of the sur-
vey form (#5 to 16) is designed to encourage trainees to think about their
personal criteria for accepting or rejecting the use of animals in research.
The survey can be completed in class, but it may be useful as a homework
assignment to allow for more thoughtful consideration. For the purposes
of analysis, it should be of value to compare the relative importance placed
on species (where is the cut-off and why?), the adverse consequences of the
experiment (pain, distress, or discomfort), and the balance between the
utilitarian value of the studies (increased understanding of the mechanisms
of cancer versus cosmetic safety) and deontological responsibilities to pro-
tect the rights or welfare of the individual. It is to be expected that opin-
ions will vary widely, even among scientists who use animals in their
research.
Survey 9: Conflicts of interest (chapter 7)

Financial conflicts of interest in academia and science have become a matter
of serious concern in recent years. The survey begins by exploring the risks
of conflicts of interest (#1 to 4). Different perceptions about disclosure are
next considered (#5 to 9), and the survey concludes with a focus on possible
protections from bias due to conflicts of interest (#10 to 13). Discussion of
these issues will typically help to sharpen rationales about what we are wor-
ried about and what solutions are most likely to have an impact.
Survey 10: Collaboration (chapter 8)

This survey deals with a defining characteristic of modern science: collab-
orations. The very first question (#1) asks for student perspectives on the
importance of collaboration to good research. This is followed by several
questions (#2 to 7) about the risk of problems in collaborations. The re-
maining questions (#8 to 13) list issues that might be seen as important to
be addressed before initiating a collaboration. Discussions of these ques-
tions are likely to reveal that scientists, unfortunately, tend to not think
about these issues until they become a problem.
Survey 11: Data ownership (chapter 9)

This survey opens with a case discussion scenario to address some possible
reasons for ambivalence about sharing of research data (#1 to 5). Questions
about ownership and sharing of data (#6 to 19) should serve to illustrate the
importance of these issues and some of the dilemmas faced by researchers.
392 Appendix I
Survey 12: Record keeping (chapter 10)

Although most scientists had the experience of an early lab course in which
rigorous standards were proposed for keeping a lab notebook, it is not nec-
essarily the case that these standards for record keeping are common prac-
tice. The first questions on this survey (#1 to 9) offer a variety of possible
characterizations of how research records should be kept. The focus of the
remaining questions (#10 to 13) is the disposition of those records follow-
ing completion of the project. Discussion of the answers to these questions
will hopefully reveal the variation in common practice but also encourage
a shift toward improved record keeping.
Survey 13: Science, technology, and society (chapter 11)

The application of advances in molecular genetics has created ethical chal-
lenges as well as fears related to misuse of these technologies. The survey
opens with some questions (#1 to 14) about what people would and would
not want to know about their possible future. It is likely that these ques-
tions will lead to sharp divisions of opinion during class discussion. This
division of opinion then raises further questions about who should give
consent for research studies involving searches for genetic predispositions
(#15 to 19). The difficulty of such questions is further exacerbated when a
study risks providing information about a particular behavioral trait in a
given racial group (#20 to 22).
References
Print
1. Eastwood S, Derish P, Leash E, Ordway S. 1996. Ethical issues in biomedical

research: perceptions and practices of postdoctoral research fellows responding
to a survey. Sci Eng Ethics 2:89–114.
2. Kalichman MW, Friedman PJ. 1992. A pilot study of biomedical trainees’ per-
ceptions concerning research ethics. Acad Med 67:769–775.
Online
Some organizations conduct public surveys on matters related to research.
These reports are generally available in the public domain. Typically, the
results are compiled in useful formats and can be presented to catalyze
discussion in a variety of relevant areas. For example, a survey done by the
Wellcome Trust Monitor reported survey data on such things as public
awareness and understanding of science, participation in medical research,
and attitudes toward genetics. The list of organizations that engage in such
survey activities is given below, along with their URLs. At these sites you
can search for survey results or reports that may be useful in generating
class discussion. Specific links to current surveys of interest posted by these

organizations will be listed and updated on this text’s companion website:
http://www.scientificintegrity.net.
Research!America
http://www.researchamerica.org/
Science and Engineering Indicators, National Science Foundation

http://www.nsf.gov/statistics/seind
Virginia Commonwealth University Life Sciences Surveys

http://www.vcu.edu/lifesci/centers/cen_lse_surveys.html
Wellcome Trust
http://www.wellcome.ac.uk
Survey 1: Overview
1. Which of the following best describes your position?

Grad student Postdoc Faculty Staff
2. Which of the following best describes your experience in research?

None 1 year 1–5 years 5 years
3. Have you ever been the author of a published paper or abstract?

Yes No
4. Has your name been omitted from a paper for which you made a sub-
stantial contribution?
Yes No
5. Have you been an author on a paper for which any of the authors had
not made a sufficient contribution to warrant credit for the work?
Yes No
6. Do you have firsthand knowledge of scientists plagiarizing the work of

someone else?
Yes No
7. Have you ever plagiarized the work of someone else?

Yes No
394 Appendix I
8. Do you have firsthand knowledge of scientists intentionally falsify-

ing or fabricating research or experimental results for the purpose of
publication?
Yes No
9. Do you have firsthand knowledge of scientists intentionally falsify-

ing or fabricating research or experimental results to enhance a grant
application?
Yes No
10. Have you ever falsified or fabricated research or experimental results

for the purpose of publication or a grant application?
Yes No
11. Have you ever reported research or experimental results that you
knew to be untrue?
Yes No
12. Would you report a coworker who you believe had violated scientific
integrity standards?
Yes No
13. Would you report your supervisor/advisor who you believe had vio-
lated scientific integrity standards?
Yes No
Which of the following topics have been discussed

among members of your research group?
14. Methods for proper record keeping
15. Responsible ownership, sharing, and retention of

research data
16. The importance of collaboration and steps to promote

successful collaborations
17. Principles for responsible use of animal subjects
18. Principles for responsible use of human subjects
19. Importance of honestly reporting what you find
20. Criteria for what and when to publish

21. Criteria for authorship
22. Risks of conflicts of interest
23. Responsibilities of peer reviewers
24. Roles and responsibilities of mentors and trainees
25. Special ethical concerns for research involving genetic

technology
26. Responsibility and strategies for action after having

witnessed research misconduct
27. Responsibilities of scientists to society
Survey 2: Research Misconduct
Please use the scale below to rank the level of your agreement or disagree-
ment with each of the following statements.
1 Strongly disagree
2 Disagree
3 Neither agree nor disagree
4 Agree
5 Strongly agree
It is never appropriate to take credit for

1. the words or writing of someone else.
2. the data generated by someone else.
3. the ideas generated by someone else.
If you are confident of the experimental outcome, it is acceptable to

4. report experimental data that have been created without
actually having conducted the experiment.
5. alter experimental data to make an experiment look better

than it actually was.
6. try a variety of different methods of analysis until one is

found that yields a result that is statistically significant.
396 Appendix I
7. selectively omit contradictory results to expedite publication.
8. falsify or fabricate data to expedite publication.
9. It is more important that data reporting be completely

truthful in a publication than in a grant application.
10. If you witness someone committing research misconduct,

you have an ethical obligation to act.
11. If you witnessed a coworker or peer committing research

misconduct, you would be willing to report that misconduct
to a responsible official.
12. If you witnessed a supervisor or principal investigator

committing research misconduct, you would be willing to
report that misconduct to a responsible official.
13. If fabricated data are discovered in a published paper, all

coauthors should equally share in the blame.
14. If fabricated data are discovered in a published paper, all

coauthors should receive the same punishment.
Survey 3: Mentoring
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
1. A mentor is an advisor, not a supervisor.
2. A mentor is a supervisor, not an advisor.
Heads of research groups should

3. not accept a trainee without the student first spending
a brief rotation period working in the research group.
4. limit the number of trainees they accept based on financial

and physical resources as well as on supervisory
considerations.
5. provide specific instruction to their trainees on data

management, including issues related to format, collection
and recording of data, retention of data, and ownership
of data.
6. have a defined policy, formally communicated to trainees

early in their training program, with regard to scientific
publication, manuscript preparation, and authorship
attribution.
7. meet privately and regularly (at least twice monthly) with

each trainee to discuss her/his research progress, analyze
data, plan experiments, and set goals as appropriate.
8. hold regularly scheduled meetings of their whole research

group to review individual projects.
9. encourage healthy competition among trainees in their

laboratories.
10. provide trainees with assistance and instruction in how

to write a scientific paper.
11. provide trainees with assistance and instruction in how

to read a scientific paper.
Mentors should
12. be active in introducing their advisees to other scientists
(e.g., visiting seminar speakers, at scientific meetings).
13. provide career counseling, especially in the latter stages

of the trainee’s program of education.
14. provide advisees with assistance and instruction in

classroom teaching skills.
398 Appendix I
Trainees should
15. invest time and effort to find an appropriate mentor.
16. consider developing a relationship with more than one

mentor.
17. seek the help of a mentor to provide advice rather than

to make decisions for them.
Survey 4: Publication
You have just completed a small clinical study in which the drug appears to
have worked, but the result just misses statistical significance. It occurs to
you that by randomly selecting values from your previously published
study you could increase the size of your control group and thereby
demonstrate a significant effect.
1. Should you supplement your data with numbers from the previously
published experiment?
Yes No
2. Would using the previously published data be unethical?

Yes No
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
We publish our research findings to

3. contribute to the body of scientific knowledge.
4. improve our experimental work.
5. meet research funding requirements.
6. advertise our work to future trainees and lab associates.
7. promote our careers.

It is acceptable to
8. omit contradictory results from a paper.
9. publish the same paper in two very different journals.
10. publish the same data in two very different journals.
11. republish data with clear citation of the earlier work.
12. use words written by a colleague without citing the source.
13. use data from a colleague without citing the source.
A published paper should be retracted if

14. it is discovered that errors were made in the conduct of
one or more of the reported experiments.
15. subsequent attempts to repeat the published experiments

have failed.
16. a coauthor was found to have falsified or fabricated data

for one or more of the reported experiments.
17. a coauthor was found to have falsified or fabricated data

for one or more of the reported experiments—even though
subsequent attempts to repeat the study resulted in findings
the same as those reported in the publication.
Survey 5: Authorship
Two months after joining a new research group, you are preparing to sub-
mit a manuscript based on work you had completed while in your previous
position. Dr. Helix, one of your new colleagues, has just recommended
that you include Dr. Spiral, the head of the new research group, as an au-
thor on the paper. When you point out that Dr. Spiral had made no contri-
butions to the work, Dr. Helix observes that adding Dr. Spiral’s name
would improve the chances for publication and increase your prospects for
advancement within Dr. Spiral’s research group.
1. Should you add Dr. Spiral’s name to the manuscript?

Yes No
2. Would adding Dr. Spiral’s name as an author be unethical?

Yes No
400 Appendix I
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
Authorship is appropriate for someone who has approved the final

manuscript and
3. provided the idea for a critical experiment.
4. provided unique materials, critical to the experiments

reported in the paper.
5. provided large amounts of unskilled work needed to

complete the project.
6. performed an experiment using specialized equipment.
7. provided unpublished data to augment data obtained

for the paper.
8. provided statistical analysis of data presented in the paper.
9. organized the results and wrote the first draft of the paper.
Authorship is not appropriate

10. for someone who contributed to the work only on a
fee-for-service basis.
11. solely to advance a student’s career.
12. solely to recognize leadership of the research group.
13. solely to increase chances for publication because of

name association.
14. for someone who cannot scientifically defend all data

presented in the paper.
15. for someone who has not read and approved the final
manuscript.
Survey 6: Peer Review
You are a postdoc in the laboratory of Dr. Strauss. Dr. Strauss has been asked
to review a manuscript, which she has now handed to you for your com-
ments. When you ask if she has notified the journal editor that you will be
reviewing the manuscript, she replies that there is no need to do so because
sharing the responsibility of manuscript review is common practice.
1. Should you agree to review the manuscript?

Yes No
2. Would reviewing the manuscript without notifying the journal editor

be unethical?
Yes No
Find at least one investigator who is willing to give you a few minutes of
time to talk about the process of manuscript review. Please use the scale
below to ask the investigator about his or her own practice (“Investigator”)
as well as his or her impressions of what constitutes “common practice” for
each of the following (questions #3 to 6).
1 Never
2 Rarely
3 Occasionally
4 Often
5 Always
Without notifying the editor of the journal, reviewers

Investigator Common
practice
3. share the manuscript with a student or
colleague to obtain additional help
with the review.
4. share the manuscript and review with others

as a means of training about the process of
manuscript review.
5. share the manuscript with others to keep

them current with the latest research.
6. make use of the contents of the submitted

manuscript in their own research prior to
publication of the article.
402 Appendix I
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
Without notifying the journal editor, a reviewer should never

7. get help with the manuscript from a graduate student,
postdoc, or faculty member.
8. use the manuscript review as a tool for training his or

her students.
9. use the manuscript to keep his or her trainees and

colleagues up-to-date.
10. make scientific use of the manuscript prior to its publication.
If a trainee has been asked to participate in the review of a manuscript

submitted for journal publication, then he/she
11. should ask if the journal editor has been notified.
12. should ask if the journal editor will be notified.
13. should ask what role the reviewer assigned by the editor
will have in independently reviewing the manuscript or
editing the review the trainee writes.
14. can list this review experience on a curriculum vitae only

if the journal editor knew and approved of his or her
participation in the review process.
15. Someone who is asked to review a manuscript or proposal

that is in an area central to his or her own area of research
should decline because of the risk of bias.

from someone with whom he or she has a close personal or
research relationship should decline because of the risk of bias.

from someone with whom he or she has a serious personal
disagreement should decline because of the risk of bias.
Survey 7: Human Subjects
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
Institutional review board (IRB) approval is necessary for conducting

research with human subjects to
1. test the effectiveness of a new drug or treatment.
2. compare the effectiveness of two clinically proven treatments.
3. survey perceptions about physical or sexual abuse.
4. evaluate the effectiveness of a course.
The purpose of the IRB is to protect the interests of

5. research subjects.
6. researchers.
7. the institution.
A research subject should participate in a research study

only if he or she
8. is doing so for altruistic reasons.
9. believes that the personal benefits will be greater than

the personal risks.
10. completely understands the rationale, risks, and benefits

of the study.
11. has the capacity to make his or her own decisions.

404 Appendix I
12. If a research study is sufficiently important, then it should

be acceptable to reduce the barriers to recruiting subjects.
13. If research subjects are willing to take the risk of

participating in a study, then the study should be approved.
14. A research study should be stopped early if it has been

determined that the experimental treatment is effective,
even if insufficient data have been collected to assure
its relative safety.
Survey 8: Animal Subjects
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
Institutional Animal Care and Use Committee approval is

required for any research project involving
1. animal subjects.
2. rodents, cats, or dogs.
3. frogs or fish.
4. leeches or snails.
Experiments designed to better understand mechanisms

of cancer are justifiable in
5. human subjects.
6. nonhuman primates.
7. dogs.
8. pigs.
9. frogs.
10. cockroaches.
Experiments designed to test cosmetic safety are justifiable in

11. human subjects.
12. nonhuman primates.
13. dogs.
14. pigs.
15. frogs.
16. cockroaches.
Survey 9: Conflicts of Interest
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
1. Significant financial conflicts of interest can cause an

investigator to falsify or fabricate data.
2. Significant financial conflicts of interest increase the

risk of unintentional bias.
3. Any significant conflict of interest, not just a financial

conflict of interest, can cause an investigator to falsify
or fabricate research data.
4. Any significant conflict of interest, not just a financial

conflict of interest, increases the risk of unintentional bias.
5. Authors of research publications always disclose

financial conflicts of interest.
406 Appendix I
6. Authors of research publications are always required

to disclose any financial conflicts of interest in the
subject of their research.
7. It is essential for readers of research publications to

know about the financial conflicts of interest of the
authors of the publications.
8. It is essential for readers of a research publication

about the genetic basis of depression to know whether
one or more of the authors have been diagnosed with
clinical depression.
9. It is essential for readers of a research publication

about the genetic basis of homosexuality to know the
sexual orientations of the authors of the study.
Protection against bias due to conflicts of interest is provided by

10. replication of experiments by many researchers.
11. the peer review system.
12. objective research endpoints.
13. blinding of research data.
Survey 10: Collaboration
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
1. Good research depends on collaboration with other

researchers.
2. Collaborations in research often result in disputes

and misunderstandings.
Problems in collaborations are likely to develop if

3. planning is poor.
4. collaborators are contributing similar expertise

(because it is more difficult to apportion credit for
contributions of time than for a distinct area of expertise).
5. collaborators are from different research disciplines

(because of different standards and expectations in
different disciplines of science).
6. collaborations occur between academia and industry

(because of different goals for the products of
collaboration).
7. collaborations are multinational (because of

cultural or language barriers).
Before beginning a collaboration, researchers should discuss

8. who will be responsible for what.
9. timelines for completion.
10. plans for sharing of raw data.
11. criteria for authorship.
12. order of authorship.
13. plans for how research products will be divided if the

collaboration comes to an end.
Survey 11: Data Ownership
In a poster presentation at a national meeting, a junior-level scientist re-

ports cultivation of a tumor cell line never before established in vitro.
Growth in vitro of this tumor and of other previously noncultivable tumors
is made possible using a culture medium that she has invented. The com-
position and preparation of the medium require specialty chemicals from
foreign distributors as well as custom preparation of animal tissue extracts
that are added to the medium. Neither her poster nor her published ab-
stract discloses the composition of her new culture medium, and she re-
fuses all requests to reveal its contents. She has a small lab (one technician
408 Appendix I
and a part-time student) and is struggling to win federal grant support and
tenure. Indicate on the following scale the degree to which each of the
following reasons justifies her not sharing data.
1 Not justifiable
2 Rarely justifiable
3 Sometimes justifiable
4 Generally justifiable
5 Always justifiable
1. Patent protection: Release of the contents of the medium

will compromise her ability to protect her invention
under intellectual property law.
2. Priority: She wants to be the first to report her exciting

finding, and release of the medium’s contents will
compromise her chances of doing so.
3. Career advancement: She wants to establish priority

through publication in the peer-reviewed literature to
help her professional advancement.
4. Fair competition: She fears that availability of the medium

will enable larger, established labs to gain a decisive
advantage in the field; she views her actions as fair
competition.
5. Expense and time: The transfer of this technology

would be too expensive and time-consuming to be effective.
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
The data that you generate in a research project are owned by

6. you.
7. the principal investigator.

8. the institution.
9. the funding agency or organization.
The responsibility for deciding what and when to publish

or share with others is held by
10. you.
11. the principal investigator.
12. the institution.
13. the funding agency or organization.
Sharing of your data or reagents, even before publication, is good for

14. you.
15. science.
Consider your current primary research project. Using the scale below,
answer the following questions to indicate your willingness to share with
someone you do not know from another university.
1 Never
2 Only after the paper is accepted for publication
3 Only after the paper is submitted for publication
4 Only after it is possible to begin writing the paper
5 At any time
16. Raw data
17. Methods
18. Reagents
19. Relatively rare (or expensive) reagents
Survey 12: Record Keeping
1 Strongly disagree
2 Disagree
410 Appendix I

4 Agree
5 Strongly agree
1. Research records should be written in ink.
2. Research records should be kept in a bound lab notebook.
3. Research records should be kept in a bound lab notebook

with numbered pages.
4. Research records should be dated in chronological order.
Daily research records should include

5. the date.
6. the name(s) of the investigator(s).
7. a summary of what was planned.
8. a summary of what was done.
9. a countersignature or notarization by someone else.
10. Original research records should always be kept in the

institution in which they were created.
11. On leaving a research group, a graduate student or

postdoc should take the original research records for
the work that he or she had been doing.
12. On leaving a research group, a graduate student or postdoc

should take a copy of the research records for the work
that he or she had been doing.
13. On leaving a research group, a graduate student or

postdoc should not take copies or originals of the
research records for the work that he or she had
been doing.
Survey 13: Science, Technology, and Society
1 Strongly disagree
2 Disagree
4 Agree
5 Strongly agree
I would want to know if I had a gene

1. that was associated with an increased risk of
early-onset Alzheimer’s disease.

contracting treatable cancer.

contracting untreatable cancer.

any life-threatening disease or disorder.

any life-threatening disease or disorder, but
only if it was curable.

any life-threatening disease or disorder, but
only if it was at least treatable.

pain or suffering.
8. that would have an impact on my ability to

have children. _____
9. only if the predictive probably were high.

[1. And if so, how high (%): ]
10. that would have an impact on my life in the near future.

[1. And if so, how soon (years): ]
412 Appendix I
11. if it could explain my previously unexplained disorder.
12. if there were important genetic implications for my

family members.
13. if it would not put my insurability and/or

employability at risk.
14. if and only if adequate resources were available for

testing and counseling.
Before testing for a genetic predisposition to a debilitating disorder, it is

first necessary to have the consent of
15. the individual research subject.
16. the individual research subject’s siblings.
17. the individual research subject’s children.
18. the individual research subject’s parents.
19. the individual research subject’s partner.
Before testing for a genetic predisposition to a behavioral trait

within a particular racial group, it is first necessary to
have the consent of
20. the individual research subject.
21. the family members of the research subject.
22. a representative sample of the community of those with

a racial background similar to that of the research subject.
appendix II
Student Exercises
T his appendix contains six exercises that cover topics presented in the
chapter material. Exercises 1, 3, 4, 5, and 6 may be given as writing
assignments or used for in-class discussion. Exercise 2 is a dramatic script
that students (and instructors) may use to role-play a scenario. This exer-
cise provides the participants with scripted material regarding their contri-
bution to a research project. The actors must then add their own ad lib
commentary as to the rationale they will use to make a case for (or against)
authorship on a planned manuscript.
Exercise 1: Authorship Rationale

(Chapter 4)
Background information
You are a postdoctoral trainee who has just completed a major research
project that is now ready to be written up as a manuscript for submission to
a peer-reviewed journal. The project has involved collaborating with an-
other postdoc in the lab as well as a predoctoral student and a technician.
Student assignment
Write an e-mail of no more than 350 words to your postdoctoral mentor
in which you make a case for being the first author on the paper. Indicate
the journal to which you propose to submit the work. You can make any
assumptions about your work on and contributions to the project. Com-
pare your contributions to those of your collaborators in making your
doi:10.1128/9781555818487.AppII
413
414 Appendix II
argument for first authorship. Consult any guidelines on authorship that

you consider relevant and build your rationale on their guidance, as ap-
propriate. You may craft your response in terms of your own discipline or
personal research project.
Exercise 2: Dramatic Script: A Case for

Authorship (Chapters 3 and 4)
Dr. Shin-Cho Lee, a chemistry professor at a major university, is the prin-
cipal investigator of a large federal grant to study the properties of natu-
rally occurring substances isolated from lower plants that live in unusual
environments (e.g., mushrooms, fungi). A fungus isolated by Chris Evans 2
years ago in Yellowstone National Park has been under intense study in
Lee's lab ever since. A heat-resistant form of the enzyme DNA ligase has
been purified from it. This enzyme, which seals gaps in DNA strands,
has been thoroughly characterized. The gene for this ligase has been
cloned and overexpressed in recombinant Escherichia coli, and the enzyme
has been purified. The nucleotide sequence of the gene has been deter-
mined and analyzed. This enzyme has sparked enormous intellectual and
commercial interest. A heat-resistant DNA ligase has never been reported
in a fungus before, so this discovery creates interesting questions about
molecular evolution, gene transfer, and DNA synthesis and repair. What’s
more, Dr. Lee and collaborators have designed a new genetic test using
their heat-resistant DNA ligase. They have demonstrated its utility in link-
ing select stretches of DNA that may be diagnostic for certain genetic dis-
eases. At the regular Friday noon meeting of all lab personnel and
collaborators, Dr. Lee says it’s time to prepare a manuscript describing
these results and submit it to either the Proceedings of the National Academy
of Sciences or the Journal of Biological Chemistry. Dr. Lee starts a discussion
to decide whose names will appear in the author byline of the paper (or
alternatively in the acknowledgments). Dr. Lee asks everyone to describe
his or her involvement in the work in order to begin a discussion about
what contributions merit authorship on the paper.
The players
The players include members of the Lee laboratory and their collabora-
tors. There are parts for a total of 11 people in this script: 9 lab members
or collaborators and 2 “consultants.” By selecting just certain players in the
cast, the script can be performed with fewer participants.
Dr. Shin-Cho Lee: university professor of chemistry, principal investi-
gator (lab chief)
Student Exercises 415
Dr. Kim Ward: a research assistant professor working under Dr. Lee
Pat Langella: a fourth-year predoctoral trainee; Dr. Lee is Langella’s
Ph.D. supervisor
Dr. Fran McClure: an assistant professor in the department of chemis-
try whose area of research is enzymology
Phil Newton: a research associate in the department of genetics who
directs the university’s nucleic acid shared resource; this facility pro-
vides high-throughput DNA sequencing and synthesis on a fee-for-
service basis
Robin Willow: one of Dr. Lee’s technicians
Casey Tucker: a Ph.D. biochemist, presently enrolled in law school and
doing part-time postdoctoral research in Lee’s lab
Chris Evans: an undergraduate student who is doing a multiyear honors
project under Dr. Lee’s guidance
Dr. Sydney Chance: a postdoctoral fellow in Dr. Fran McClure’s lab
The following players have no scripted lines but are free to comment at
any point during the play. They were invited to the meeting as “consul-
tants” by Dr. Lee. Both are journal editorial board members whose publi-
cations have guidelines that may be found on the journals’ websites. (In
preparing for this exercise, all cast members will be aided by reviewing the
information found on these sites and by reading chapter 4.)
Dr. Lyndsey Shutte: editorial board member for Journal of Biological

Chemistry (http://www.jbc.org/site/misc/itoa.xhtml)
Dr. V. J. Rana: editorial board member, Proceedings of the National Acad-
emy of Sciences (http://www.pnas.org/site/authors/index.xhtml)
The play
Dr. Shin-Cho Lee: Good morning, everyone. As you may remember
when this project began, we had some casual conversations about who
would be authors on a paper, should the results be publishable. Well, we
now have exciting results and they certainly are publishable! So today, we
need to get serious about who goes in the author byline or in the acknowl-
edgments. I asked you each to prepare a concise statement about your part
in the work in order to get this ball rolling. Today, we’ll just arrive at who
will be authors. We’ll work out the order of the authors’ names in the by-
line at a later time. Let me begin with my comments.
I wrote the NIH grant proposal that provided funding for this work. It
paid for research materials and the salaries of Syd Chance and Kim Ward.
The idea to look for a heat-resistant DNA ligase was Fran McClure’s,
and the idea to commercially apply this discovery was mine. These
416 Appendix II
experimental approaches were described in my NIH proposal, but the

work of the entire DNA ligase project was only a minor part of the over-
all thrust of the work. And I did not hypothesize a heat-resistant ligase in
the proposal. McClure and Ward provided a lot of the scientific guidance
to others in the lab who did experiments on this project. I did no experi-
mental work on this project, but I insist on reading, editing, and approv-
ing the planned manuscript. Finally, as you’re aware, I’m Pat Langella’s
mentor.
Regarding authorship, I believe I should . . . [State your argument for
being an author, being named in the acknowledgments, or neither.]
Anyone have questions or comments?
Cast: [Response from anyone in the group (don’t be shy; challenge Dr.
Lee if you believe authorship criteria are not met).]
Dr. Lee: [Defend your position, as necessary.]
***
Dr. Shin-Cho Lee: Okay, let’s move on. Kim, tell us about your
contribution.
Dr. Kim Ward: After a long struggle, I cloned the DNA ligase gene as a
“side project” during a break in my own research activities. I did a prelim-
inary characterization of the cloned gene and made milligram amounts of
the recombinant plasmid carrying the gene. I gave this plasmid material to
Pat Langella, who performed the nucleotide sequence analysis of the DNA
ligase gene. I did a small amount of the experimental work on the pro-
posed assay.
Dr. Shin-Cho Lee: Thanks, Kim. Well, colleagues, comments or ques-

tions for Kim?
Cast: [Response from anyone in the group (challenge Dr. Ward if you be-
lieve authorship criteria are not being met).]
Dr. Kim Ward: [Defend your position, as necessary.]
***
Dr. Shin-Cho Lee: Pat, tell us about your contribution.

Pat Langella: I am a fourth-year predoctoral trainee. Although Dr. Lee is

my formal academic advisor, much of my laboratory mentoring is provided
by Fran McClure. McClure is always available to provide guidance and
critique my work. I purified and characterized the enzyme with my own
hands and completed the nucleotide sequence of the gene. I plan to write
the entire first draft of the manuscript, including composing all the data
tables and manuscript drawings. I will do the literature search needed to
critically review the field. Eventually, this manuscript will become a chap-
ter in my Ph.D. dissertation.
Dr. Shin-Cho Lee: Thanks, Pat. Comments or questions for Pat?
Cast: [Response from anyone in the group (challenge Pat if you believe
authorship criteria are not being met).]
Pat Langella: [Defend your position, as necessary.]
***
Dr. Shin-Cho Lee: Let’s hear from Fran McClure.
Dr. Fran McClure: I had the original idea to look for a heat-resistant
DNA ligase. I suggested several sources for isolating enzymes from lower
plants living in extreme conditions. I designed the enzyme purification
scheme and supervised Pat Langella in this aspect of the work. I critiqued
all data involving the enzyme isolation and purification. On several occa-
sions, I suggested new experimental approaches to the enzyme purifica-
tion, all of which proved fruitful.
I believe I should . . . [State your argument for being an author, being
named in the acknowledgments, or neither.]
Dr. Shin-Cho Lee: What do you think about Fran’s contributions,

everybody?
Cast: [Response from anyone in the group (challenge Dr. McClure if you
believe authorship criteria are not being met).]
Dr. Fran McClure: [Defend your position, as necessary.]
***
418 Appendix II
Dr. Shin-Cho Lee: Phil, tell us about your participation in this project.
Phil Newton: I am in charge of the nucleic acid support facility, which is

cosponsored by the chemistry and biochemistry departments. I used an
automated DNA synthesizer to create 42 different oligonucleotides used
by Pat Langella in determining the nucleotide sequence of the DNA ligase
gene. I worked closely with Pat in giving guidance on the design of the
primers and their use. Several times, I helped Pat troubleshoot problems
when the DNA sequencing did not work.
Dr. Shin-Cho Lee: Thanks, Phil. Any questions for Phil?
Cast: [Response from anyone in the group (challenge Phil if you believe
Phil Newton: [Defend your position, as necessary.]
***
Dr. Shin-Cho Lee: Now let’s hear from Robin.
Robin Willow: I am a program support technician employed by Dr. Lee. I

plan to do copyediting on the manuscript that Pat Langella will write. I
will also use a computer drawing program to prepare the figures needed
for the manuscript. I will produce all the photographic-quality comput-
er-generated prints of figures needed to accompany the submitted
manuscript.
Dr. Shin-Cho Lee: Thanks. Any questions or comments for Robin?
Cast: [Response from anyone in the group (challenge Robin if you believe
Robin Willow: [Defend your position, as necessary.]
***
Dr. Shin-Cho Lee: Go ahead, Casey.

Casey Tucker: Well, I’ve been doing part-time postdoctoral work in Dr.
Lee’s lab while I complete my final year of law school. I have expertise in
intellectual property law. I provided advice and guidance in both the clon-
ing and sequencing of this gene. Also, I performed about 100 hours of
background research on the technology transfer implications of this dis-
covery. I am advising Dr. Lee on the preparation of this manuscript in
terms of intellectual property protection. I will edit the final manuscript
and I will write and submit a provisional patent application.
Dr. Shin-Cho Lee: Any questions or comments for our future attorney?
Cast: [Response from anyone in the group (challenge Casey if you believe
Casey Tucker: [Defend your position, as necessary.]
***
Dr. Shin-Cho Lee: Talk to us, Chris!
Chris Evans: I am doing an undergraduate honors project under Dr. Lee’s

supervision. I and my family spent our vacation in Yellowstone 2 years ago,
and Dr. Lee asked me to bring back some water samples and fungal speci-
mens from the hot springs for my honors project. One of the fungi I culti-
vated from these samples yielded the heat-resistant DNA ligase. I did all
the necessary taxonomic work to identify this fungus and stocked it in Dr.
Lee’s culture collection.
Dr. Shin-Cho Lee: Comments, anyone?
Cast: [Response from anyone in the group (challenge Chris if you believe
Chris Evans: [Defend your position, as necessary.]
***
Dr. Shin-Cho Lee: Dr. Chance, the floor is yours.

420 Appendix II
Dr. Sydney Chance: I was asked by Dr. Lee to help Pat with the protein
bioinformatics. I showed Pat how to do comparative studies with the
amino acid sequence of the DNA ligase protein. Pat had no training or
experience in this kind of computer analysis but was a quick study! The
amino acid sequence comparisons turned out to be very interesting. I did
some sophisticated phylogenetic tree analysis using a computer program I
wrote, and together Pat and I concluded that this DNA ligase is closely
related to similar enzymes from bacteria that live in the hot springs at
Yellowstone.
Dr. Shin-Cho Lee: We’re open for discussion about Dr. Chance’s
contributions.
Cast: [Response from anyone in the group (challenge Dr. Chance if you
believe authorship criteria are not being met).]
Dr. Sydney Chance: [Defend your position, as necessary.]
Exercise 3: Postpublication Peer Review

(Chapter 4)
Shortly after the turn of the millennium, scientists began discussing the
published literature online using various forms of commentary and dia-
logue (e.g., blogs). Thus far, this practice has evolved into three platforms.
These are (i) structured websites that provide a controlled environment
for discussing the peer-reviewed scientific literature (e.g., F1000.com),
(ii) peer-reviewed journals (e.g., plos.org), and (iii) personal blogs and
popular social media. The impact of these practices has not yet been fully
appreciated. But the third of these platforms, the use of personal blogs
and social media, has garnered considerable attention. The postpublica-
tion review that appears on such sites has been criticized for being unruly,
unstructured, and rude, and it has been likened to a “free-for-all.” Such
commentary is typically delivered anonymously, and often within days or
even hours of publication. Postpublication peer review blogs have evoked
varying reactions from the authors of the papers being discussed. In one
case, the authors acknowledged they were following up on a technical
error in the work that was claimed by the bloggers, while in another case,
the authors refused to address the bloggers’ comments, saying that the
criticisms of the work should be aired in the peer-reviewed literature. In
the wake of these two cases, an editorial in Nature encouraged
“post-publication discussion on blogs and online commenting facilities as

a complement to—but not a substitute for—conventional peer review.”
Student assignment
You have been asked to write an editorial that presents your position on
online postpublication peer review. The editorial should emphasize the role
of personal blogs and social media. Points that the editor would like you to
cover include (i) whether authors have an obligation to respond to blog-
gers’ comments, and if so, the forum for doing so; (ii) whether journals and
publishers should develop policies on handling bloggers’ comments and for
follow-up action with authors; and (iii) the merits of including any and all
online commentary about a published paper in measuring its impact on the
field. Your editorial must not exceed 750 words in length.
Exercise 4: Sharing of Research Materials

(Chapters 4, 8, and 9)
You are a faculty member in the department of molecular oncology at
State Research University (SRU). While attending an international sym-
posium, you listen to a presentation by Dr. Isabelle Salazar describing a
new synthetic compound that binds to certain types of cancer cells. Besides
being a useful research tool, the compound has the potential for the devel-
opment of both cancer diagnostics and therapeutics. You speak to Dr. Sala-
zar about obtaining a sample of the compound to test against some unusual
cancer cell lines you maintain in your laboratory as well as some specific
rodent tumors. You believe this compound may provide new capabilities
for early identification of cancer. Dr. Salazar, who works in a private labo-
ratory called the Cancer Research Institute, tells you to send her a written
request for a sample of the compound. Upon returning home, you send
her a letter describing the cell lines you plan to investigate and the hypoth-
eses you plan to test using her compound. You get a prompt written re-
sponse from the vice president of the Cancer Research Institute. This
communication describes the terms under which Dr. Salazar’s compound
(referred to in the letter as “the material”) will be released to you (“the
faculty member”). You, as an employee of SRU, must agree to all of the
following in order to receive the compound.
1. The material must not be administered to humans.

2. Before the material may be used in animals, the Cancer Research
Institute must approve a verbatim copy of the animal use protocol
and a letter from the SRU Institutional Animal Care and Use Com-
mittee authorizing the experiments.
422 Appendix II
3. The material is being provided only for the stated use; permission
must be sought from the Cancer Research Institute if other uses of
the material are planned.
4. The material may not be released to any other investigators outside
of the faculty member’s lab.
5. The faculty member must provide the names of any and all lab staff
or trainees working with the material.
6. SRU must certify that it will not hold the Cancer Research Insti-
tute legally responsible for any harm or injury that may be caused
by the material or its use.
7. The faculty member or SRU cannot disclose, by any means, any of
the work done or results obtained with this material without first
seeking and obtaining the permission of the Cancer Research Insti-
tute.
8. Dr. Salazar reserves the right to be an author on any manuscripts
submitted for publication.
9. The faculty member or SRU cannot use the material for any com-
mercial or profit-making purposes.
10. Any patentable invention that relates to new uses of the material
that could not have been made but for the contribution of the ma-
terial will be jointly owned by SRU and the Cancer Research Insti-
tute. Any revenues arising for any use or implementation of such an
invention will be shared by SRU and the Cancer Research Insti-
tute. The sharing of such revenues will be negotiated in good faith
based on the relative contribution of the material to the invention.
11. At the conclusion of the work, the material will be returned to the
Cancer Research Institute or destroyed.
12. All lab members must be notified in writing of the terms of the re-
lease of the material and its use under those terms.
You are asked to countersign this letter and return it to the Cancer Re-
search Institute before the material can be released to you. This is your
first experience with such a letter, and it does raise some concerns and
questions in your mind.
You show the letter to a colleague, who comments that such agreements
aren’t worth the paper they’re printed on. She advises you to just sign it
and return it so you can get the compound and move ahead with your
work.
You show the letter to your departmental chair, who informs you that
the letter must be approved and countersigned by someone authorized to
sign on behalf of SRU, in this case the director of sponsored programs.
You show the letter to another faculty colleague, who confirms your
notions that some of the items are too restrictive and inappropriate
according to current standards of exchange of biological materials com-

monly used by universities and U.S. federal agencies. He suggests you send
the letter back and suggest the deletion or modification of items you con-
sider inappropriate or unacceptable.
Student assignment
Comment on the advice being given by each of these individuals. What, if
any, clauses are unacceptable to you? Why? Are all of these conditions con-
sistent with current standards of the transfer of biological materials for
research purposes? Finally, explain the course of action you would take in
this situation, specifically providing the edits you’d make to any of the
items and the rationale for making them.
Exercise 5: Conflict of Conscience

(Chapters 6 and 7)
You are chair of your institutional advisory committee on the care and use
of laboratory animals. This committee reviews and recommends policies
and practices on the use of laboratory animals and reviews experimental
protocols prepared by investigators. It consists of nine faculty, two mem-
bers outside the institution, and you as chair. One-third of the faculty
members rotate off the committee each year. A professor in a basic science
department asks you to nominate him for membership on the committee.
Some salient points are as follows:
1. The basic science professor is a theoretical biologist who is interna-

tionally known for his computer simulations.
2. The professor has testified before legislative bodies opposing the use
of animals in research.
3. The professor has known associations with members of a militant
animal rights and animal liberation group.
4. The professor has been very active in developing computer-assisted
instructional material.
5. The professor has been very active in university governance.
6. Your institution has a nationally accredited laboratory animal facility
managed by a team of veterinarians and trained animal care
workers.
7. The faculty of your institution has a number of extramurally funded
research projects using rodents, rabbits, cats, dogs, and nonhuman
primates.
8. The extramurally funded research is sponsored by private agencies,
federal agencies, and private industry.
424 Appendix II
9. The animal research encompasses nutrition, immunology, drug test-

ing, biochemistry, neurology, toxicology, infectious diseases, and
chemical dependency.
Student assignment
You discuss this with the senior administrator for research who appoints
the membership of this committee. She asks you to make a decision based
on your best judgment and to
1. Write a letter to her, advising her of your recommendation, along
with reasons for your decision.
2. Write a letter to the professor who asked you to nominate him for
committee membership, giving your decision and reasons for your
decision.
3. Prepare a draft of your response should members of the institutional
advisory committee ask you about the matter.
4. Prepare a draft of your plan of action should a member of the press
or an animal rights organization ask you about the matter.
Exercise 6: Conflict of Interest (Chapter 7)
The following policy is in force at your institution, Research University.
RESEARCH UNIVERSITY
Policy on Industry Relationships
POLICY STATEMENT AND PURPOSE

Universities and academic medical centers have opportunities to engage in pro-
fessional activities with industry that contribute to the missions of research, edu-
cation, and clinical care; reflect the faculty’s talent, expertise, knowledge, and
skills; and enhance their national and international recognition. Such interaction
may create perceived conflicts of interest. Transparency is key to oversight of
conflicts of interests and requires ongoing internal reporting and external disclo-
sure. This document outlines Research University’s policy concerning relation-
ships and interactions with industry in a manner that avoids real or perceived
conflicts.
WHO SHOULD READ THIS POLICY

All faculty, credentialed health care providers, staff, students, and trainees in all
programs and units of Research University should read and comply with this
policy.
DEFINITIONS
“Industry” refers to any person or company seeking to do or doing business with
Research University, including any pharmaceutical, medical device, medical pub-
lishing, or medical equipment companies.
“Conflict of interest” (COI) exists whenever an individual or an institution has a

primary allegiance that requires certain actions and, simultaneously, has a second-
ary interest that (i) could abrogate that primary allegiance and (ii) is sufficiently
tempting to raise a reasonable possibility that it might actually do so.
“Gift” means any gratuity, favor, discount, entertainment, hospitality, loan, for-
bearance, or other item having monetary value. It includes services as well as gifts
of transportation, local travel, lodgings, and meals, whether provided in kind, by
purchase of a ticket, payment in advance, or reimbursement after the expense has
been incurred.
POLICY
1.0 Gifts
Gifts from industry and/or representatives are prohibited. This encompasses gifts
from equipment and service providers as well as pharmaceutical and device
manufacturers.
2.0 Pharmaceutical Samples
Samples must be deposited with the nurse manager or other appropriate profes-
sional in each clinic/unit. Each clinic/unit must implement a reconciliation process
and policy for handling pharmaceutical samples. The clinic administration and the
department in concert with Research University Compliance must develop this
process.
3.0 Site Access by Pharmaceutical Representatives

3.1 To protect patients, patient care areas, and work schedules, access by pharma-
ceutical representatives to individual physicians is restricted to non-patient care
areas and nonpublic areas and should take place only by appointment or invitation
of the physician.
3.2 Involvement of students and trainees in such individual meetings should occur
only for educational purposes and only under the supervision of a faculty member.
3.3 Pharmaceutical representatives may be invited to a patient care area when the
faculty provider requests training or demonstration of a product.
3.4 Each department is responsible for enforcement of central registration of in-

dustry representatives.
4.0 Site Access by Device Manufacturer Representatives

4.1 Access by device manufacturer representatives to patient care areas is permit-
ted only when the representatives are appropriately credentialed by Research Uni-
versity and should take place only by appointment or invitation of the physician.
4.2 Representatives should not be allowed to be present during any patient care in-
teraction unless there has been prior disclosure to and consent by the patient, and
then only to provide in-service training or assistance on devices and equipment.
4.3 Student interaction with representatives should occur only for educational
purposes under faculty supervision.
426 Appendix II
5.0 Continuing Medical Education

5.1 All requests for continuing medical education (CME) industry support and
receipt of funds should be coordinated and overseen by the Research University
CME Central Office.
5.2 The CME Central Office will institute audit mechanisms to ensure compli-
ance with Accreditation Council for Continuing Medical Education (ACCME)
Standards for Commercial Support of CME. The CME Central Office requires
financial disclosure/COI management for those involved in planning and/or pre-
senting a CME activity.
5.3 Faculty must disclose personal and professional relationships with industry in
formal lectures to students, residents, and other health care professionals.
5.4 Faculty, residents, and students are strongly discouraged from attending
industry-supported medical education that is non-CME or that is not offered by
hospitals, health systems, specialty societies, and medical schools accredited
by ACCME. This does not apply to required training or instruction associated with
new devices or equipment.
6.0 Participation in Industry-Sponsored Programs

6.1 Faculty participation in industry-sponsored speakers’ bureaus is strongly dis-
couraged, with the exception of settings in which investigators are presenting re-
sults of their industry-sponsored studies to peers and there is opportunity for
critical exchange.
6.2 Faculty and staff who participate in industry-sponsored, FDA-regulated pro-

grams should adhere to the following standards:
6.2.1 There should be full transparency and disclosure to the institution when
participating in such programs; and
6.2.2 Payments received should be only at fair market value.
6.3 Faculty and trainees are strongly discouraged from attending non-ACC-
ME-accredited industry events billed as CME.
6.4 Faculty and trainees are prohibited from engaging in the following
activities:
6.4.1 Accepting payment for attendance at industry-sponsored meetings; and
6.4.2 Accepting personal gifts from industry at such events.
7.0 Industry-Sponsored Scholarships and Educational Funds

7.1 All scholarships or other educational funds from industry must be given to a
central coordinating office designated by administration.
7.2 No quid pro quo is to be involved in any way.
7.3 The evaluation and selection of recipients of such funds must be the sole re-
sponsibility of the designated office/official based on institutional guidelines and
with no involvement by the donor industry.
8.0 Food
8.1 Industry-supplied food and meals can be provided in connection with
ACCME-accredited programming and in compliance with ACCME guidelines.
There are no exceptions that permit industry-supplied food and meals within the
medical center.
8.2 Faculty and trainee participation in industry-sponsored off-site functions (e.g.,

satellite symposia, meetings, dinner talks) is strongly discouraged.
9.0 Professional Travel
9.1 Faculty, trainees, and students are directly prohibited from accepting travel
funds from industry, other than for legitimate reimbursement or contractual
services.
9.2 The centrally designated administrative office must coordinate travel funds/
scholarships for faculty, trainees, and students.
10.0 Ghostwriting
Research University prohibits faculty, trainees, and students from allowing their
professional publications and presentations of any kind, oral or written, to be ghost-
written by any party, industry or otherwise. All listed authors should have made sub-
stantial contributions to the content of the paper and participated sufficiently in the
work to take public responsibility for the paper. In addition, the use of a slide presen-
tation developed and compiled by another party or individuals other than the pre-
senter is prohibited.
11.0 Purchasing
11.1 Faculty and personnel with any financial interest in any particular manufac-
turer of pharmaceuticals, devices, or equipment, or any provider of services, are
required to disclose such interests according to institutional policies and to recuse
themselves from involvement in purchasing decisions relevant to the conflicting
interests.
11.2 To the extent that an individual’s expertise is necessary in evaluating any

product, that individual’s financial ties to any manufacturer of that or any related
product must be disclosed to those charged with the responsibility for making the
decision.
12.0 Physician/Patient Interactions and Conflicts of Interest

12.1 Relationships that tie compensation to individual or institutional use of
products or devices are prohibited.
12.2 All credentialed providers must file a disclosure statement of personal inter-
est in a contract or transaction pursuant to engagement in such activities.
12.3 Relationships between all credentialed health care providers and industry
must be disclosed to patients at or before the establishment of the physician-patient
relationship and made available to the public.
428 Appendix II
13.0 Faculty Members as Consultants to Industry

13.1 Faculty members may qualify as consultants if they are engaged for an ex-
change of information about important treatments or developments, to review and
comment on a product, to discuss independent research projects or their results,
and to explore the potential for research.
13.2 Faculty members whose activity qualifies as consulting must comply with the
related policies governing fair market value compensation for services performed
and specified in advance, and with guidelines on potential COIs, publications, and
disclosure requirements.
13.3 Disclosure and approval of this relationship must occur through the outside
professional activity request process.
The dilemma
You are an assistant professor at Research University. You have received an
e-mail from a new assistant professor, Nora Okonjo, seeking your advice.
As part of her recruitment, Nora was provided with funds to purchase a
high-performance electron microscope (EM). She has done much research
on EMs that will fulfill her needs and has narrowed down her choice to
two manufacturers. One company is in Philadelphia and the other is in
Munich, Germany. She is striving to learn as much as possible about each
of these instruments in advance of Research University issuing a request
for bids that must be submitted by each company before a purchasing de-
cision can be made. The sales representative from the Munich company
has invited Nora to visit their facility with some of her samples and evalu-
ate the performance of the EM firsthand. He tells her this is a standard
company practice and that all of her travel expenses will be paid by the
company. Shortly after Nora agrees to the visit, she discovers that Research
University has a Policy on Industry Relationships (see above). Although it
appears to be aimed at industry relationships connected to health care
practice, research, and training, she wonders if the policy has implications
for her planned visit to Munich. She writes you stating that her visit’s pur-
pose is to perform the due diligence needed to make the best investment in
her research program. She asks you to look at the policy and comment on
whether it is relevant to her situation.
Student assignment
In an e-mail of no more than 350 words, write a response to Nora explain-
ing your interpretation of the policy in terms of how it may apply to her.
Your message should have enough detail to make your reasoning clear. If
you conclude that the situation presents a conflict of interest, can it be
managed? If so, describe the management plan you would propose. Finally,
taking the totality of your analysis and advice under consideration, give her
a definitive answer as to whether she should make the trip or cancel it, and
under what conditions.
appendix III
Standards of Conduct
Sources for Guidelines
The following provides general information on the location of documents

that deal with standards of conduct in the research and academic settings.
Appropriate professional society codes of ethics

or standards for scientific conduct
Professional scientific societies have conduct and ethics codes, which may
be published from time to time, usually in society-sponsored journals or
publications or on their websites. Alternatively, the Center for the Study of
Ethics in the Professions at the Illinois Institute of Technology has a web-
site that contains many codes of ethics of professional societies, corpora-
tions, government, and academic institutions. The Codes of Ethics Online
Project may be found at
http://ethics.iit.edu/PublicWWW/codes/index.html
The Ethics Collaborative Online Resource Environment (Ethics

CORE) also features links to access professional societies’ ethics codes and
ethics committees:
https://nationalethicsresourcecenter.net/
doi:10.1128/9781555818487.AppIII
429
430 Appendix III
Federal agency documents

Federal agency documents are concerned with such things as procedures
and regulations related to the identification and prosecution of scientific
misconduct. They also deal with other specific issues related to scientific
integrity and responsible conduct. They are usually available at the institu-
tional level or can be found in the Federal Register or the NIH Guide for
Grants and Contracts, both of which are available online.
Federal Register
http://www.gpo.gov/fdsys/browse/collection.action?collectionCode=FR
NIH Guide for Grants and Contracts

http://grants.nih.gov/grants/guide/index.html
Often, the subject matter in the Federal Register is published in order to

seek public comment. In such cases, subsequent publication occurs follow-
ing consideration of comments in which the implementation of the policy
is announced. This is indicated by the inclusion of the phrase “Final Rule”
in the title of the article. These documents may reflect the activities and
authority of the Office of Research Integrity of the U.S. Public Health
Service (which deals with the National Institutes of Health [NIH]) or the
Office of the Inspector General of the National Science Foundation.
Following the issuance of a Final Rule on a topic, funding agencies will
publish policies and standards on their websites. A good example of this
practice is seen with conflict-of-interest policies. The National Science
Foundation embeds its official conflict-of-interest policy in a chapter of its
Award and Administration Guide:
http://www.nsf.gov/pubs/policydocs/pappguide/nsf10_1/aag_4.jsp
The NIH (under the U.S. Department of Health and Human Services)
has a Web page in its Grants Policy document that is devoted to conflict of
interest, including a link to the most recently implemented Final Rule:
http://grants.nih.gov/grants/policy/coi/
Federal and institutional guidelines for the use and

protection of human research subjects and of animals
Guidelines for human and animal experimentation can usually be located
at institutional sponsored programs offices or the institutional offices of
the federally mandated institutional review board (IRB). They are fre-
quently found online at institutional home pages, usually under the head-
ing of “Research.”
Standards of Conduct 431
Guidelines for scholarly publication

Scientific journals regularly publish guidelines for contributors. They may
appear in every issue of the publication, at the beginning or end of volume
sequences, or at the beginning or end of the calendar year. Typically, they
are also readily available on the journal’s or publisher’s website. These guide-
lines vary in scope and content and may cover such things as authorship at-
tribution, sharing of research materials, conflict-of-interest disclosure, and
communication of results to the media before manuscript acceptance (see
chapter 4). Investigators should be familiar with the publication guidelines
of any journal to which they intend to submit a scientific manuscript.
Institutional policy documents for conduct of research

A growing number of academic and research institutions have developed
policy documents dealing with the responsible conduct of research. These
documents are also frequently found online at institutional home pages
under the heading of “Research.” Other things to look for at the institu-
tional level, either in print or online, include computer ethics policies,
copyright and intellectual property policies, conflict-of-interest policies,
workers’ right-to-know and hazard communication documentation, and
institutional academic honor code documents. These documents are usu-
ally distributed periodically, or faculty and trainees are reminded of their
location on the institutional website.
The Guidelines for the Conduct of Research at the National Institutes of
Health (http://sourcebook.od.nih.gov/ethic-conduct/Conduct%2Research
%206-11-07.pdf) are now in their fourth edition (2007). A verbatim copy of
the Guidelines is reproduced here as a relevant example.
Guidelines for the Conduct of Research in

the Intramural Research Program at NIH
The Guidelines for the Conduct of Research set forth the general princi-
ples governing the conduct of good science as practiced in the Intramural
Research Programs at the National Institutes of Health (NIH). They ad-
dress needs arising from the rapid growth of scientific knowledge, the in-
creasing complexity and pace of research, and the influx of scientific
trainees with diverse backgrounds. Accordingly, the Guidelines should as-
sist both new and experienced investigators as they strive to safeguard the
integrity of the research process.
The Guidelines, originally developed by the Scientific Directors of the
Intramural Research Programs at the NIH, have been revised for this edi-
tion by the intramural scientists on the NIH Committee on Scientific
Conduct and Ethics, and approved by the Scientific Directors. General
432 Appendix III
principles are set forth concerning the responsibilities of research staff in

the collection and recording of data, publication practices, authorship de-
termination, mentoring, peer review, confidentiality of information, col-
laborations, human subjects research, financial conflicts of interest, and
animal care and use.
It is important that every investigator involved in research at NIH read,
understand, and incorporate the Guidelines into everyday practice. The
progress and excellence of NIH research is dependent on our vigilance in
maintaining the highest quality of conduct in every aspect of science.
Michael M. Gottesman, M.D.

Deputy Director for Intramural Research, NIH
Introduction
Scientists in the Intramural Research Programs at the National Institutes
of Health generally are responsible for conducting original research con-
sonant with the goals of their individual Institutes and Centers. These
Guidelines were developed to promote high ethical standards in the con-
duct of research by intramural scientists at the NIH. It is the responsibility
of each Principal Investigator who oversees a research group, and succes-
sive levels of supervisory individuals (especially Institute and Center Sci-
entific Directors), to ensure that every NIH scientist is cognizant of these
Guidelines and to resolve issues that may arise in their implementation.
Intramural scientists at NIH, as is true for all scientists, should be com-
mitted to the responsible use of scientific tools and methods to seek new
knowledge. While the general principles of scientific methodologies—
formulation and testing of hypotheses, controlled observations or experi-
ments, analysis and interpretation of data, and oral and written presentation
of all of these components to scientific colleagues for discussion and fur-
ther conclusions—are universal, their detailed application may differ in
different scientific disciplines and in varying circumstances. All research
staff in the Intramural Research Programs should maintain exemplary
standards of intellectual honesty in formulating, conducting, presenting,
and reviewing research, as befits the leadership role of the NIH.
These Guidelines complement existing NIH regulations for the con-
duct of research such as those governing human subjects research, animal
use, radiation, chemical and other safety issues, and the Standards of Con-
duct that apply to all federal employees.
The formulation of these Guidelines is not meant to codify a set of
rules, but rather to elucidate, increase awareness and stimulate discussion
of patterns of scientific practice that have developed over many years and
are followed by the vast majority of scientists, and to provide benchmarks
when problems arise. Although no set of guidelines, or even explicit rules,
is likely to prevent willful scientific misconduct, it is hoped that formula-

tion of these Guidelines will contribute to the adoption of exemplary stan-
dards of intellectual honesty in the conduct of research by all scientists.
The public and our scientific colleagues will ultimately judge the NIH
by its adherence to high intellectual and ethical standards, as well as by its
development and application of important new knowledge through scien-
tific creativity.
Responsibilities of research supervisors and trainees

Research training is a complex process, the central aspect of which is an
extended period of research carried out under the supervision of an experi-
enced scientist. This supervised research experience is not merely perfor-
mance of tasks assigned by the supervisor, but rather is a process wherein
the trainee takes on an increasingly independent role in the selection, con-
ceptualization and execution of research projects. The trainee should be
provided with training in the necessary skills and knowledge necessary for
a successful career as a research investigator. It should be recognized that
the trainee has unique, time-sensitive needs relevant to career advance-
ment. Guidance and advocacy from the supervisor in this regard are essen-
tial components of training.
In general, a trainee will have a single primary supervisor, but may also
have other individuals who function as mentors for specific aspects of
training and career development. It is the responsibility of the primary
supervisor to serve as a role model and provide a rich research environ-
ment in which the trainee has the opportunity to acquire both the concep-
tual and technical skills of the field. In this setting, the trainee should be
provided with clear expectations and undertake a significant piece of re-
search, usually chosen as the result of discussions between the mentor and
the trainee, which has the potential to yield new knowledge of importance
in that field. In order to provide a meaningful, high quality training expe-
rience, the mentor should monitor and guide the trainee’s progress closely,
and interact personally on a regular basis to give timely feedback regarding
research findings and progress. Supervisors and mentors should limit the
number of trainees in their laboratory or branch to the number for whom
they can provide an appropriate and productive training experience. Men-
toring should be adapted to the needs and career stage of each individual
trainee.
Specific aspects of the mentor-trainee relationship deserve emphasis.
Training should impart to the young investigator appropriate standards of
scientific conduct both by instruction and by example. Mentors should be
particularly diligent to involve trainees in research and related activities
that contribute to their careers, including participation in intramural or
extramural collaborations, encouragement of presentations at scientific
434 Appendix III
meetings, and networking. Mentors should provide trainees with timely

and realistic appraisals of their performance and with advice regarding ca-
reer opportunities and advancement.
Trainees have responsibilities to their supervisors and to their institu-
tions as well. These responsibilities include adherence to these Guidelines
and other applicable rules, and programmatic constraints related to the
needs of the research team and Institute/Center. The same standards of
professionalism and collegiality apply to trainees as to their supervisors
and mentors.
Data management and archiving

Research data, including detailed experimental protocols, all primary data,
and procedures of analysis and presentation are the essential components
of scientific processes and progress. Scientific integrity is inseparable from
meticulous attention to the acquisition and maintenance of these research
data.
The results of research should be carefully recorded in a form that will
allow continuous access for analysis and review. When possible, it is best to
store data in both electronic and hard-copy form. Attention should be
given to annotating and indexing notebooks and documenting computer-
ized information to facilitate detailed analysis and review of data. All data,
even those from observations and experiments not directly leading to pub-
lication, should be treated comparably. All research data should be avail-
able to supervisors and scientific collaborators for timely review, consistent
with requirements of confidentiality. Investigators should be aware that
research data are legal documents for purposes such as establishing patent
rights or defending the veracity of published results, and are subject to
subpoena by congressional committees and the courts.
Research data, including the primary experimental results and
computer and statistical analyses, should be retained for a sufficient pe-
riod to allow analysis and repetition by others of published material
resulting from those data. Seven years is specified by the Federal Gov-
ernment (http://www.ori.dhhs.gov/documents/FR_Doc_05-9643.shtml)
as the minimum period of retention but this may be longer under some
circumstances, such as clinical research.
Notebooks, other research data, and supporting materials, such as
unique reagents, belong to the National Institutes of Health, and should
be maintained and made available, in general, by the Laboratory in which
they were developed. Departing scientists may take copies of notebooks or
other data for further work. Under special circumstances, such as when
required for continuation of research, departing investigators may take
primary data or unique reagents with them if adequate arrangements for
their safekeeping and availability to others are documented by the
appropriate Institute or Center official. Transfer of reagents should be

documented through a Material Transfer Agreement.
Data management, including the decision to publish, is the responsi-
bility of the principal investigator. After publication, the research data
and any unique materials that form the basis of that communication
should be made available promptly and completely to all qualified scien-
tists seeking further information. Exceptions may be necessary to main-
tain confidentiality of clinical data or if unique materials were obtained
under agreements that preclude their dissemination. Consult the
PHS policy relating to the distribution of unique research resources for
further guidance (http://grants2.nih.gov/grants/guide/notice- files/not
96-184.html).
Publication
Publication of results is an integral and essential component of research.
Other than presentation at scientific meetings, publication in a scientific
journal should normally be the mechanism for the first public disclosure of
new findings. Exceptions may be appropriate when serious public health
or safety issues are involved. Although generally considered the end point
of a particular research project, publication is also the beginning of a pro-
cess in which the scientific community at large can assess, correct and fur-
ther develop any particular set of results.
Timely publication of new and significant results is important for the
progress of science. Fragmentary publication of the results of a scientific
investigation or multiple publications of the same or similar data are inap-
propriate. Each publication should make a distinct and substantial contri-
bution to its field. As a corollary to this principle, tenure appointments and
promotions should be based on the importance of the scientific accom-
plishments and not on the number of publications in which those accom-
plishments were reported.
Each paper should contain sufficient information for the informed
reader to assess its validity, including all the information that would be
necessary for scientific peers to repeat the experiments. Essential data
that are not included in the published paper due to space limitations (e.g.
nucleic acid and protein sequences, microarray data and crystallographic
information) should be deposited in the appropriate public databases or
made available online. It is not necessary to provide materials (such as
proteins) that others can prepare by published procedures, materials
(such as polyclonal antisera) that may be in limited supply, or clinical
specimens (whose distribution is controlled by human subjects protec-
tion requirements, as described in a later section). However, it is an obli-
gation of NIH intramural scientists to make reasonable amounts of
expandable materials (e.g. monoclonal antibodies, bacterial strains,
436 Appendix III
mutant cell lines) and analytical amounts of reagents (e.g. polyclonal an-
tibodies, purified proteins, uniquely-synthesized compounds) that are
essential for repetition of the published experiments available to quali-
fied scientists, using appropriate Material Transfer Agreements or collab-
orative agreements consistent with NIH policy. This can be achieved by
making arrangements to send such materials to a central repository.
Consult the PHS policy relating to the distribution of unique research
resources for further guidance (http://grants2.nih.gov/grants/guide
/notice-files/not96-184.html).
The current NIH Public Access Policy (http://publicaccess.nih.gov/
policy.htm) requests and strongly encourages all NIH-funded investiga-
tors to make their peer-reviewed final manuscripts available to other re-
searchers and the public at the NIH National Library of Medicine’s
(NLM) PubMed Central (PMC) (http://www.pubmedcentral.nih.gov) im-
mediately after publication of the final version. Authors are given the op-
tion to release their manuscripts at a later time, up to 12 months after the
official date of final publication. NIH expects that only in limited cases will
authors deem it necessary to select the longest delay period.
Authorship
Authorship refers to the listing of names of participants in all communica-
tions, both oral and written, of experimental results and their interpretation
to scientific colleagues. Authorship is the fulfillment of the responsibility to
communicate research results to the scientific community for external eval-
uation. Authorship is also the primary mechanism for determining the allo-
cation of credit for scientific advances and thus the primary basis for
assessing a scientist’s contributions to developing new knowledge. As such, it
potentially conveys great benefit, as well as responsibility.
For each individual the privilege of authorship should be based on a
significant contribution to the conceptualization, design, execution, and/or
interpretation of the research study, as well as on drafting or substantively
reviewing or revising the research article, and a willingness to assume re-
sponsibility for the study. Individuals who do not meet these criteria but
who have assisted the research by their encouragement and advice or by
providing space, financial support, reagents, occasional analyses or patient
material should be acknowledged in the text but not be authors. These
authorship guidelines are comparable to those now described in the Uni-
form Requirements for Manuscripts Submitted to Biomedical Journals,
which were developed by the International Committee of Medical Journal
Editors (http://www.icmje.org/).
Because of the variation in detailed practices among disciplines, no uni-
versal set of standards for authorship can easily be formulated. It is ex-
pected, however, that each research group and Laboratory or Branch will
freely discuss and resolve questions of authorship, including the order of

authors, before and during the course of a study. Further, each author
should review and support the manuscript that is to be submitted (origi-
nally or in revision) for publication. Each author should be willing to sup-
port the general conclusions of the study. The NIH recommends that the
transmittal letter accompanying a manuscript submission identify the ex-
act contribution of each author.
The corresponding author should be considered the primary author
(but is not necessarily the first author), with the additional responsibili-
ties of coordinating the completion and submission of the work, satisfy-
ing pertinent rules of submission, and coordinating responses of the
group to inquiries or challenges. The corresponding author should as-
sure that the contributions of all collaborators are appropriately recog-
nized and that each author has reviewed and authorized the submission
of the manuscript in its original and revised forms. Corresponding au-
thors must be especially vigilant that the above criteria are met before
sending articles to journals that publish submissions on line upon accep-
tance of the manuscript.
All manuscripts and abstracts coming from the Intramural Research
Program must be cleared in accordance with the instructions included at
http://www1.od.nih.gov/oir/sourcebook/oversight/pub-clear.htm.
Peer review and privileged information

Peer review is expert critique of either a scientific treatise, such as an arti-
cle prepared or submitted for publication, a grant proposal, or a clinical
research protocol, or of an investigator’s research program, as in a site visit.
Peer review is an essential component of the conduct of science. Decisions
on the funding of research proposals and on the publication of experimen-
tal results must be based on thorough, fair and objective evaluations by
recognized experts. Therefore, although it is often difficult and time-
consuming, scientists have an obligation to participate in the peer review
process. In doing so, they make an important contribution to science.
Peer review requires that the reviewer be expert in the subject under re-
view. The reviewer should avoid any real or perceived conflict of interest
that might arise because of a direct competitive, collaborative or other close
relationship with one or more of the authors of the material under review.
Normally, such a conflict of interest would require a decision not to partici-
pate in the review process and to return any material unread. Some review
activities may require review and approval by a supervisor and/or deputy
ethics counsellor in an IC (see http://www1.od.nih.gov/oir/sourcebook/
ethic-conduct/officialdutypolicy.htm).
The review must be objective. It should be based solely on scientific
evaluation of the material under review within the context of published
438 Appendix III
information and should not be influenced by scientific information not

publicly available.
All material under review is privileged information. It should not be
used to the benefit of the reviewer unless it previously has been made pub-
lic. It should not be shared with anyone unless necessary to the review
process, in which case the names of those with whom the information was
shared should be made known to those managing the review process. Ma-
terial under review should not be copied and retained or used in any man-
ner by the reviewer unless specifically permitted by the journal or reviewing
organization and the author.
Collaborations
Collaborative research brings together investigators with distinct strengths
to work together on a defined problem or address a specific research goal.
Research collaborations, within NIH as well as with extramural institu-
tions, are strongly encouraged and supported; the complex scientific ques-
tions that face us today often require interdisciplinary or multidisciplinary
approaches.
Successful collaborations are characterized by a strong sense of direc-
tion, a willingness to commit time and effort, an efficient communication
strategy for discussion among the group members, a system in place for
reevaluation as the project progresses, and a clear definition of roles and
responsibilities. It is advisable that the ground rules for collaborations, in-
cluding eventual authorship issues, be discussed openly among all partici-
pants from the beginning. The NIH Ombudsman Office has developed a
useful set of criteria to consider in establishing collaborations (http://
ombudsman.nih.gov/resourcesScientist.html).
Whenever collaborations involve the exchange of biological materials
they are routinely formalized by written agreements. Material Transfer
Agreements (MTAs) are used for the simple transfer of proprietary re-
search material without collaboration, for example if you request a reagent
from, or give one to, a colleague outside the NIH. Cooperative Research
and Development Agreements (CRADAs) are agreements between one or
more NIH laboratories and at least one non-federal group (private sector,
university, not-for-profit, non-federal government).
CRADAs provide a protected environment for long-term collabora-
tions; they confer intellectual property rights to NIH inventions. CRADAs
are handled by the Technology Transfer Office of your Institute (http://
ott.od.nih.gov/).
Consulting can be viewed as a one-way collaboration, in which an NIH
scientist is asked to contribute to an outside project by providing expert
advice. Information about the NIH guidelines governing consulting activ-
ities and forms for obtaining permission can be found at http://ethics
.od.nih.gov/.
Financial Conflicts of Interest

Real or perceived conflicts of interest due to financial relationships with out-
side organizations may not be recognized by others unless specific informa-
tion is provided. Therefore, the scientist should disclose all relevant financial
interests, including those of the scientist’s immediate family, to the Institute
or Center during the planning, conducting and reporting of research stud-
ies; to funding agencies before participating in peer review of applications
for research support; to meeting organizers before presentation of results; to
journal editors when submitting or refereeing any material for publication;
and in all written communications and oral presentations. Financial interests
include, but are not limited to, ownership of stock or equity, patents, con-
sulting arrangements, collaboration agreements, honoraria, service on advi-
sory boards, or management appointments. Failure to disclose conflicts of
interest can threaten the integrity of research and undermine the public’s
trust in the NIH’s intramural research activities. When there is a potential
conflict of interest, full disclosure and complete transparency are always the
best policy. The NIH’s Ethics Program (http://ethics.od.nih.gov/) has spe-
cific rules concerning conflicts of interest, outside activities (such as consult-
ing and speaking), gifts, honorary awards, and investments. Intramural
researchers should become familiar with these rules and refer any questions
to the Deputy Ethics Counselor of their Institute or Center.
A specific Guide to Preventing Conflicts of Interest in Human Subjects Re-
search at NIH covers participation in human subjects research in the Intra-
mural Research Program (http://intranet.cc.nih.gov/od/conflict_interest
/conflict_memo.shtml).
Human subjects research

For the purposes of these Guidelines, clinical research is defined as inter-
actions with human subjects, or with material or information obtained
from human subjects, in order to produce generalizable knowledge. This is
distinguished from interactions designed solely to benefit a particular pa-
tient. The NIH Intramural Research Program has a formal human re-
search protection program supervised by the Office of Human Subjects
Research (OHSR). All intramural research must be consistent with the re-
quirements of the human research protection program and all intramural
investigators are responsible for knowledge of, and compliance with, them.
OHSR can help investigators understand and comply with the ethical
guidelines and regulatory requirements for clinical research.
All scientists working with human samples/subjects must take the
course “Protecting Human Subjects” (http://phrp.nihtraining.com/users
/login.php). In addition, OHSR has published a booklet “Guidelines for
the Conduct of Research Involving Human Subjects at the NIH” (http://
ohsr.od.nih.gov/guidelines/GrayBooklet82404.pdf ) to assist those doing
clinical research.
440 Appendix III
Investigators involved in clinical research have special responsibilities

regarding the preparation of research protocols, registration of clinical tri-
als, protection of human subjects, supervision of trainees, collection and
storage of research data, and conduct of epidemiologic research. These
responsibilities are briefly discussed below.
Protocols: Investigators must prepare a written clinical research protocol
describing the scientific background, objectives, subject eligibility criteria,
design, methods of data collection and analysis, risks and benefits of the
proposed research, and qualifications of the investigators. The protocol
must undergo IC-specific scientific review and then be reviewed and ap-
proved by the IC Institutional Review Board (IRB) (unless the research is
specifically exempt by the OHSR because it does not qualify as human
subjects research, e.g., when samples are fully anonymized). All clinical
studies require that informed consent be obtained from prospective sub-
jects prior to commencing the research. Studies using investigational drugs
or devices must also be reviewed and approved by the Food and Drug Ad-
ministration (FDA).
Collection and Storage of Data: Investigators must ensure the integrity
and confidentiality of data collected in the course of clinical research, and
protect the privacy, as well as safety, of human subjects. Attention should
be paid to appropriate storage and retention of research records, data, and
samples, in accordance with NIH and FDA guidelines. Investigators are
responsible for the oversight of all research personnel involved in the clin-
ical study, ensuring that they adhere to the research protocol and Good
Clinical Practice.1
Intramural investigators who receive human samples or data from ex-
tramural investigators are responsible for ensuring that they were col-
lected in accordance with ethical guidelines and regulatory requirements.
This is usually satisfied by a clinical research protocol and consent docu-
ment approved by an IRB at the extramural institution, but sometimes
may require a parallel clinical research protocol at the NIH. Similar pro-
tections are required prior to sending personally identifiable human sam-
ples or data to extramural collaborators. The IC IRB and OHSR should
be consulted prior to any transfer to determine the appropriate review
and approval mechanisms. Specific regulations govern the use of archival
materials (http://ohsr.od.nih.gov/info/DDIR_memo.html).
Registration of Clinical Trials: Clinical trials (i.e., studies evaluating the
safety or efficacy of a diagnostic test or treatment intervention) should be
registered with a public trials registry (e.g., www.clinicaltrials.gov).
1
Guidelines for Good Clinical Practice, developed by the International Confer-
ence on Harmonization of Technical Requirements for Registration of Pharma-
ceuticals for Human Use (ICH) can be accessed at www.ICH.org.
Epidemiologic Research: Epidemiologic research, the study of the distri-

bution and determinants of disease in groups of individuals, presents spe-
cial challenges for investigators. Although epidemiologists are not usually
responsible for clinical care, they must nevertheless ensure that epidemio-
logic investigations do not interfere with the clinical care or privacy of
patients. The epidemiologist must ensure that abnormal findings that
could affect a subject’s health and require medical attention are dealt with
appropriately. Data on diseases, habits, and behavior must be presented
and published in a way that protects the identity of particular individuals,
families, and groups.
Although it is the practice of some journals not to publish research find-
ings that have been partially released to the public, it may be necessary for
reasons of immediate public health considerations to report the findings of
epidemiologic research to the study participants, institutional leadership,
other researchers, and, in some cases, health officials, before the study has
been completed. The health and safety of the public has precedence.
Development and review of detailed protocols are as important in epi-
demiologic research as in clinical research and any other health science.
However, the time for protocol development and review may be appropri-
ately shortened in circumstances such as the investigation of an acute epi-
demic or toxicological danger where the epidemiologic investigation may
provide data of crucial importance to the identification and mitigation of a
threat to public health. Nevertheless, even in these situations, systematic
planning is necessary and the investigator should formalize the study de-
sign in a written document and have it peer-reviewed in an expedited man-
ner before the research is begun.
Animal care and use

The use of laboratory animals is often essential in biomedical research and
humane and effective use of animals is a necessary and important element
of such research activities. Animal research, for the purposes of these
Guidelines, is defined as in vivo research performed on laboratory animals
in order to develop knowledge that contributes to improvement of health
and well-being of humans as well as other animals. The NIH Office of
Animal Care and Use (OACU) (http://oacu.od.nih.gov/) has developed
NIH Policy Manuals for Animal Care and Use in the Intramural Program
to assist NIH intramural investigators to understand and comply with the
ethical guidelines and regulatory requirements for testing, research or
training involving laboratory animal subjects. The use of animals in re-
search is covered by protocols that must be reviewed and approved by an
NIH Animal Care and Use Committee (ACUC). Investigators conducting
animal research must take the NIH course “Using Animals in Intramural
Research”.
442 Appendix III
The animal care and use program of each IC is directed by a senior

veterinarian, the Animal Program Director, and falls under the oversight
of an ACUC. All components of the intramural NIH Animal Care and Use
program are accredited by the Association for Assessment and Accredita-
tion of Laboratory Animal Care International.
Prior to commencing animal studies, an animal study protocol must be
prepared according to existing guidelines. Investigators should contact the
IC ACUC for guidance on the requirements for approval and implementa-
tion of animal study protocols. When developing research proposals in-
volving animals, investigators should consider alternatives to the use of
animals based upon the following guidance:
• Reduction: Reduction in the numbers of animals used to obtain in-
formation of a certain amount and precision;
• Refinement: Decrease in the incidence or severity of pain and dis-
tress in those animals that are used;
• Replacement: Use of other materials, such as cell lines or eggs, or
substitution of a lower species, which might be less sensitive to pain
and distress, for a higher species.
The animal research protocol should be circulated for comment and review
by the investigators and collaborators involved in the project, and requires
approval by the IC ACUC prior to study initiation. It should be scrupu-
lously adhered to in the conduct of the research, which should be carried
out by appropriately qualified investigators and staff who are experienced in
conducting procedures on living animals.
Research misconduct
The scientific community and general public rightly expect adherence to
exemplary standards of intellectual honesty in the formulation, conduct,
reporting and reviewing of scientific research. Investigators must act with
honesty and integrity when editing, analyzing, and presenting data. De-
ceptive manipulation of data, be it misrecording of data, inappropriate ex-
clusion of outlying data points, or enhancement of images is research
misconduct.
Allegations of scientific misconduct are taken seriously by the National
Institutes of Health. The process of investigating allegations must be bal-
anced by equal concern for protecting the integrity of research as well as the
careers and reputations of researchers. The procedures followed at the NIH
are intended to permit allegations of scientific misconduct to be processed
promptly, confidentially, and fairly. Prompt action on an allegation helps
minimize any harm to the public that could result if misconduct is found
that has potential impact on health, and allows those who are incorrectly
implicated to have their names cleared without going through a lengthy
process. Allegations of misconduct that are shown to be untrue, even if they

were made in good faith, can damage careers and have a chilling effect on
research. Confidentiality helps protect both the innocent scientists who are
incorrectly or unjustly accused and those who raise the allegations. Fairness
allows all who become involved in scientific misconduct cases to have the
opportunity to participate appropriately in this important oversight process
and address the specific issues at hand, while at the same time protecting
innocent participants from adverse consequences.
Scientific misconduct or misconduct in research—Research mis-
conduct is defined as fabrication, falsification, or plagiarism in proposing,
performing, or reviewing research, or in reporting research results.
Fabrication is making up data or results and recording or reporting
them.
Falsification is manipulating research materials, equipment, or pro-
cesses, or changing or omitting data or results such that the research is not
accurately represented in the research record.
Plagiarism is the appropriation of another person’s ideas, processes, re-
sults, or words without giving appropriate credit.
Research misconduct does not include honest error or honest differ-
ence of opinion.
(from Federal Policy on Research Misconduct <http://www.ori.dhhs

.gov/documents/42_cfr_parts_50_and_93_2005.pdf>)
Concluding statement
These Guidelines are not intended to establish rules or regulations. Rather,
their purpose is to provide a framework for the fair, open, and responsible
conduct of research without inhibiting scientific freedom or creativity.
Advice on any of the topics can be obtained from the offices cited in the
previous sections. You can consult with members of the NIH Committee
on Scientific Conduct and Ethics (http://www1.od.nih.gov/oir/source
book/comm-adv/sci-conduct.htm), with your Scientific Director or with
your IC Training Director. Advice is also available from the NIH Office of
the Ombudsman (http://www4.od.nih.gov/ccr/).
appendix IV
Sample Protocols for Human and

Animal Experimentation
A s discussed in chapters 5 and 6, United States federal law governs the

use of humans and certain animal species in research. To fulfill com-
pliance requirements, the investigator prepares a written description of the
research, commonly referred to as a protocol. Such protocols are reviewed
and, if legally and ethically appropriate, approved by mandated institu-
tional committees. Human subjects research is reviewed by the institu-
tional review board (IRB), while animal subjects research is reviewed by
the Institutional Animal Use and Care Committee (IACUC).
There are exceptions to this process where full protocol preparation
and review are not required. The disposition of such cases is typically de-
pendent on institutional policy. In the case of human subjects experimen-
tation, an example of an exception would be research that falls under any
of the exempt categories defined by federal law. An example involving ani-
mal experimentation would be research involving invertebrate species. Re-
gardless of institutional policies, it is advisable for investigators to formally
communicate with either the IRB or the IACUC or a member of the sub-
jects protection program office to confirm they are meeting any compli-
ance requirements in such cases.
This appendix contains material that has been adapted from a human
subjects and an animal subjects protocol. It aims to provide the reader with
the detail and content of such protocols. Additional information and re-
sources to assist the reader in honing skills related to protocol develop-
ment are also included.
doi:10.1128/9781555818487.AppIV
445
446 Appendix IV
This appendix has four parts:
1. Abridged human subjects protocol. An abridged version of a protocol in-

volving human subjects, condensed from an actual protocol document, is
presented. The material has been modified to facilitate reading. Deletions of
material are noted in italics, and protocol appendix material has also been
removed. But the modifications do not affect the reader’s ability to capture
the scope and detail that must be presented in a human subjects protocol.
Modifications have also been made to render the protocol anonymous. For
a quick appreciation of the research described in the protocol, you are urged
to first read the informed consent document. This will give you an overview
of the work in terms designed to be understood by someone who might be
considering volunteering for the study. In short, the research will evaluate
the effect of using an antiseptic mouthwash to prevent pneumonia in pa-
tients who have tubes inserted in their airways to assist them with breathing.
This procedure is called mechanical ventilation. Patients who receive me-
chanical ventilation treatment have a significant risk of developing pneumo-
nia, and a common origin of such infections is bacteria that reside normally
in the oral cavity. The antiseptic mouthwash will be applied regularly by
swabbing the oral cavity. Such antimicrobial intervention will be evaluated
in terms of reducing the incidence of bacterial pneumonia in patients using
breathing tubes. The proposal has some special features including a request
to use, as needed, a waiver of prospective written consent. The investigators
also request to waive the requirement to obtain assent from decisionally im-
paired subjects. The study will also form and use a data and safety monitor-
ing board (DSMB). The DSMB will function as an independent group to
monitor all aspects of the study, including the occurrence of unexpected ad-
verse events. The findings of the DSMB will be reported to both the IRB
and the study sponsor, the National Institutes of Health (NIH), on a regular
basis. The DSMB is empowered to determine or to recommend that the
study be stopped for reasons of safety.
2.
Informed consent document. The full text of the informed consent doc-
ument for the above human subjects protocol is included, providing an
example of the required scope and level of presentation.
3. Animal-use protocol. The abridged text of an actual animal-use proto-

col is presented to illustrate the detail of preparation for such documents.
The study described in this protocol aims to identify cellular targets in
certain bacteria that could be used to create vaccines to prevent heart valve
infections (endocarditis) caused by such bacteria. It blends the use of mo-
lecular genetics to create modified bacteria with the testing of the resultant
modified strains in animal models of heart valve disease. New knowledge
Sample Protocols for Human and Animal Experimentation 447
gained in this work is expected to lead to the creation of vaccines that

could prevent endocarditis in humans. The protocol is robust and involves
the use of both rabbits and rats. Animals will experience pain consistent
with USDA category D: pain or distress appropriately relieved with anes-
thetics, analgesics, and/or tranquilizer drugs or other methods for reliev-
ing pain or distress. Also addressed in the protocol is the study’s use of
recombinant DNA and biohazardous agents.
4.
Resources. This appendix material will help you appreciate the con-
text and content of illustrative subjects protection protocols. To write a
protocol that will serve you and your research subjects well will take addi-
tional study, mentoring, and practice. The “Resources” section below of-
fers some advice, additional protocol content requirements, and an
electronic portal to resources.
1. Abridged Human Subjects Protocol

Title: Infection Control in Mechanically Ventilated Adults
Staffing
Note: This section of the protocol contains a table listing the principal investigator (PI) and all coinvestigators involved in
the study, their qualifications, and their responsibilities. This information has been omitted to preserve anonymity, but the
following narrative from the protocol describes investigator participation and training.
A Project Director and the Graduate Research Assistants (GRAs) will be hired when funding is obtained. All personnel will
complete required institutional Human Subjects training. A comprehensive study training manual will be developed and
distributed to all study personnel. The training manual will include a study overview and all data collection procedures
and will be updated as needed. Prior to data collection, all study personnel will be trained to perform tasks appropriate to
their role in the project. The Project Director will be trained by the PI and co-investigators in all study procedures includ-
ing subject recruitment, obtaining consent consistent with applicable state and federal statutes, all interventions and
data collection procedures. Role specific training will include intervention procedures, blood and endotracheal secretion
sample collection, and use of PDAs for data collection for all personnel.The GRA who will provide pre-intubation interven-
tions will be trained in the procedure by the Project Director. After training is complete, each GRA will perform a return
demonstration on a dental mannequin model satisfactorily completing all critical elements identified (100% accuracy)
before interventions will begin. Each GRA will also be tested every 3 months throughout the study period to ensure that all
critical elements of each procedure are included. Monthly study meetings will be used to review study procedures and
communicate essential information; time sensitive information regarding study operations will be communicated by
called study team meetings and by e-mail.
None of the investigators will benefit from subjects’ participation in this project or completion of the project in general.
Resources
A research proposal has been submitted to the National Institutes of Health to support the conduct of this project. Budget
items include personnel costs for investigators and support staff (including support of release time for investigators),
supplies, laboratory equipment, and chlorhexidine (CHX) mouthwash (dispensed for a fee from the Investigational Phar-
macy) for all subjects. Subjects will be recruited at University Medical Center. Medical Center Clinical Laboratories will
be used for processing of clinical microbiological specimens. The institutional Clinical Research Core will be used for
analysis of biomarkers and for data management.
448 Appendix IV
Hypothesis
Pneumonia is the second most common nosocomial infection in the US,1 and the leading cause of death from all nosoco-
mial infections, with mortality rates of 20-75%.1;2 Nosocomial pneumonia adds billions of dollars to health care costs,
prolongs mechanical ventilation time, increases ICU length of stay, and adds significantly to the hospital stay of surviving
patients.2-5 Ventilator-associated pneumonia (VAP) occurs in 25-30% of mechanically ventilated patients and is respon-
sible for 90% of nosocomial infections in this patient population.6;7 The risk is greatest in the first week of mechanical
ventilation, and this risk increases by as much as 3% per ventilator day in the first five days.8
Growth of potentially pathogenic bacteria in the oral cavity provides a nidus of infection for microorganisms that have
been shown to be responsible for VAP.9;10 The endotracheal tube provides a pathway for direct entry of bacteria from the
oropharynx through an open glottis to the lower respiratory tract. Once in place, the endotracheal tube promotes micro-
bial colonization by interfering with the cough reflex and the function of the mucociliary escalator and by stimulating ex-
cessive mucus secretion.5
We showed that VAP was reduced by topical application of CHX in our previous NIH-funded study. This randomized
clinical trial tested application of CHX initiated after intubation (within 24 to 48 hours) in critically ill adults. CHX is a broad
spectrum antibacterial agent that is FDA approved for control of dental plaque. Although recent research11-12 achieved a
reduction in VAP by topical oral CHX after intubation, these post-intubation interventions did not completely eliminate risk
of VAP.
Other procedures in which a tube is passed through a contaminated area into a sterile area (for example, insertion of
vascular lines, urinary tract catheters, and chest tubes) include cleaning the area prior to tube insertion to reduce
procedure-associated contamination. During the intubation procedure, organisms may be dragged by the tube from the
contaminated oropharynx to the sterile lung. Organisms introduced into the lung at the time of intubation would not be
suppressed by CHX applied after intubation, and may contribute to cases of VAP found in patients who receive therapies
only after intubation. Therefore, reducing the number of microorganisms in the mouth pre-intubation by application of
CHX, added to continual microbial suppression by CHX applied after intubation, is a theoretically attractive method to re-
duce the risk of VAP and is a logical extension of the previous study.
Little is known about the effects of pre-intubation CHX in mechanically ventilated critically ill patients. Definitive scien-
tific studies evaluating the addition of pre-intubation CHX in the general ICU population have not been conducted. Thus,
this proposal focuses on evaluating the benefit of adding a pre-intubation CHX dose to the known benefit of post-
intubation CHX to reduce the risk of VAP.
Specific Aims
This project is a continuation of our previously funded study, conducted under IRB #6789. The primary aim of this study is
to test the effect of a pre-intubation oral application of CHX on the development of VAP in a variety of mechanically venti-
lated, critically ill adults. We hypothesize that the intervention group (who receive a pre-intubation oral application of
CHX) will have lower scores on the Clinical Pulmonary Infection Score (CPIS) than the control group (who do not receive
pre-intubation intervention). Secondary aims are 1) to test the effect of a pre-intubation oral application of CHX on early
endotracheal tube colonization in mechanically ventilated adults, and 2) to explore potential biomarkers, including pro-
calcitonin and a panel of cytokines, of VAP development and resolution. We hypothesize that, for subjects extubated
within 24 hours of intubation, the intervention group will have fewer bacteria present on cultures of endotracheal tubes
removed at 24 hours. We further hypothesize that patterns of procalcitonin and serum cytokines will be associated with
the development and resolution of VAP.
Background and Significance

VAP is a significant clinical problem that occurs in an estimated 20% of mechanically ventilated patients4 and is the most
common nosocomial infection in patients requiring mechanical ventilation.1 There is evidence that CHX applied after in-
tubation in a variety of ICU populations reduces the development of VAP, and there is evidence that CHX initiated prior to
intubation and continued throughout the hospital stay is effective in reducing nosocomial infections (including surgical
and respiratory tract infections) in elective cardiac surgery patients. In studies of elective cardiac surgery adults, CHX
was self-administered for several doses prior to intubation for anesthesia. However, the effect of pre-intubation applica-
tion of CHX on the development of VAP in the larger population of mechanically ventilated critically ill adults has not been
tested. The initiation of CHX prior to intubation that will be tested in this project may further reduce the incidence of VAP
compared to post-intubation application alone. This study will be the first randomized clinical trial of a pre-intubation in-
tervention to reduce VAP in a variety of mechanically ventilated critically ill patients, and involves a single pre-intubation
intervention which is more feasible for most ICU patients than the self-administration of CHX shown to be effective in
elective cardiac surgery.
Microorganisms in the mouth are available for translocation to and colonization of the lung, which can result in
VAP.9;13-17 Oral organisms are concentrated in dental plaque, which is a complex environmental niche of interdependent
microorganisms embedded in bacterial and salivary products. Dental plaque may serve as a reservoir for pathogens in
patients with poor oral hygiene,14;18 and dental plaque of persons in the ICU has been shown to be colonized by potential
respiratory pathogens such as methicillin-resistant S. aureus and P. aeruginosa.10 Fourrier et al.9 found a high bacterial
concordance between dental plaque cultures and tracheal aspirate cultures in 57 ICU adult subjects. In 4 cases of VAP,
the causative organism of the pneumonia was isolated from the subject’s dental plaque prior to the diagnosis of pneumo-
nia. The dorsal tongue may also be a reservoir for potential VAP pathogens. Bahrani-Mougeot et al. compared bacteria
from the dorsal tongue and BAL in 16 trauma ICU subjects who had VAP.17 Using bacterial DNA sequencing, they found
that 14 subjects had potential pathogens colonizing the lung which were identical to those found in the subject’s oral
cavity.
Previous work demonstrated the relationship of oral health to VAP. In a descriptive study,16 it was demonstrated that
higher dental plaque scores conferred greater risk for ventilator-associated pneumonia, particularly for patients with
greater severity of illness. Oral health and CPIS were followed in 66 critically ill mechanically ventilated subjects for up to
7 days; a regression model was used to predict risk of pneumonia at day 4. Correlations were significant with day 4 CPIS
for score on the Acute Physiology and Chronic Health Evaluation (APACHE) II (P=.007), day 4 salivary volume (P=.02), in-
teraction of APACHE II score and day 1 CPIS (P<.001), and the interaction of day 1 CPIS and plaque (P=.01). Dental plaque
and oral organisms increased over time, and potential pathogens were identified in oral cultures for 6 patients before or
at the same time as the appearance of the organisms in tracheal aspirates.
The studies discussed above support the hypothesis that oropharyngeal organisms can serve as a reservoir for poten-
tial VAP pathogens.15;16 Because the endotracheal tube must pass through the microbially rich oral cavity and intubation
is usually performed without prior cleansing of the mouth, there is great opportunity for organisms to be introduced onto
the endotracheal tube and/or into the lung at the time of intubation. Thus, reducing the number of microorganisms in the
mouth pre-intubation by application of CHX, added to continual microbial suppression by CHX applied after intubation, is
a theoretically attractive method to reduce the risk of VAP, and underpins the primary aim of this study, which is to test the
effect of a pre-intubation oral application of CHX on the development of VAP in a variety of mechanically ventilated, criti-
cally ill adults.
Colonization of the endotracheal tube in mechanically ventilated adults is common and although it generally precedes
VAP, not all patients with colonization of the endotracheal tube develop VAP. However, the endotracheal tube can serve
as a reservoir for potential VAP pathogens. Cardenosa-Cendrero et al.19 found that 80 of 110 patients had tracheal coloni-
zation during the first day of mechanical ventilation. A pre-intubation application of CHX will likely have its greatest effect
on the incidence of early colonization and early VAP.
Adair et al. conducted microbiological examination of endotracheal tube aspirates in 40 mechanically ventilated sub-
jects (20 with VAP) and endotracheal tubes following extubation in the same subjects.20 Seventy per cent of patients with
VAP had identical pathogens (by genotyping) isolated from both ET tubes and endotracheal secretions. In adults under-
going elective intubation, Ogata et al.21 studied the effect of pre-intubation gargling with povidone-iodine on early coloni-
zation (during anesthesia) of the endotracheal tube. In the control group who gargled with water pre-intubation (n=19),
every subject’s endotracheal tube had organisms that matched pre-intubation oropharyngeal organisms. No organisms
were recovered from endotracheal tubes of subjects who gargled with povidone-iodine pre-intubation, although oropha-
ryngeal cultures were positive. These studies provide theoretical support for the proposed pre-intubation CHX interven-
tion, and our microbiological examination of endotracheal tubes removed in the first 24 hours (Secondary aim 2) will
provide an indication of the effectiveness of pre-intubation CHX in reducing early contamination of the endotracheal tube
in critically ill adults.
Interventions to reduce VAP through reducing the number of oral organisms have been reported recently. Several
studies have demonstrated that application of antimicrobials to the oral cavity following intubation reduces development
of VAP.22-26 The association between oral microbial flora and VAP is well documented, but no studies have compared pre-
intubation methods to reduce oral colonization in mechanically ventilated patients to treatment beginning after intubation
for removal of microorganisms or reduction of VAP.
The most recent (2004) Centers for Disease Control and Prevention (CDC) recommendations for prevention of nosoco-
mial bacterial pneumonia in patients receiving mechanically-assisted ventilation specifically address the importance of
oral microbial flora in the development of VAP.1 Recommendations for elective cardiac surgery patients direct the use of
CHX during the peri-operative period, based upon studies in which subjects began using CHX prior to hospital admission
450 Appendix IV
for elective cardiac surgery and CHX use was continued throughout the hospital stay.27-29 However, for other critically ill
patients the recommendations are much more general, and evidence available when the guidelines were updated was
insufficient to recommend CHX in the general ICU population. Since publication of the guidelines, we and others have
demonstrated reduction in VAP from post-intubation CHX, but the benefit of beginning CHX prior to intubation has not
been tested outside of elective cardiac surgery and the differential benefit of addition of pre-intubation CHX to post-
intervention application has not been tested in any population.
CHX is a broad spectrum antibacterial agent that has been used extensively in healthy populations as an oral rinse to
control plaque and to prevent and treat gingivitis.30;31 Microbial resistance to CHX has never been demonstrated, and it
has minimal side effects, making it an attractive alternative to the oral topical antibiotics used in the studies discussed
above.
Three investigative teams27-29 have examined the effectiveness of oral CHX in reducing nosocomial respiratory tract in-
fections in elective cardiac surgery patients. Importantly, in each of these studies the intervention was begun preopera-
tively (before intubation) and continued throughout the ICU stay. DeRiso et al.27 conducted a double- blinded,
placebo-controlled study of CHX in elective cardiac surgery subjects. In this study, subjects were randomly assigned to
receive CHX or placebo by oral rinse. Results demonstrated reductions in respiratory tract infection rates in cardiac sur-
gery subjects who received CHX pre-intubation as well as postoperatively (17/180 vs 5/173; p < 0.05). However, cardiac
surgery patients who present for elective surgery are likely to present with different comorbidities and better physiologic
status at the time of intubation than emergently intubated patients. This is reflected in the relatively low incidence of respi-
ratory tract infections (9%) noted in DeRiso et al.’s placebo group. The DeRiso study did not focus exclusively on VAP, but
used a broad definition of respiratory tract infection which included both tracheobronchitis and pneumonia. Houston and
coworkers28 conducted a randomized controlled trial examining the effect of CHX, begun before hospital admission and
continued throughout the hospital stay, on the incidence of postoperative infection (including surgical and respiratory tract
infections) in elective cardiac surgery patients. Recently, Segers et al.29 investigated the effect of 0.12% CHX on nosoco-
mial infections (including surgical and respiratory tract infections) in a randomized controlled trial of 954 elective cardiac
surgery patients. They also found a lower rate of postoperative infection in the CHX group than in the placebo group (9.3 vs.
15.8%; p = 0.002). The three studies discussed above focused broadly on nosocomial infection rather than on VAP. Although
all three studies demonstrated reductions in nosocomial infection rates in cardiac surgery subjects who received CHX pre-
intubation as well as postoperatively, no study has examined the effects of pre-intubation CHX in reducing VAP in other
critically ill populations, and none have examined whether pre-intubation intervention provides added benefit compared to
initiation of CHX after intubation. However, many patients undergoing intubation are not able to anticipate the event as
elective cardiac surgery patients do, and thus cannot self-administer multiple doses of CHX prior to intubation. It is feasible
to deliver a single pre-intervention dose prior to intubation, and if effective, the pre-intubation CHX could be broadly appli-
cable to a variety of ICU patients.
Recently, CHX has been investigated in other ICU populations as well. Koeman, et al.12 randomized subjects to control
or to oral topical application of either 2% CHX or 2% CHX with colistin. Both CHX groups had reduced daily risk of VAP
compared to control subjects (CHX vs control, p = 0.012; CHX + colistin, p=0.03).12 It should be noted that the concentration
of CHX used by Koeman et al. is higher than the FDA approved dental solution of 0.12% used in other reported studies. A
randomized controlled trial of 0.2% CHX versus placebo in 228 ICU patients by Fourrier, et al.32 failed to show an effect of
CHX on VAP rate, with reported VAP rates of 11% in each group. Our previous study demonstrated that CHX 0.12% solu-
tion applied topically to the oral cavity significantly reduced the incidence of pneumonia (defined by CPIS ≥ 6) among
subjects who were without pneumonia at baseline (p=0.0243). Reported studies conducted outside of the elective cardiac
surgery setting have not examined the effect of applying CHX prior to intubation, as we propose to do in this renewal
application.
Studies of VAP are complicated by the absence of a “gold standard” for diagnosis which can be scored prospec-
tively and at repeated intervals. Determination of VAP has been conducted using 2 broad categories of methods: micro-
biologic analysis of samples from the lung to demonstrate an etiologic agent, and clinical scoring tools to evaluate
clinical features indicating VAP. The optimal method for identification of VAP remains controversial, and is complicated
by the different needs of researchers (for robust research variables) and clinicians (for prompt patient treatment). There
has been considerable interest in identifying reliable and valid biomarkers that might precede clinical signs of VAP.33
Recent interest has centered on procalcitonin (PCT) and proinflammatory cytokines. Changes in PCT and cytokines are
early markers of immune activation, and activation of the immune system characterizes infections including VAP. The
performance of individual cytokines as indicators of VAP has been disappointing thus far, and PCT has been examined
in the context of VAP primarily as a prognostic indicator. However, no published studies have evaluated multiple cyto-
kines simultaneously with PCT at frequent intervals (i.e., daily) in an effort to understand immune system interactions in
the development of VAP. Thus, in this project, we will evaluate the usefulness for future research of PCT and a panel of
cytokines daily in a subset of subjects (the first 100 subjects enrolled who remain intubated beyond 24 hours) as bio-
markers of the development of VAP. The proposed work will add to the body of knowledge regarding immune response
in VAP, and holds promise for improving accuracy of VAP outcome definitions for future research.
Preliminary Progress/Data Report

Our previous research project used a randomized controlled 2×2 factorial experimental design to test the ability of de-
fined oral care interventions (toothbrushing and CHX) to reduce bacterial colonization in mechanically ventilated criti-
cally ill adults, thereby reducing the risk of developing VAP. All intubated patients in medical, surgical/trauma, and
neuroscience ICUs at the university health system were screened for inclusion (n = 4,603). Exclusion criteria were: in-
tubated more than 24 hours, edentulous, or had a clinical diagnosis of pneumonia at the time of intubation. Consent for
participation in the research study was obtained prospectively from the subject’s legally authorized representative
(LAR) for 547 subjects who met study criteria. Subjects were randomly assigned to 1 of 4 groups: 0.12% solution CHX
gluconate 5 ml by oral swab twice daily, toothbrushing protocol three times a day, combination (both toothbrushing and
CHX), or control (usual care). CHX and toothbrushing interventions were provided by study personnel. VAP was scored
using the Clinical Pulmonary Infection Score (CPIS). Subjects remained in the study for a maximum of 7 days, unless
extubated. 249 subjects remained in the study for Day 3 analysis, with 209 subjects having complete day 3 CPIS data.
Subjects were 61% male and 58% non-white. Mean age was 47.9 years ±17.4; mean APACHE III (severity of illness)
score was 77 ±25.6. There were no significant differences for clinical characteristics among groups. 24% of subjects
without pneumonia at baseline developed pneumonia (CPIS ≥ 6) by day 3. We identified two subsets of subjects based
upon initial CPIS score on admission to the study: 1) subjects without pneumonia at baseline (i.e., did not meet the re-
search definition of pneumonia of CPIS score < 6 on day 1), and 2) subjects with pneumonia at baseline (i.e., did meet
the research definition of pneumonia CPIS ≥ 6 on day 1 even though they had not received a clinical diagnosis of pneu-
monia). CHX significantly reduced the incidence of pneumonia (CPIS ≥ 6) among the subset of subjects who were
without pneumonia at baseline (p=0.0243). Toothbrushing had no effect on CPIS. When subjects with pneumonia (CPIS
≥6) and without pneumonia (CPIS < 6) at baseline were analyzed together, mixed models analysis found no effect of
either CHX (p=0.6903) or toothbrushing (p=0.9526). We concluded that CHX oral swabbing was effective in reducing
early VAP in subjects without pneumonia at baseline. Our data did not demonstrate any VAP reduction benefit from
toothbrushing.
In a companion study, presently underway and funded by the Department of Defense, the study team is also evaluating
the effect of a single post-intubation oral application of 5 ml CHX 0.12% solution on oral microbial flora and the develop-
ment of VAP in traumatic injury. This randomized, controlled, clinical trial includes the administration of CHX within 12
hours after endotracheal intubation in 200 trauma victims. The results will provide additional information about post-
intubation interventions to reduce VAP, but will not address the effect of pre-intubation therapy.
Our previous work determined that application of CHX beginning after intubation reduced the risk of VAP, while a de-
fined toothbrushing protocol did not. The preliminary work described above points to a pre-intubation intervention as the
next logical step in development of this line of research. The extensive experience of the research team in oral health and
VAP provides an excellent foundation for the proposed work. This proposal focuses on evaluating the benefit of adding a
pre-intubation CHX dose to the known benefit of post-intubation CHX to reduce the risk of VAP. In addition, we will exam-
ine the effect of pre-intubation administration of CHX on endotracheal tube colonization in the first 24 hours of intubation,
and explore potential biomarkers of VAP in an effort to improve measures of VAP outcomes for future work.
Research Method and Design

Research design
The primary aim of this study is to test the effect of a pre-intubation oral application of CHX on the development of VAP in
a variety of mechanically ventilated, critically ill adults. Secondary aims are to 1) test the effect of a pre-intubation oral
application of CHX on endotracheal tube colonization in mechanically ventilated adults, and 2) explore potential biomark-
ers of VAP development and resolution.
The specific aims will be accomplished using a prospective, randomized, experimental design. Each subject will be
randomly assigned to one of two conditions:
1) Intervention: Oral application of 5 ml CHX gluconate 0.12% solution pre-intubation, and 5 ml CHX gluconate 0.12%
solution twice a day following intubation.
2) Control: No pre-intubation intervention, 5 ml CHX gluconate 0.12% solution twice a day following intubation.
452 Appendix IV
Subjects will be enrolled in the study prior to intubation. Subjects will remain in the study for five days or until extuba-
tion if extubated before five days. The length of participation for subjects was chosen based on increased risk of develop-
ment of VAP in the early part of ICU hospitalizations, and the theoretical consideration that the intervention is most likely
to reduce initial risk of early VAP.
Setting
The study will be conducted in four adult critical care units at the University Medical Center: the Medical Respiratory In-
tensive Care Unit (MRICU), the Surgical/Trauma Intensive Care Unit (STICU), Cardiac Surgery Intensive Care Unit (CSICU)
and the Neuroscience Intensive Care Unit (NSICU).
Sample
The sample of 200 subjects will be drawn from all patients over the age of 18 years admitted to the MRICU, STICU, CSICU
and NSICU at the University Medical Center who are being intubated and mechanically ventilated. Both male and female
subjects from all ethnic and racial backgrounds will be recruited. Subjects will be randomized to treatment according to
a permuted block design developed by the biostatistician such that after every k subjects balance will be maintained be-
tween the groups. To preserve the benefits of randomization, the value of k was determined by the study biostatistician
when the randomization tables were prepared.
Exclusion Criteria. The exclusion criteria will be clinical diagnosis of pneumonia at the time of intubation. Those who
have a diagnosis of pneumonia at the time of intubation will be excluded because a new episode of superimposed VAP
cannot be distinguished with certainty from worsening of the patient’s initial community acquired or nosocomial
pneumonia.
Power Analysis. Sample size required for statistical power was calculated based on detecting a difference in CPIS
scores of 1 between the two groups (Intervention and Control) using the data from the study described in the background
section . The common standard deviation from a two group ANCOVA model of the CPIS was estimated to be 2.2. Thus, for
a significance level of 5%, a sample size of 77 in each group (154 total) will have an 80% power and a sample size of 103 in
each group (206 total) will have a 90% power. Clearly, the planned sample of 100 for each group (200 total) will be suffi-
cient. Based upon attrition (primarily due to extubation) data in the previous study, we will plan to enroll 325 subjects in
order to assure a final analysis sample of 200 subjects who remain in the study for at least 48 hours and have outcome
data for analysis of the primary aim. Data from subjects who are enrolled but do not remain intubated until day 2 will be
used for analysis of secondary aim 1.
Oral care interventions

Subjects will be assigned to one of two study groups, intervention (oral application of 5 ml CHX gluconate 0.12% solution
pre-intubation, and 5 ml CHX gluconate 0.12% solution twice a day following intubation) or control (no pre-intubation in-
tervention, 5 ml CHX gluconate 0.12% solution twice a day following intubation) which differ in whether or not pre-
intubation oral intervention occurs. Subjects will remain in the study until extubated or up to a total of five days following
intubation. Pre-intubation interventions will be performed by study personnel in order to assure treatment integrity.
Pre-Intubation Intervention. The pre-intubation intervention involves administration of 5 ml CHX gluconate 0.12% solu-
tion. CHX has bacteriocidal properties against both gram positive and gram negative species.34 It is not absorbed through
skin or mucous membranes, so dosage adjustments are not necessary for renal or hepatic insufficiency. CHX adminis-
tered by oral swab or rinse has not been associated with serious side effects.35-37 Reported side effects include discolor-
ation of the teeth and tongue, and transient alterations in taste (dulling of taste sensation for several hours). Discoloration
of the teeth occurs in about 50% of patients with long term administration and is similar to tooth staining seen after
smoking and consumption of tannic acids such as tea, coffee, and wine. CHX discoloration is easily removed by profes-
sional dental hygiene.
In healthy populations, CHX is self-administered as a 0.12% solution oral rinse. The dosage is 15 ml administered twice
daily as a gargle. Although CHX is used primarily as a mouthwash or rinse, it has also been used by swab and found to be
equally effective.35;38 In this study, it is not possible to have subjects rinse with the solution; instead, a 5 ml volume will be
swabbed over the entire oropharynx. The optimal amount of CHX 0.12% required to cover all tooth surfaces was determined
using a full mouth model in a laboratory setting and in human volunteers. This swabbing procedure was effectively used in
the previous study, and was optimized in our pilot studies of a single peri-intubation intervention.39 The 0.12% strength solu-
tion is FDA approved for use as an oral rinse in the United States. Dr. Bond will serve as the medical monitor for the study.
Table 1 Key study variables

Enrollment (day 0) Day 1 Day 2 Day 3 Day 4 Day 5
Intervention group (5 ml CHX CHX bid CHX bid CHX bid CHX bid
CHX 0.12% pre-intubation pre-intubation
and bid post-intubation)
Admission data CPIS CPIS CPIS CPIS CPIS
CPIS Serum Serum Serum Serum Serum
Serum biomarkers biomarkers biomarkers biomarkers biomarkers
biomarkers ET tube culture if
extubated
Control group (5 ml CHX CHX bid CHX bid CHX bid CHX bid
0.12% bid post-intubation)
Admission data CPIS CPIS CPIS CPIS CPIS
CPIS Serum Serum Serum Serum Serum
Serum biomarkers biomarkers biomarkers biomarkers biomarkers biomarkers
ET tube culture if
extubated
Key variables and their measurement

Data on key variables will be collected on admission to the study and every day throughout study participation up to day
5. Key study variables, their measurement, and the data collection schedule are shown in Table 1.
Development of VAP. A graded clinical tool will be used in this proposed renewal to measure the development of VAP.
The Clinical Pulmonary Infection Score (CPIS) developed by Pugin et al.40 and used in our previous study is based on six
easily obtained variables: temperature, WBC count, tracheal secretions, oxygenation (calculated by PaO2 /FiO2), chest
radiograph (interpreted by Dr. Bond, co-investigator), and tracheal aspirate culture. The CPIS will be scored based on the
developers’ procedure.
Endotracheal Tube Microbial Flora. Endotracheal tubes removed from study subjects in the first 24 hours of the study
will be placed in broth culture and microbial species and a quantitative count of colony forming units for each species will
be determined. Because in the previous study, 24% of subjects were extubated within 24 hours of study enrollment, we
anticipate that 78 tubes will be obtained for examination. Examination of tubes removed in the first 24 hours of intubation
will illuminate the relationship between CHX administered prior to intubation and colonization of the endotracheal tube
(as reflected by microbial growth in the first 24 hours of intubation). Microbiological examination of endotracheal tubes
from subjects intubated for longer than 24 hours is more likely to be confounded by the ongoing administration of CHX in
all subjects, and would reduce the likelihood that we will be able to see a difference in early colonization due to the pre-
intubation portion of the intervention. Standard protocols were developed for the previous study by the Clinical Research
Core for specimen acceptance, handling, and processing to ensure accuracy and reproducibility of results.
Biomarkers. Serum will be collected daily from every subject, and stored at –70C in the Clinical Research Core until
samples have been collected from the first 100 subjects who have remained intubated beyond 24 hours. Biomarkers will
be assessed in thawed daily samples from the first 100 subjects enrolled who remain intubated beyond 24 hours. PCT will
be assayed from serum using a Lumat LB 9507 tube luminometer assay (Brahms AG, Hennigsdorf, Germany), according to
the assay manufacturer’s protocol. This commercially available assay has been used successfully in research involving
critically ill subjects. Levels of cytokines in serum will be determined using a Bio-Plex Suspension Array System (Bio-Rad)
with a commercial 17-plex cytokine detection kit according to the kit manufacturer’s protocol. Assays will be performed
in the Clinical Research Core.
Additional Data Collection. Data will be collected on additional factors in order to provide a comprehensive description
of the study sample and to assess equivalence of groups and will include the patient’s gender, ethnic background, and
reason for admission to the unit; severity of illness score (Acute Physiology, Age, and Chronic Health Evaluation-APACHE
III)41; global oral health (Decayed, Missing, and Filled Tooth Index at study admission42); administration of antibiotics prior
to entry into the study; type of intubation (emergent, oral vs nasal); daily ventilatory support data (ventilator mode, rate,
type of support, positive end-expiratory pressure, pressure support ventilation, FiO2, PaO2, and SaO2); daily enteral nutri-
tion data (presence, route, rate, type of enteral nutrition, and highest daily gastric pH); presence of antibiotic, histamine
blocker, proton pump inhibitors, and antacid therapy during the study period; backrest elevation; and time, type and
454 Appendix IV
number of mouth care interventions provided by caregivers. All data collected daily, will be collected in the morning and
will be documented from information in the patient’s medical record.
Procedures
Prestudy Training. A comprehensive study training manual will be developed and distributed to all study personnel. The
training manual will include a study overview and all data collection procedures and will be updated as needed. Prior to
data collection, all study personnel will be trained to perform tasks appropriate to their role in the project. The Project
Director will be trained by the PI and co-investigators in all study procedures including subject recruitment, obtaining
consent consistent with applicable state and federal statutes, all interventions and data collection procedures. Role
specific training will include intervention procedures, blood and endotracheal secretion sample collection, and use of
PDAs for data collection for all personnel. The graduate research assistants (GRAs) who will provide pre-intubation inter-
ventions will be trained in the procedure by the Project Director. After training is complete, each GRA will perform a re-
turn demonstration on a dental mannequin model satisfactorily completing all critical elements identified (100% accuracy)
before interventions will begin. Each GRA will also be tested every 3 months throughout the study period to ensure that all
critical elements of each procedure are included. This testing will be done both using a dental mannequin and by direct
observation of study personnel providing interventions to subjects. If any critical element is found to be omitted, retrain-
ing and return demonstrations will occur immediately until the omissions are corrected. If interventions are scheduled
before retraining can occur, the Project Director, PI, or Co-investigator will supervise the intervention to ensure that all
critical elements are present until retraining and revalidation can occur.
In addition, all study personnel involved in medical record data collection will achieve inter-rater reliability with the in-
vestigators and Project Director of 90% or greater before they can participate in data collection. This training will occur
prior to the start of the study using medical records similar to subjects who would be enrolled in the study. Once data col-
lection begins, the Project Director will review every data for completeness and appropriate entries before the data are
entered into the study database. At the beginning of the data entry process a minimum of 1 in every 10 participants entered
will be checked for entry errors. As the study progresses, the frequency of monitoring will be based on the results of previ-
ous data entry checks. If the error rate is unacceptable then the monitoring will increase until the error rate is acceptable
(less than 5% of all data entered). Data monitoring will consist of choosing a participant’s data, printing out all the data for
that participant from the database, and providing this print-out and the original forms to the PI for comparison purposes.
When inaccuracies are found, retraining will occur immediately and results will be monitored by the Project Director.
Subject Recruitment, Enrollment, and Assignment to Treatment Group. All patients being intubated (and subsequently
admitted to the MRICU, STICU, CSICU or NSICU) will be assessed for possible inclusion in the study. Because the inter-
vention is time-sensitive, study personnel assigned to enrollment will carry pagers for notification of intubations; the
pager numbers will be included on call lists for the rapid response team. Medical center respiratory therapists are rou-
tinely present at elective, urgent, and emergent intubation procedures; the Project Director will make routine rounds in
the units to identify potential subjects (patients anticipating elective or emergent intubation). In order to identify urgent
intubations, the Project Director will interact closely with the respiratory therapists on duty in the units and with the Uni-
versity Medical Center Rapid Response Team. The Project Director (or GRA on off shifts or weekends) will also round on
each unit for subject recruitment, and will be available via pager for notification by the MRICU, STICU, CSICU, NSICU and
respiratory therapy staff as well as the rapid response team about potential subjects. The Project Director will review
each subject’s medical record and confirm with the medical staff that the subject is age 18 or older and does not have a
clinical diagnosis of pneumonia; if there are no barriers to inclusion, the subject will be enrolled. Because the patient
undergoing intubation is generally incapacitated, family are not usually present at the time of intubation, study proce-
dures are associated with minimal risk (since the intervention involves timing of the first dose of an FDA-approved study
drug), and the intervention is time limited and must be initiated pre-intubation, a waiver of prospective written consent
will be sought from the IRB. The subject and the subject’s legally authorized representative (LAR) will be provided with an
oral explanation of the nature of the study and study information, and in writing, at the earliest opportunity. The informa-
tion will include all elements required for informed consent, and will include all pertinent contact information as well as
information about withdrawal from the study. If the subject or LAR does not wish continued participation in the study, no
additional interactions with the subject will take place, no follow-up data will be collected and that subject’s data will be
destroyed. We will seek consent for continued participation from the LAR and will invite the research subject to provide
his/her assent if capable. Further, subject’s willingness to continue participation will be assessed on an ongoing basis
throughout the project.
Once the subject has been enrolled, the Project Director will assign the subject to one of the two groups using a ran-
domization schedule generated by our biostatistician. A set of sequenced, sealed opaque envelopes will be prepared,
each containing the assignment of an individual subject. At the time of enrollment, the Project Director will open the next
envelope and proceed accordingly. The Biostatistician and the Data Manager will each keep a master copy of the ran-
domization assignment.
Study Processes. The Project Director or GRAs will recruit and enroll subjects and collect data. The Project Director (GRA
on off shifts and weekends) will complete all admission data collection including subject’s age, gender, ethnic background,
severity of illness score (APACHE III), reason for ICU admission, administration of antibiotics prior to entry into the study,
and type of intubation (emergent, oral vs. nasal). All baseline clinical data will be collected at the time of intubation, includ-
ing components for the CPIS (including endotracheal culture), and serum samples for measurement of selected biomarkers
will be collected and delivered to the Clinical Research Core for storage at –70C until analysis. The investigator scoring
chest radiographs, laboratory personnel, and all clinical caregivers will be blinded to subject group assignment.
Endotracheal aspiration of sputum for culture and gram stain (for the CPIS) will be obtained using a single use sterile
catheter as per the standard unit procedure (no saline will be used). Endotracheal specimens for culture and sensitivity
as well as Gram staining will be transported to the medical centers Clinical Support Laboratory by the Project Director or
GRA. Records of the Respiratory Therapy Department will be the source of data on mechanical ventilation. Data related
to description of the sample will also be collected each morning on all subjects. This will include ventilator support data
(ventilator mode and rate, type of support, PEEP, PSV, FiO2, PaO2, and SaO2); enteral nutrition data (presence, route, rate
and type of enteral nutrition, and highest daily gastric pH over the last 24 hours); and the presence of antibiotic, histamine
blocker, proton pump inhibitors, antacid, sucralfate and vasopressor therapy.
When the subject has been randomized to the intervention group, the prescribed pre-intubation intervention will be
performed by the Project Director (or GRAs on off shifts and weekends), who will not have any clinical responsibilities
related to the intubation. The intervention will be interspersed with the care team’s activities, and at no time will the
study personnel delay or interfere with the intubation procedure; if the needs and activities of providers are such that
the study personnel are unable to access the subject to provide CHX prior to intubation, the subject will be withdrawn
from the study. At all times we will place the subject’s need for medical treatment, and avoidance with interference
with treatment, foremost. For both groups, an order for 5 ml topical oral CHX 0.12% solution, beginning at least 12 hours
following intubation and continuing until extubation, will be entered on the subject’s medication administration record
to be administered by the clinical nurse. Further data collection will occur as scheduled as described in Table 1.
Oral care interventions

Pre-intubation intervention will be performed by the Project Director (or other study personnel on off shifts and week-
ends) as specified by subject group assignment. Delivery of interventions will be documented on a flow sheet developed
for the study.
Control Group. Subjects will not receive any CHX prior to intubation. Administration of 5 ml of CHX gluconate (0.12%
solution) applied topically to the oral cavity will begin at least 12 hours after intubation and continue twice daily through-
out the study. Subjects will receive the usual oral comfort care as provided in each ICU. Data collection will occur as
described in the data collection schedule below.
Intervention Group. Will receive the pre-intubation intervention, which will consist of 5 ml of CHX gluconate (0.12% solu-
tion) applied topically to the oral cavity prior to intubation. CHX gluconate (0.12%) solution will be swabbed on all oral
surfaces by the Project Director/GRA. A defined swabbing method of application will be used. We developed procedures
for this method in the previous study. The actual intervention requires less than one minute to perform. Subjects will also
receive the usual oral comfort care as provided in each ICU.
Data management
Data forms include an admission form, the APACHE III form, a daily data form, the lab data form and a form to capture mor-
tality and discharge data (Appendix A). All data will be collected by subject study number without identifying personal infor-
mation. The PDA will be the primary data acquisition method. Visual as well as automated data verification of all data will
occur with each subject. All data will be downloaded into a relational database. The Clinical Research Core currently has
the data processing, software, database development tools, and expertise to provide this data management support.
The Data Manager in consultation with the Principal Investigator and the Biostatistician will develop reports that will
help in the coordination and management of the project and also allow project staff to monitor the quality of the data and
the progress of the study. Furthermore, only a unique identifier, assigned by the Principal Investigator or Data Manager, in
the database will identify each subject. The data files will be backed up daily during the data entry process and once a
week during other times by the Project Director. All data files will be housed on the university server which is backed up
456 Appendix IV
every 24 hours and copies are stored off-site for additional security. Access to the database will be limited to the investi-
gators, Project Director, and Data Manager.
Plan for Control of Investigational Drugs

CHX mouthwash will be supplied by the medical center Investigational Pharmacy for all subjects.
Data Analysis Plan

The primary aim of this study is to test the effect of a pre-intubation oral application of CHX on the development of VAP in
a variety of mechanically ventilated, critically ill adults. It is anticipated that the groups will be compared using a two-
group analysis of covariance (ANCOVA) model.
Secondary aims are: 1. test the effect of a pre-intubation oral application of CHX on endotracheal flora in mechanically
ventilated adults, and 2. explore additional biomarkers of VAP development and resolution (serum PCT and cytokines). Sim-
ilar to the analysis of the primary aim, it is anticipated that an ANCOVA model will be used to test secondary aim 1. For this
aim, a quantitative count of colony forming units will be determined from the endotracheal tubes removed from study sub-
jects in the first 24 hours after intubation. With the colony counts as the response variable, the ANCOVA model will contain
the group variable (CHX vs. control) and time to extubation as a covariate. The analysis of secondary aim 2 will be con-
ducted in two phases. In the first phase, graphic representation of the PCT and cytokine data in the context of CPIS will be
examined. We have used graphical approaches to illuminate complex relationships among data in previous studies of
VAP,16;43 and have further refined graphical methods for examination of potential VAP biomarkers in this proposal. In the
second phase of the analysis of secondary aim 2, a repeated measures regression model would regress the offset PCT and
the cytokine panel against CPIS. The scaled estimated model coefficients for the PCT and cytokines from the regression
model will be evaluated as indicators of VAP development. A forward and backward stepwise modeling procedure will be
used to ascertain the subset of biomarkers (PCT and cytokines) which best predicts development and resolution of VAP.
Data Safety and Monitoring

An independent Data and Safety Monitoring Board will be assembled for the purpose of monitoring all aspects of the
study, including but not limited to review of adverse events. The DSMB will include a biostatistician, a pulmonologist, and
an advanced practice critical care nurse who are not directly associated with the project. The DSMB will convene after
data collection has been completed for the first 20 subjects and every six months thereafter to review all safety and ad-
verse events data, as well as to monitor patient recruitment and retention. Summary reports of data will be prepared by
the PI for review by the DSMB prior to each meeting. The Board can request additional information to assist in safety
monitoring. Written minutes of DSMB meetings with summaries of adverse events will be forwarded to the IRB and NIH
as part of the annual reporting process. Determinations or recommendations for early stopping of the trial by the DSMB
will be for reasons of safety only. Research staff will report any adverse event immediately to the PI. All adverse events
will be reported to the Data Safety Monitoring Board, the IRB, and the NIH, following institutional and NIH guidelines.
Multi-Center Studies
N/A
Involvement of Non-Institutional Sites

N/A
Involvement of Independent Investigators

N/A
Human Subjects Instructions

Description
Subjects will be enrolled in the study prior to intubation. Each subject will be randomly assigned to one of two conditions:
1) Intervention: Oral application of 5 ml CHX gluconate 0.12% solution pre-intubation, and 5 ml CHX gluconate
0.12% solution twice a day following intubation.
2) Control: No pre-intubation intervention, 5 ml CHX gluconate 0.12% solution twice a day following intubation.
Table 2 Characteristics of study hospital and ICU populations (FY 2006)

Hospital
(inpatient) STICU CSICU MRICU NSICU
Gender
Male 47.8% 64.9% 58% 51.7% 55.2%
Female 52.2% 35.1% 42% 48.3% 44.8%
Ethnic category
Hispanic or Latino 6% 1.5% 1.5% 1.1% 2.5%
Not Hispanic or Latino 94% 98.5% 98.5% 98.9% 97.5%
Racial category
American Indian/Alaska 0.2%
Native 0.2%
Asian 0.1% 0% 0.3% 0% 0%
Native Hawaiian/Pac 0.8% 0.3% 0.9% 0% 40.5%
Islander 0% 0% 0% 0% 53.8%
Black / African American 47.4% 42.1% 42.1% 58% 5.3%
White 42.9% 51.8% 53% 38.1%
Other / Unknown 8.8% 5.8% 3.7% 3.9%
Average age 40.3 48.4 58 52.4 53
Subjects will remain in the study for five days or until extubation if extubated before five days. If extubated in the first
24 hours, a microbial culture of the endotracheal tube will be done. Data will be collected from the medical record daily;
a sample of serum (1 ml blood) will be obtained daily at the time of routine blood draw for clinical purposes. A sample of
sputum obtained at the time of suctioning for clinical indications will be obtained daily.
Subject population
The University Medical Center, where subject recruitment will occur, is a 875-bed tertiary care center that provides care
to more than 30,000 inpatients and emergency department patients and 500,000 outpatients per year and is the single
largest provider of indigent care in the state. Characteristics of inpatients at the Medical Center are presented in Table 2.
Patients in the projected study units are representative of the hospital wide patient characteristics in relation to gender
and ethnic background. Based on study unit characteristics and the investigators’ prior ICU research experience, it is
anticipated that the subjects selected for this study will be representative in both gender and ethnicity of the population
of patients at the Medical Center. The sample will be drawn from all patients over the age of 18 years admitted to the
MRICU, STICU, CSICU and NSICU at the University Medical Center who are being intubated and mechanically ventilated.
Both male and female subjects from all ethnic and racial backgrounds will be recruited. The exclusion criteria will be
clinical diagnosis of pneumonia at the time of intubation. Those who have a diagnosis of pneumonia at the time of intuba-
tion will be excluded because a new episode of superimposed VAP cannot be distinguished with certainty from worsen-
ing of the patient’s initial community acquired or nosocomial pneumonia.
Research material
Data will be obtained from the patient’s record, oral health exam, from biologic fluids (blood and endotracheal tube
aspirates collected for research purposes). ICU admission data will include the patient’s age, gender, ethnic back-
ground, severity of illness (APACHE III) score, reason for unit admission, administration of antibiotics prior to entry into
the study, and type of intubation (emergent, oral vs nasal). CPIS and nursing care data will be collected every day
during the study. Ventilator support data (ventilator mode and rate, type of support, PEEP, PSV, FiO2, PaO2, and SaO2),
enteral nutrition data (presence, route, rate and type of enteral nutrition, and highest daily gastric pH over the preced-
ing 24 hours); and data related to the presence of antibiotic, histamine blocker, proton pump inhibitors, antacid, and
vasopressor therapy will also be collected from the medical record each morning on all subjects.
Recruitment plan
The Investigators, Project Director or GRAs will recruit and enroll subjects. Participants and/or their families will be pro-
vided with a verbal explanation of the nature of the study. Informed consent for continued participation will be obtained
from the subject’s legally authorized representative (LAR) and a study information packet, including information about the
study, study withdrawal and contact numbers of investigators will be given to all subjects.
458 Appendix IV
Potential risks
There are minimal physical and psychological risks associated with this study. The only documented side effects of oral
administration of CHX are transient alterations in taste (dulling of taste sensation for several hours) and discoloration of
teeth and tongue similar to that which occurs with smoking and consumption of tannic acids such as tea, coffee and
wine. CHX discoloration is easily removed by professional dental hygiene. Removal of a total of 6 ml (6 samples of 1 ml
each) might contribute to anemia, but this small amount of blood (approximately one teaspoon) is less than daily ICU
blood drawing and blood will be aspirated through existing catheters not by venipuncture. Subjects may elect not to
participate and may withdraw from the study at any time without affecting the care they receive.
Risk reduction
To reduce risk, blood samples will not be drawn if hemoglobin levels are less than 10 mg/dl. The intervention will be inter-
spersed with the care team’s activities, and at no time will the study personnel delay or interfere with the intubation pro-
cedure; if the needs and activities of providers are such that the study personnel are unable to access the subject to
provide CHX prior to intubation, the subject will be withdrawn from the study. At all times we will place the subject’s need
for medical treatment, and avoidance with interference with treatment, foremost.
Additional safeguards if any participants will be vulnerable

The trained Project Director or GRAs will review the potential subject’s medical record, and if there are no exclusions, the
subject will be enrolled. In the Code of Federal Regulations (CFR-Part 46), the IRB has the authority “to waive the require-
ment to obtain informed consent provided the IRB finds and documents that the research (1) involves no more than mini-
mal risk to the subjects; (2) the waiver or alteration will not adversely affect the rights and welfare of the subjects; (3) the
research could not practicably be carried out without the waiver or alteration; and (4) whenever appropriate, the subjects
will be provided with additional pertinent information after participation.” Therefore, because the patient undergoing in-
tubation is generally incapacitated, family are not usually present at the time of intubation, study procedures are associ-
ated with no more risk than activities of daily living, and the intervention is time limited and must be initiated pre-intubation,
a waiver of prospective written consent will be sought from the IRB. The subject and the subject’s LAR will be provided
with an oral explanation of the nature of the study and study information, in writing, at the earliest opportunity. The infor-
mation will include all elements required for informed consent, and will include all pertinent contact information as well
as information about withdrawal from the study. If the subject or LAR does not wish to continue to participate in the study,
no additional interactions with the subject will take place, no follow-up data will be collected and that subject’s data
forms will be destroyed. The Principal Investigator and study co-investigator have extensive experience in obtaining
consents from family members of critically ill adults, and have used the process described above (after approval of the
IRB) successfully in previous studies involving time-sensitive interventions with critically ill adults. The study staff will
work closely with the staff of the ICUs, the nurse managers and medical directors to ensure that all eligible patients have
an equal opportunity for inclusion.
Confidentiality
Each participant will be assigned an arbitrary code number to ensure anonymity of the research data, and all research
data will be maintained in locked file cabinets under the direct supervision of the PI. Study information obtained will be
kept strictly confidential, and it will not be possible to identify any participant from the reports of publications that may
result from this research.
Privacy
All interactions with subjects and LARs will be conducted in the subject’s hospital room or a private area of the ICU.
Risk/benefit
There are minimal physical and psychological risks associated with this study. Benefits to participation include potential
reduction in the incidence of ventilator associated pneumonia in the treatment group and provision of post-intubation
CHX mouthwash to all subjects. The findings will be used to improve clinical practice in ways that might decrease the
incidence of pneumonia in patients receiving mechanical ventilation in the future.
Compensation plan
No subject compensation is planned.
Consent Issues
Consent process
The Investigators, Project Director or GRAs will recruit and enroll subjects. Study personnel will review each subject’s
medical record and confirm with the medical staff that the subject is age 18 or older and does not have a clinical diag-
nosis of pneumonia; if there are no barriers to inclusion, the subject will be enrolled. Because the patient undergoing
intubation is generally incapacitated, family are not usually present at the time of intubation, study procedures are
associated with minimal risk (since the intervention involves timing of the first dose of an FDA-approved study drug),
and the intervention is time limited and must be initiated pre-intubation, a waiver of prospective written consent is
sought from the IRB. The subject and the subject’s legally authorized representative (LAR) will be provided with an oral
explanation of the nature of the study and study information, and in writing, at the earliest opportunity. The information
will include all elements required for informed consent, and will include all pertinent contact information as well as
information about withdrawal from the study. If the subject or LAR does not wish continued participation in the study,
no additional interactions with the subject will take place, no follow-up data will be collected and that subject’s data
will be destroyed. The Principal Investigator and the study co-investigator have extensive experience in obtaining
consents from family members of critically ill adults, and have used the process described above (after approval of the
IRB) successfully in previous studies involving time-sensitive interventions with critically ill adults. In our experience,
potential subjects who are critically ill and approached for study inclusion, especially prior to and during the first 24
hours of intubation, are always sedated to some degree. In addition, their ability to communicate effectively through-
out the study is compromised by endotracheal intubation. As a result it has always been appropriate to discuss study
participation with the LAR. However, there may be rare occurrences when potential subjects are adequately oriented
and lucid to be able to provide informed consent. Therefore, we will evaluate the potential subject’s level of orientation
and response to our discussions of the study, and if the potential subject is able to respond in a manner that is clearly
understandable, we will use the potential subject’s own consent to continue participation. However, in any instance
where the potential subject’s ability to comprehend and communicate his/her desires is in question, we will seek con-
sent for continued participation from the LAR and will invite the research subject to provide his/her assent. Further,
subject’s willingness to continue participation will be assessed on an ongoing basis throughout the project. We will
follow the IRB Written Policies and Practices (WPP) and in the WPP, Section IZ-4, Item C, where the appropriate use
and definition of the LAR is outlined based on the state code (§11.1-1234). In the State Code, the LAR is defined and a
specific order of priority of representation is outlined.
Special consent provisions

We will obtain consent for ongoing study participation from the LAR for subjects unable to provide consent because of
emergent intubation and inability to communicate.
If Request is being made to WAIVE SOME OR ALL ELEMENTS OF INFORMED CONSENT FROM SUBJECTS OR PERMIS-
SION FROM PARENTS
The proposed research, which involves timing of the first dose of a commonly administered antiseptic mouthwash, in-
volves no more than minimal risk to subjects. The rights and welfare of subjects are not adversely affected by timing of
the first dose of mouthwash (before or after intubation). Because the intervention is time-sensitive and must be accom-
plished before intubation when the subject is generally incapacitated and family are not usually present, the research
could not practicably be carried out without the waiver. The subject and the subject’s legally authorized representative
(LAR) will be provided with an oral explanation of the nature of the study and study information, and in writing, at the
earliest opportunity. The information will include all elements required for informed consent, and will include all pertinent
contact information as well as information about withdrawal from the study. If the subject or LAR does not wish continued
participation in the study, no additional interactions with the subject will take place, no follow-up data will be collected
and that subject’s data will be destroyed.
Waiver of Documentation of Consent

We request to waive documentation of consent based on the research presenting no more than minimal risk of harm to
subjects and involves no procedures for which written consent is normally required outside of the research context.
Swabbing the mouth with CHX mouthwash presents no more than minimal risk, and oral care does not normally require
written consent outside of the research context. The subject and the subject’s legally authorized representative (LAR) will
be provided with an oral explanation of the nature of the study and study information, and in writing, at the earliest
460 Appendix IV
opportunity. The information will include all elements required for informed consent, and will include all pertinent contact
information as well as information about withdrawal from the study. If the subject or LAR does not wish continued partic-
ipation in the study, no additional interactions with the subject will take place, no follow-up data will be collected and that
subject’s data will be destroyed.
Assent process for decisionally impaired subjects

We will evaluate the potential subject’s level of orientation and response to our discussions of the study on a daily basis,
and if the potential subject is able to respond in a manner that is clearly understandable, we will use the potential sub-
ject’s own consent to continue participation. However, in any instance where the potential subject’s ability to compre-
hend and communicate his/her desires is in question, we will seek consent for continued participation from the LAR and
will invite the research subject to provide his/her assent. Further, subject’s willingness to continue participation will be
assessed on an ongoing basis throughout the project.
We request to WAIVE THE REQUIREMENT TO OBTAIN ASSENT from decisionally impaired subjects, who are unable to
provide assent.
In our experience, potential subjects who are critically ill and approached for study inclusion, especially prior to and
during the first 24 hours of intubation, are always sedated to some degree. In addition, their ability to communicate effec-
tively throughout the study is compromised by endotracheal intubation. The proposed research, which involves timing of
the first dose of a commonly administered antiseptic mouthwash, involves no more than minimal risk to subjects. The
rights and welfare of subjects are not adversely affected by timing of the first dose of mouthwash (before or after intuba-
tion). Because the intervention is time-sensitive and must be accomplished before intubation when the subject is gener-
ally incapacitated and family are not usually present, the research could not practicably be carried out without the
waiver. The subject and the subject’s legally authorized representative (LAR) will be provided with an oral explanation of
the nature of the study and study information, and in writing, at the earliest opportunity. The information will include all
elements required for informed consent, and will include all pertinent contact information as well as information about
withdrawal from the study. If the subject or LAR does not wish continued participation in the study, no additional interac-
tions with the subject will take place, no follow-up data will be collected and that subject’s data will be destroyed.
Genetic Testing
N/A
References
1. Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh 7. Alvarez-Lerma F, Palomar M, Martinez-Pellus AE, et al.
R. Guidelines for preventing health-care–associated pneumo- Etiology and diagnostic techniques in intensive care-acquired
nia, 2003: recommendations of CDC and the Healthcare In- pneumonia: A Spanish multi-center study. Clin. Intensive Care
fection Control Practices Advisory Committee. MMWR 1997;8:164-70.
Recomm. Rep. 2004;53:1-36. 8. Cook DJ, Walter SD, Cook RJ, Griffith LE, Guyatt GH,
2. Cook D. Ventilator associated pneumonia: perspectives on Leasa D et al. Incidence of and risk factors for ventilator-
the burden of illness. Intensive Care Med. 2000;26 Suppl 1: associated pneumonia in critically ill patients. Ann. Intern. Med.
S31-S37. 1998;129:433-40.
3. Warren DK, Shukla SJ, Olsen MA, Kollef MH, Hollen- 9. Fourrier F, Duvivier B, Boutigny H, Rourrel-Delvallez
beak CS, Cox MJ et al. Outcome and attributable cost of M, Chopin C. Colonization of dental plaque: A source of nos-
ventilator-associated pneumonia among intensive care unit pa- ocomial infections in intensive care unit patients. Crit. Care
tients in a suburban medical center. Crit. Care Med. 2003;31: Med. 1998;26:301-08.
1312-17. 10. Scannapieco FA, Stewart EM, Mylotte JM. Colonization
4. Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and of dental plaque by respiratory pathogens in medical intensive
economic consequences of ventilator-associated pneumonia: A care patients. Crit. Care Med. 1992;20:740-45.
systematic review. Crit. Care Med. 2005;33:2184-93. 11. Munro CL, Grap MJ, McClish D, Sessler CN. Chlor-
5. Alp E, Voss A. Ventilator associated pneumonia and infec- hexidine reduces ventilator associated pneumonia (VAP) in
tion control. Ann. Clin. Microbiol. Antimicrob. 2006;5:7. mechanically ventilated ICU adults. Crit. Care Med. 2006;34(12
6. Chevret S, Hemmer M, Carlet J, Langer M. Incidence suppl):A1.
and risk factors of pneumonia acquired in intensive care units. 12. Koeman M, van der Ven AJ, Hak E, Joore HC, Kaasjager
Results from a multicenter prospective study on 996 patients. K, de Smet AG et al. Oral decontamination with chlorhexi-
European Cooperative Group on Nosocomial Pneumonia. In- dine reduces the incidence of ventilator-associated pneumonia.
tensive Care Med. 1993;19:256-64. Am. J. Respir. Crit. Care Med. 2006;173:1348-55.
13. Fourrier F, Cau-Pottier E, Boutigny H, Roussel- nonprophylactic systemic antibiotic use in patients undergoing
Delvallez M, Jourdain M, Chopin C. Effects of dental plaque heart surgery. Am. J. Respir. Crit. Care Med. 1996;109:1556-61.
antiseptic decontamination on bacterial colonization and noso- 28. Houston S, Hougland P, Anderson JJ, LaRocco M,
comial infections in critically ill patients. Intensive Care Med. Kennedy V, Gentry LO. Effectiveness of 0.12% chlorhexi-
2000;26:1239-47. dine gluconate oral rinse in reducing prevalence of nosocomial
14. El-Solh AA, Pietrantoni C, Bhat A, Okada M, Zambon pneumonia in patients undergoing heart surgery. Am. J. Crit.
J, Aquilina A et al. Colonization of dental plaques: a reservoir Care 2002;11:567-70.
of respiratory pathogens for hospital-acquired pneumonia in 29. Segers P, Speekenbrink RG, Ubbink DT, van Ogtrop
institutionalized elders. Am. J. Respir. Crit. Care Med. 2004;126: ML, de Mol BA. Prevention of nosocomial infection in car-
1575-82. diac surgery by decontamination of the nasopharynx and oro-
15. Garcia R. A review of the possible role of oral and dental pharynx with chlorhexidine gluconate: a randomized controlled
colonization on the occurrence of health care-associated pneu- trial. JAMA 2006;296:2460-66.
monia: underappreciated risk and a call for interventions. Am. 30. Iacono VJ, Aldredge WA, Lucks H, Schwartzstein S.
J. Infect. Control 2005;33:527-41. Modern supragingival plaque control. Int. Dent. J. 1998;48:
16. Munro CL, Grap MJ, Elswick RK Jr., McKinney J, Ses- 290-97.
sler CN, Hummel RS III. Oral health status and develop- 31. Newman HN. The rationale for chemical adjuncts in
ment of ventilator-associated pneumonia: a descriptive study. plaque control. Int. Dent. J. 1998;48:298-304.
Am. J. Crit. Care 2006;15:453-60. 32. Fourrier F, Dubois D, Pronnier P, Herbecq P, Leroy O,
17. Bahrani-Mougeot FK, Paster BJ, Coleman S, Barbuto Desmettre T et al. Effect of gingival and dental plaque anti-
S, Brennan MT, Noll J et al. Molecular analysis of oral and septic decontamination on nosocomial infections acquired in
respiratory bacterial species associated with ventilator- the intensive care unit: a double-blind placebo-controlled mul-
associated pneumonia. J. Clin. Microbiol. 2007;45:1588-93. ticenter study. Crit. Care Med. 2005;33:1728-35.
18. Gipe B, Donnelly D, Harris S. A survey of dental health 33. Soto GJ. Diagnostic strategies for nosocomial pneumonia.
in patients with respiratory failure. Am. J. Respir. Crit. Care Curr. Opin. Pulm. Med. 2007;13:186-91.
Med. 1995;151:A340. 34. Micromedex. DrugDex Database. Micromedex 102. 1999.
19. Cardenosa Cendrero JA, Sole-Violan J, Bordes BA, 35. Stiefel DJ, Truelove EL, Chin MM, Zhu XC, Leroux
Noguera CJ, Arroyo FJ, Saavedra SP et al. Role of different BG. Chlorhexidine swabbing applications under various con-
routes of tracheal colonization in the development of pneumo- ditions of use in preventive oral care for persons with disabili-
nia in patients receiving mechanical ventilation. Am. J. Respir. ties. Spec. Care Dentist. 1995;15:159-65.
Crit. Care Med. 1999;116:462-70. 36. Owens J, Addy M, Faulkner J, Lockwood C, Adair R. A
20. Adair CG, Gorman SP, Feron BM, Byers LM, Jones DS, short-term clinical study design to investigate the chemical
Goldsmith CE et al. Implications of endotracheal tube bio- plaque inhibitory properties of mouthrinses when used as ad-
film for ventilator-associated pneumonia. Intensive Care Med. juncts to toothpastes: applied to chlorhexidine. J. Clin. Peri-
1999; 25:1072-76. odontol. 1997;24:732-37.
21. Ogata J, Minami K, Miyamoto H, Horishita T, Ogawa 37. Elworthy A, Greenman J, Doherty FM, Newcombe RG,
M, Sata T et al. Gargling with povidone-iodine reduces the Addy M. The substantivity of a number of oral hygiene prod-
transport of bacteria during oral intubation. Can. J. Anaesth. ucts determined by the duration of effects on salivary bacteria.
2004;51:932-36. J. Periodontol. 1996;67:572-76.
22. Wiener J, Itokazu G, Nathan C, Kabins SA, Weinstein 38. Stiefel DJ, Truelove EL, Chin MM, Mandel LS. Efficacy
RA. A randomized, double-blind, placebo-controlled trial of of chlorhexidine swabbing in oral health care for people with
selective digestive decontamination in a medical-surgical in- severe disabilities. Spec. Care Dentist. 1992;12:57-62.
tensive care unit. Clin. Infect. Dis. 1995;20:861-67. 39. Grap MJ, Munro CL, Elswick RK Jr., Sessler CN, Ward
23. Abele-Horn M, Dauber A, Bauernfeind A, Russwurm W, KR. Duration of action of a single, early oral application of
Seyfarth-Metzger I, Gleich P et al. Decrease in nosocomial chlorhexidine on oral microbial flora in mechanically venti-
pneumonia in ventilated patients by selective oropharyngeal de- lated patients: a pilot study. Heart Lung 2004;33:83-91.
contamination (SOD). Intensive Care Med. 1997;23: 187-95. 40. Pugin J, Auckenthaler R, Mili N, Janssens JP, Lew PD,
24. Pugin J, Auckenthaler R, Lew DP, Suter PM. Oropha- Suter PM. Diagnosis of ventilator-associated pneumonia by
ryngeal decontamination decreases incidence of ventilator- bacteriologic analysis of bronchoscopic and nonbronchoscopic
associated pneumonia. A randomized, placebo- controlled, “blind” bronchoalveolar lavage fluid. Am. Rev. Respir. Dis.
double-blind clinical trial. JAMA 1991;265:2704-10. 1991;143:1121-29.
25. Bergmans DC, Bonten MJ, Gaillard CA, Paling JC, van 41. Knaus WA, Wagner DP, Draper EA, Zimmerman JE,
der Geest S, van Tiel FH et al. Prevention of ventilator- Bergner M, Bastos PG et al. The APACHE III prognostic sys-
associated pneumonia by oral decontamination: a prospective, tem. Risk prediction of hospital mortality for critically ill hospi-
randomized, double- blind, placebo-controlled study. Am. J. talized adults. Am. J. Respir. Crit. Care Med. 1991;100: 1619-36.
Respir. Crit. Care Med. 2001;164:382-88. 42. Munro CL, Grap MJ, Jablonski R, Boyle A. Oral health
26. Schultz MJ, De Jonge E, Kesecioglu J. Selective decon- measurement in nursing research: state of the science. Biol. Res.
tamination of the digestive tract reduces mortality in critically Nurs. 2006;8:35-42.
ill patients. Crit. Care 2003;7:107-10. 43. Grap MJ, Munro CL, Hummel RS III, Elswick RK Jr.,
27. DeRiso AJ, Ladowski JS, Dillon TA, Justice JW, Peter- McKinney JL, Sessler CN. Effect of backrest elevation on the
son AC. Chlorhexidine gluconate 0.12% oral rinse reduces the development of ventilator-associated pneumonia. Am. J. Crit.
incidence of total nosocomial respiratory infection and Care 2005;14:325-32.
462 Appendix IV
2. Informed Consent Document

RESEARCH SUBJECT INFORMATION
Title: Infection Control in Mechanically Ventilated Adults
UNIV IRB PROTOCOL NUMBER: XX123456
INVESTIGATOR: PI Name
SPONSOR: National Institutes of Health
This form may contain words that you do not understand. Please ask the study doctor or the study staff to explain any
words or information that you do not clearly understand. You may take home an unsigned copy of this form to think about
or discuss with family or friends before making your decision.
In this form, “you” always refers to the subject. If you are a legally authorized representative, please remember that
“you” refers to the study subject.
Purpose of the Study

The purpose of this study is to test an oral antiseptic mouthwash (chlorhexidine mouthwash) to see if using it before in-
sertion of a breathing tube (intubation) can decrease the bacteria in the mouth, and as a result, reduce the risk of pneu-
monia after intubation. You are being asked to participate in this study because you needed a breathing tube and you met
the study requirements.
Description of the Study

Pneumonia is a common complication of insertion of a breathing tube (endotracheal intubation). Bacteria in the mouth
have been shown to increase risk for pneumonia, since the tube provides a pathway for entry of bacteria from the mouth
to the lungs. Reducing bacteria in the mouth may reduce risk of pneumonia. This study will examine if using an antiseptic
mouthwash (chlorhexidine) before the breathing tube is inserted reduces the risk of pneumonia more than using the
mouthwash after the tube has been inserted.
Your participation in this study will last until your breathing tube is removed, or up to a maximum of 5 days. Approxi-
mately 325 subjects will participate in this study.
Significant new findings developed during the course of the research which may relate to your willingness to continue
participation will be provided to you.
Procedures
Before your breathing tube was inserted, you were randomly assigned (like a flip of a coin) as to whether or not you would
get the antiseptic mouthwash (swabbed into your mouth using a foam swab) before tube insertion. You had an equal
chance of being assigned to either mouthwash before tube insertion or no mouthwash before tube insertion. Everyone
will get the antiseptic mouthwash swabbed into their mouths after the tube is inserted. Neither you, nor the study doctor
will know which group you are in. This information is available to the study doctor if needed in an emergency. This is done
(blinding) so that a fair evaluation of results may be made.
If your breathing tube is removed in less than 24 hours, we will save it to look at the bacteria on it.
For the next five days after the breathing tube is inserted, you will receive the antiseptic mouthwash twice a day; the
mouthwash will be applied with a foam swab. Information will be collected from your medical record (about your clinical
condition and what medications you are taking). Once every day, when you are having blood drawn for your clinical care,
we will take less than one additional teaspoon of blood to look for factors that might predict pneumonia. People who have
a breathing tube have to be suctioned out periodically; your nurse will do this as part of your routine care whether or not
you participate in this study. A small sample of mucus from your breathing tube (produced when the nurse does routine
suctioning), will be sent to the laboratory every day to identify any bacteria present.
Risks and Discomforts

Side effects associated with the use of chlorhexidine mouthwash include staining of your teeth. This staining happens in
about half of the people who use chlorhexidine mouthwash for more than 1 week, and looks similar to tooth staining from
drinking tea or coffee. The stains are not permanent; stains are removed by the cleaning done at a routine dentist visit. In
addition, chlorhexidine can cause a change in taste for a short time. This change in taste is not permanent, and is usually
gone a few hours after the mouthwash is discontinued. Allergic reaction to chlorhexidine is possible but very rare. Severe
allergic reactions can be life-threatening.
There may be side effects which are unknown at this time. Your condition may not get better or may become worse
while you are in this study.
Benefits to You and Others

There is no guarantee that you will receive any medical benefits from being in this study. The information from this re-
search study may lead to a better treatment in the future for people who need breathing tubes.
Costs
The antiseptic mouthwash will be provided by the sponsor. There are no charges to you for the laboratory analysis of
samples from your breathing tube or blood samples which are being done for this study.
Alternatives
Your alternative is not to participate in the study. If you decide not to participate in this study, we will destroy all of the
samples we have taken and all of your research records. You do not have to participate in this study to receive the anti-
septic mouthwash.
Confidentiality
Data is being collected only for research purposes. Your data will be identified by a study ID number, not your name, and
stored separately from medical records in a locked research area. All personal identifying information will be kept in
password protected files and these files will be deleted after the study is completed. Access to all data will be limited to
study personnel. A data and safety monitoring plan is established.
You should know that research data or medical information about you may be reviewed or copied by the sponsor of the
research or by University Medical Center. Personal information about you might be shared with or copied by authorized
officials of the Department of Health and Human Services.
Although results of this research may be presented at meetings or in publications, identifiable personal information
pertaining to participants will not be disclosed.
Compensation for Injury

The University Medical Center or the University have no plan for providing long-term care or compensation in the event
that you suffer injury as a result of your participation in this research study.
If you are injured or if you become ill as a result of your participation in this study, contact your study doctor immedi-
ately. Your study doctor will arrange for short-term emergency care or referral if it is needed.
Fees for such treatment may be billed to you or to appropriate third party insurance. Your health insurance company
may or may not pay for treatment of injuries as a result of your participation in this study.
Voluntary Participation and Withdrawal

Your participation in this study is voluntary. You may decide to not continue to participate in this study. Your decision not
to take part will involve no penalty or loss of benefits to which you are otherwise entitled. If you do participate, you may
freely withdraw from the study at any time. Your decision to withdraw will involve no penalty or loss of benefits to which
you are otherwise entitled.
You may withdraw at any time by telling the investigator that you do not wish to continue your participation.
Your participation in this study may be stopped at any time by the study doctor or the sponsor without your consent.
The reasons might include:
the study doctor thinks it necessary for your health or safety;

you have not followed study instructions;
the sponsor has stopped the study; or
administrative reasons require your withdrawal.
464 Appendix IV
Questions
In the future, you may have questions about your study participation. You may also have questions about a possible side
effect, reaction to study medication, or a possible research-related injury. If you have any questions, complaints, or con-
cerns about the research, contact:
PI Name
State University
School of Medicine
University City, USA
(888) 555-1234
If you have questions about your rights as a research subject, you may contact:
Office of Research
State University
School of Medicine
University City, USA
(888) 555-5678
You may also contact this number for general questions, concerns or complaints about the research. Please call this
number if you cannot reach the research team or wish to talk to someone else.
Additional information about participation in research studies can be found at http://www.appropriate-url.suv.edu.
3. Animal Use Protocol

Introductory Comments
This document is adapted from an IACUC-approved animal protocol that was prepared using an online submission sys-
tem. Except for these introductory comments, the document represents a direct download from the institution’s secure
computer server. It was downloaded by the protocol’s principal investigator and provided to the author for use in this
appendix. Some formatting of this document was arbitrary owing to the inability to fully replicate the structure of the
download output.
Omitted from the protocol presented here are the following.
• Names and qualifications of the principal investigator and all staff members who will work on the project
• Emergency contact information for the principal investigator and all staff
• Funding information, including active research grants that would support the protocol as well as pending propos-
als that would provide support, if awarded
Names, locations, and other identifiers in this document have been either removed or replaced with terms that preserve
the anonymity of the investigators and the institution.
###
Title: Genetics of Oral Microflora

Summary of Research
1.0 Describe your proposed protocol, emphasizing the use of animals and including a brief statement of the
overall purpose of the study:
Study Objectives.
This study seeks to understand the properties of certain bacteria, particularly those that live in the mouth, that enable
them to occasionally cause a serious heart infection called infective endocarditis. There is currently no vaccine for this
disease, and the only method for preventing it is to give antibiotics to people at high risk for endocarditis when they go to
the dentist. However, we now realize that even though these bacteria are an important cause of endocarditis, most
people who get this disease don’t get it from a dental visit. Instead, it appears that these bacteria get into the bloodstream
and cause the infection from daily activities such as eating. We therefore need new targets to specifically prevent dis-
ease that would be safe to use every day for people at risk. Our research attempts to identify new targets by testing vac-
cine candidate proteins for their effectiveness in preventing disease in animals and by testing bacterial mutants to assess
the importance of the mutated genes for causing disease. Rats and rabbits are used. Catheterization of animals to pro-
duce minor heart valve damage is required to predispose the animals to endocarditis since, as with humans, animals with
normal hearts are not prone to disease.
Experimental design and animal procedures.

We plan to perform three types of procedures in the study.
Procedure 1. Endocarditis infection model (rabbits and rats).

The rat and rabbit catheterization models for endocarditis are very similar. We have retained both in our protocol because
the rabbit model produces more reliable infections, but larger animal numbers can be used with rats (because all proce-
dures are quicker), and more immunological reagents are available for rats. All animals are housed in separate cages.
For some studies, blood samples (1 ml for rats or 10 mls for rabbits) will be removed from animals prior to surgery. For
rats, blood will be withdrawn from the tail vein using a butterfly blood collection set with 23G needle. A rubber band will
be looped around the base of the tail and tightened to constrict venous but not arterial flow. Once the needle is positioned
in the vein (indicated by blood flashback at base of needle), the band will be loosened, and approximately 1 ml of blood
collected into a vacutainer serum collection tube. The needle will be removed, and pressure applied to the sampling site
until hemostasis. For this procedure, acetylpromazine is provided SC at 2 mg/kg. Ten minutes later, the rabbit is placed in
a restrainer, its ear swabbed with isopropanol, and the 23-Ga needle attached to a butterfly blood collection set is in-
serted into the artery. When the 10-ml vacuum tube is filled, the needle is withdrawn, and pressure maintained on the
artery until hemostasis. All animals will be placed in restrainers (metal for rabbit and a spiral plastic restrainer for rats) for
the brief period of the blood draw (typically <5 min, with the restrainers loosened while waiting for hemostasis).
For all animals, surgeries are performed in the surgical suite in room 4-051. Injectable anesthesia is given in the outer
room. Once animals are fully anesthetized, their necks are shaved. For rabbits, the ears and abdomen are shaved as well
to facilitate later injections and necropsy, and ophthalmic ointment is applied to the eyes. For both species, betadine is
swabbed onto the shaved area and bupivacaine injected subcutaneously at the incision site. Animals are carried to the
surgery room and placed on a sterile bottom drape. Beneath the bottom drape is a surgery board fitted with a warmed
isothermal pad to prevent hypothermia for rats. Rabbits are protected from the surgical table by a “space drape” beneath
the bottom drape.
For rabbits, a sterile pack containing all surgical instruments, skin clips, sutures, and a sterility indicator is assembled
for each animal. Catheters are supplied in individual, pre-sterile packaging. For rats, several sterile packs are created.
After each set is used, it is cleaned with disinfectant, rinsed with water, and placed in a “Germinator 500” glass bead
sterilizer for 2-10 seconds, as recommended by the manufacturer. The instruments are then removed and placed in be-
tween top and bottom sterile drapes to cool for at least one minute prior to use. (The manufacturer states that 30 seconds
is sufficient.) Handles are then oriented in the same direction to avoid contamination. Catheters for rats are cut, pre-
sealed, soaked in a high-level disinfectant, rinsed, and stored in a container of sterile water or PBS before use.
Once animals are in place and covered with a sterile top drape, an incision is made in the neck above the sternum. The
right carotid artery is gently dissected away from surrounding tissue and exposed. The artery is tied off with suture at the
head end, and clamped at the base of the neck or occluded with a forceps. A bent needle is used to introduce the cathe-
ter into the artery. The clamp or forceps is loosened, and the catheter threaded through the artery until resistance is met,
indicating contact with the aortic valves or the ventricle wall. Sutures are tied around the artery and catheter at the base
of the neck in order to secure the catheter and prevent bleeding. For rabbits, the catheter is crimped, tied, and trimmed,
whereas the rat catheters are pre-cut to size and pre-sealed. With either animal, the short remaining head end of the
catheter is tucked under the subcutaneous tissue of the neck, and the incision closed with skin clips. Rabbit surgeries
typically last 20 minutes, but may range from 15 to 45 minutes. Rat surgeries typically last 10 to 15 minutes.
After surgery, animals are returned to the outer room of the surgical suite. They are placed in a carrier (for rabbits) or
cage (for rats), which contains a warmed isothermal pad underneath a sheet of absorbent paper. At least every 15 min-
utes, animals are monitored. Assuming other parameters are normal, when rats are moving about normally and when
rabbits have achieved sternal recumbency, the thermal pads and papers are removed and animals are returned to their
room. At the end of the surgical day, animals are given buprenorphine injections.
Animals are monitored every 12 hrs following surgery. Additional buprenorphine injections are provided every 12 hrs
for 48 hrs, then as needed afterward. After surgery (typically 2 days later), animals are inoculated with up to 108 live bac-
teria in 0.5 ml, using a tail vein for rats or a peripheral ear vein for rabbits. As with the blood collection described above,
466 Appendix IV
rabbits are placed in a metal restrainer and are provided acepromazine as a sedative and to dilate the veins prior to inoc-
ulation and rats are placed in a spiral restrainer.
Two hours to 5 days later (for rabbits) or 4 hours to 1 day later for rats, animals will be euthanized, using CO2 inhalation
for rats and Euthasol injection for rabbits. For all animals, the chest cavity will be opened and infected cardiac tissue will
be removed for microbiological or microscopic analysis. In some cases, blood may be drawn immediately postmortem
from the right atrium. One spleen and kidney may also be removed postmortem for further analysis. Euthanasia will be
performed early if species-appropriate signs of pain are observed that are not corrected by buprenorphine injection.
Criteria for pain assessment are those found at https://www.univ.edu//Assessing_pain_and_distress.pdf for each spe-
cies. Rabbits will be assumed to be in pain if they are hunched, drag their hind legs, squeal, or face the back of the cage.
Rats will be assumed to be in pain if they squeak or squeal, run in circles, exhibit rounded backs, or are ataxic. In addition,
animals will be euthanized if found to be unresponsive or to demonstrate signs of stroke (a possible complication of
endocarditis).
Procedure 2. Endocarditis vaccination model (rabbits and rats).

These studies begin with subcutaneous immunization with purified protein plus adjuvant, with dosing described else-
where. Some of our previous experiments have used CFA as adjuvant for the first immunization because we were using a
pool of 10 proteins for each vaccine, requiring a strong adjuvant. Thus, we expect to continue to need CFA for if we re-
ceive funding to follow up these experiments. If new studies employing new individual test antigens are initiated, we will
begin by trying TiterMax, which we have also used previously. If CFA is used for the first immunization, IFA will be used as
adjuvant for two subsequent boosts, two weeks apart. If TiterMax is used for the first immunization, it will also be used for
the two subsequent immunizations.
Blood will be drawn for collection of preimmune and immune sera to monitor vaccine efficacy, as described above. For
vaccination studies with rats, blood will be withdrawn for pre-vaccination serum samples from representative animals
rather than from all animals.
Two weeks after the third immunization, the animals will be catheterized, inoculated, euthanized, and necropsied as
described for Procedure 1, except that we will collect as much blood as possible (up to 60 ml for rabbits; ~ 10 ml for rats)
from each animal immediately postmortem by cardiac puncture.
Procedure 3. Blood collection (rabbits).

For some studies, we would like to collect blood for in vitro screening of mutant strains before testing in the endocarditis
model. We plan to collect up to 10% of the animal’s blood volume (using the formula of 5% of body weight as the total
blood volume) for each draw from an ear artery as described in Procedure 1, with a frequency not greater than once ev-
ery two weeks. Alternate arteries will be used for each draw. The volumes and schedule are in compliance with the SOP
for blood sampling, and should not induce anemia. Rabbits will be retained for as much as 3 months, and then will be eu-
thanized or transferred to other investigators, in consultation with Animal Resource Division.
Justification
1.0 Provide the reason for the experiment or activity and a description of the benefits to be gained. Provide
specific information regarding disease(s) to be studied, if applicable:
Endocarditis in humans is an important health problem. It is uniformly fatal if left untreated. Even in the present era of
antibiotic availability, it causes substantial pain and death. Recent studies have reported endocarditis death rates rang-
ing from 12 to 46%. It ranks as the fourth leading cause of life-threatening infectious disease syndromes in the U.S. Oral
streptococci are a leading cause of this disease. Treatment usually involves long courses of antibiotics and often also
requires surgical valve replacement.
There is no vaccine or other reliable method for disease prevention.
It is believed that two conditions are normally required for bacterial endocarditis to occur in humans: (1) there must be
a predisposing condition that results in a damaged heart valve (such as certain congenital heart defects, valve replace-
ment, degenerative valve disease, or rheumatic fever); and (2) bacteria must gain access to and be carried through the
bloodstream to the injured heart valve. More than 30 years ago, it was established that this was also true in rabbits. It was
noted that normal rabbits did not develop endocarditis despite intravenous inoculation with bacterial species known to
cause endocarditis in humans. Also it was determined that introduction of a catheter past the aortic valve caused minor
damage to the valve, and that if bacteria were inoculated into catheterized rabbits, reliable infection occurred. Thus, the
catheterization mimics the cardiac conditions that predispose humans to disease. We are using a minor variation of this
model.
2.0 Justify the selection of the proposed animal species, strain, and numbers, including statistical or other
justification for animal numbers in and a power analysis. Provide a justification of animal numbers across different
procedures justifying animal usage for each year, species/strain, and type of animal (e.g., adult, dam, pup, etc.):
The rabbit model is the most widely used for studying endocarditis, and the rat model is second most common.
We have used the rat model for virulence and vaccine testing. We routinely obtain 50% infection rates in unvaccinated
rats inoculated with virulent strains. If we want 90% power to detect a significant difference (with alpha = .05) between
this infection rate and a 10% infection rate exhibited by a mutant or obtained as a result of vaccination, then 25 rats are
required per group. Thus, a comparison of a virulent strain to a mutant or of an experimental vaccine to a sham vaccine
requires 50 rats. Logistically, this is about the maximum number of rats that we can catheterize in a day.
In contrast to the 50% infection rate and variability in number of bacteria recovered from the rat model, the rabbit model
exhibits almost 100% infectivity and consistent yields of ~10e8 bacteria per animal when a large inoculum of our virulent
strains is used. We are therefore using the rabbit model in most of our tests. For instance, we have used the rabbit model for
competitive index (CI) assays of virulence. In this test, the parent strain and a single mutant are co-inoculated at a 1:1 ratio.
The bacteria recovered from the infected heart are then enumerated to determine the ratio of wild type to mutant.
This provides a quantitative assessment of reduction in competitiveness. For example, a CI of 0.1 would indicate that
the mutant strain was 1/10 as competitive as the parental strain. Given an SD of 0.18 logs determined from previous exper-
iments, the use of 5 rabbits provides 95% power to detect as significantly different from 1 a CI of 0.4 and 6 rabbits would
provide 98% power. We would not be interested in virulence differences smaller than this. It will also be necessary to test
some mutants individually because the wild-type strain might compensate for the mutant’s defect when co-inoculated.
(For instance, if the wild-type strain produces a secreted product required for virulence, a mutant not producing this
product may grow normally in the presence of wild-type bacteria.) Using the rabbit model for these studies, we would
measure the number of cells recovered per animal. With 8 rabbits each assigned to the mutant and parent strain and a
standard deviation of 0.5 logs calculated from our previous experience, we would have 96% power to detect a difference
of 1 log in the number of bacteria recovered. We are set up to work with 12 rabbits at a time. Thus, it works well to com-
pare two mutants to a shared control in one 12-animal experiment, then repeat the experiment to obtain the necessary 8
animals per strain. This results in a total requirement of 12 rabbits per mutant tested. The same analysis would apply to
vaccine studies performed with rabbits. We have also used rabbits for microscopic analysis of lesions, as this can reveal
differences in pathology. We could expect to use 3 rabbits per strain for these studies. Three mutants could be compared
to a shared control in a 12-rabbit experiment. Finally, we may use up to 24 rabbits for blood draws.
This gives an indication of the number of animals required per experiment. The number of each type of experiment per-
formed will depend on funding and on our initial findings. If we are funded to continue with a vaccine study, we will likely use
the rat model. We have 10 to 15 vaccine candidates we are interested in testing. This would require 500 to 1000 rats if tested
individually. However, through the use of vaccine candidate pooling and shared controls, we believe we can reduce this
number to 300 rats over the next 3 years. We envision dividing 15 candidates into 3 pools of 5, which would be tested in 12
animals each and compared to 12 animals injected with a sham vaccine. This would require 48 animals (or 50, allowing for
some mortality). Repeating the experiment would result in each pool being tested in 24 animals, which should be sufficient.
We could then perform an analogous experiment with our top 3 candidates, again comparing all 3 to a shared control. This
would leave 100 rats for repeating this study, if needed, or for testing another 3 candidates. We will continue to use the rabbit
model to test mutant bacterial strains for virulence reduction. We have separate studies that will use this model to test dif-
ferent mutants. We will use the rabbit model for CI assays and individual inoculation experiments as described above. We
may also use rabbits for vaccine studies. Altogether, the number of rabbits we are requesting for these studies is:
CI assays:
50 mutants × 6 rabbits = 300 rabbits
Individual inoculation assays comparing two mutant strains to a shared control or vaccine studies, comparing two vac-
cine candidates to a shared sham vaccine control:
23 mutants or vaccine candidates × 12 rabbits = 276 rabbits
Microscopy, comparing four mutant strains to a shared control:
16 mutants × 4 rabbits = 64 rabbits
Blood draws = 24 rabbits
Total rabbits = 664
Note that these numbers represent upper limits. If we resume vaccine studies, we will perform fewer virulence assays.
However, since we can’t predict exactly what we will do over the next 3 years, we have requested the maximum number
of both species that we might need.
468 Appendix IV
3.0 Does this experiment duplicate previous experiments (other than control data):
 Yes ● No
Database Search
1.0 Date search conducted for literature related to the three “R’s”:
7/19/2011
2.0 Database name and publications years covered:
Name From Year To Year

PubMed 1950 2011
Agricola 1979 2011
3.0 Keywords used in the search for literature for the three “R’s”:
PubMed:
“animal testing alternatives” (a MESH term) AND endocarditis endocarditis AND “in vitro model” endocarditis AND arti-
ficial AND model adjuvants AND rabbit AND alternative adjuvants AND rat AND alternative
Agricola (using advanced search form):

endocarditis AND model endocarditis AND (alternative OR alternatives) adjuvants AND rabbit AND alternative adjuvants
AND rat AND alternative
4.0 Other sources consulted (if any):

ALTBIB (http://toxnet.nlm.nih.gov/altbib.html)
(Note that there are no “live searches” for virulence studies and the vaccine potency tests search reveals attempts to
lessen animal use, not eliminate it.)
UC Davis Center for Animal Alternatives Information
(http://www.lib.ucdavis.edu/dept/animalalternatives/)
I also subscribe to the journal Lab Animal and I periodically attend Lunch and Learn sessions sponsored by the Animal
Resources Division, including a session on rodent surgery.
5.0 Based on the search results above and protocol planning, explain why you cannot replace your animal
model with a non-animal model or less sentient species:
None of the searches or sources listed above have provided alternatives to animal experimentation—that is, replace-
ment. There are some articles that have described in vitro models of endocarditis. A few years ago, I tested one such
model. I found that while it may be sufficient for testing of antibiotics, which is the purpose for which it was designed, it is
not appropriate for virulence testing. Another paper employed a fibrin matrix, which can be used as model for the attach-
ment step of endocarditis. Our studies require examination of later steps in addition to attachment, which are not
addressed.
6.0 Based on the search results above and protocol planning, explain why you cannot reduce the animal
numbers necessary for the experiment:
To attempt reduction, I have used power analyses in consultation with a statistician and competition assays to reduce
animal numbers to the bare minimum required. Further reductions are not possible.
7.0 Based on the search results above and protocol planning, explain why you cannot further minimize pain or
distress in the experiment:
I continue to look for refinements to our protocols in concert with our Animal Resources Division personnel to alleviate
suffering. The search above revealed no analgesic or anesthetic regimens superior to those we are currently using. For
vaccination, we continue to consider alternative to Freund’s Adjuvant. We now routinely use TiterMax as our first choice.
However, as is apparent from the above literature search, and sources such as Volume 46(3) of the ILAR J (2005, Immuni-
zation Procedures and Adjuvant Products), there is no adjuvant that is best for all antigens. We therefore must retain the
option to use Freund’s adjuvant if alternatives are not effective.
We have also considered the use of lower vertebrate animals for our studies. The rabbit model is the most widely used
for studying endocarditis, and the rat model is second most common. A PubMed search using the MESH terms “Endocar-
ditis, Bacterial”[MAJR] AND “Disease Models, Animal”[MeSH] yielded 117 articles when combined with “rabbit” and 26
articles when combined with “rat.” Adding the qualifier “NOT (rat OR rabbit)” to the search resulted in 54 articles. I re-
viewed all of them. Of those, four articles reported the use of dogs, two each used pigs and guinea pigs, and one article
each used calf, opossum, and mouse models. The guinea pig model would be of interest as involving a vertebrate lower
than rabbits, but it was less effective and more technically complex (employing catheterization followed by electrocoagu-
lation, as opposed to just catheterization in our model). The paper describing the mouse model was published in Dec, 2007
(Comp Med, 57(6):563-569). This model, which also employs cardiac catheterization, is attractive since it represents a lower
species. A collaborator at another institution has performed trial experiments with it, and I viewed echocardiograms from
a procedure on a recent visit to his lab. The procedure requires real-time imaging capabilities that we do not currently
possess, although I plan to follow up on this. Nevertheless, at the very least, I will need to continue to use the rabbit model
to complete ongoing studies from which we have already obtained data. If I could establish the mouse model, the results
would also need to be compared to those obtained from our current models, as my collaborator has indicated that grant
reviewers are reluctant to accept results from the mouse model until such comparisons have been made.
Documentation
Animal Groups
Instructions
1. Enter the following:

-Group Name
- Species
-# Needed Years 1-3
2. Click SAVE after all changes

3. Click icon to complete group details
4. Details MUST be complete before submission is allowed
NOTE: Once group details are complete, the copy button can be used to create a similar group.
Details Group Name Species # Yr 1 # Yr 2 # Yr 3 # Total Pain Category USDA
Rabbit Rabbits 221 221 222 664 D yes
Pain
Category D
Rat Rats 100 100 100 300 D no
Pain
Category D
New animal groups should be added only for new species or additional pain categories within species. Creating addi-
tional groups beyond this requirement makes submissions more difficult for PI’s and IACUC reviewers alike. Protocol
submissions with excessive groups may be returned to the PI for modification.
Group Details
1.0 List strain(s) in this group of animals:
Strain
New Zealand White
2.0 Age at final disposition (sacrifice or transfer) for this group of animals:
(select any that apply)
Juvenile
470 Appendix IV
3.0 Will this group of animals be fasted (food and/or water) or placed on a limited/special diet:
 Yes ● No
4.0 Will this group of animals need single housing:

● Yes  No
5.0 Will the Animal Resources Division provide environmental enrichment for this group of animals:
● Yes  No
6.0 What amount of time, if any, will this group of animals be held outside of the vivarium:
0 -11 Hours
USDA Determination
1.0 Group Species: Rabbits
Single Housing Justification
1.0 Provide a justification for single housing:
It is standard practice to house rabbits separately at our institution.
Group Drugs/Compounds
1.0 List ALL drugs/compounds used for this group of animals:
Biosafety
Drug Dose Route Frequency Duration Hazard Level
Complete Freund’s Adjuvant (CFA) 1mL of 50%, no SC Once 7 weeks Biological ABSL-1
(+ purified protein) more than 0.1mL
per site
Live bacteria, possibly containing up to 10e8 IV Once 2 hours to 5 days Biological ABSL-1
rDNA
TiterMax (+ purified protein) 1mL SC 3 times 7 weeks Biological ABSL-1
Live Bacteria: S. sanguinis, S. mutans, 500mg SC Once 7 weeks rDNA ABSL-2
S. mitis, S. salivarius, S. gordonii, S.
parasanguinis, S. bovis, S.
pneumoniae, Kingella kingae, A.
actinomycetemcomitans, E. faecalis +
Plasmid DNA/promoter pEMcat rDNA
providing antibiotic resistance
Buprenorphine 0.03mg/kg SC Twice daily 48 hours, then
PRN
Acetylpromazine ~2mg/kg SC Once 1 day
Ketamine HCl 50mg/kg or up to SC Once pre-op then Supplemental
25mg/kg supplemental
Xylazine 5mg/kg or up to SC Once pre-op then Supplemental
2.5mg/kg supplemental
Buprenorphine 0.0075mg/kg or up SC Once pre-op then Supplemental
to0.00375mg/kg supplemental
Glycopyrrolate 0.1mg/kg or up to SC Once pre-op then Supplemental
Bupivacaine (0.5%) 0.5mL or up to SC Once pre-op then Supplemental
0.5mL supplemental
Euthasol 2mL at ~200mg/kg IV Once Terminal
procedure
Group Euthanasia Methods

1.0 Select euthanasia method(s) for this group of animals:
(select all that apply)
Euthanasia Solution
2.0 Describe euthanasia method(s) for this group of animals and how carcasses will be disposed:
Method 1: Rabbits will be given 2 mg/kg acetylpromazine SC as a sedative and to dilate the ear veins. At least 10 minutes
later, a rabbit will be placed in a metal restrainer and immediately given an ear vein injection of 2 ml euthasol—equivalent
to ~200 mg/kg of sodium pentobarbital. Death occurs quickly—usually before the injection is complete.
Method 2, for experiments in which larger volumes of blood must be collected from catheterized rabbits: Rabbits will be
anesthetized with 2 mg/kg acetylpromazine as in method 1 followed by 180 mg ketamine + 18 mg xylazine SC (~60 and 6
mg/kg ketamine and xylazine, respectively). This will allow the animal to be prepped for necropsy and given 1 ml euthasol
IV in an ear vein without restraint. Heartbeat will be monitored by stethoscope. If the heart is still beating, another ml of
euthasol will be injected. Otherwise, thoracotomy will be performed, and blood will be quickly withdrawn from the right
atrium of the heart using an 18G needle attached to a 60-ml syringe.
For both methods, death is by euthasol injection.
Group Study Type(s)

1.0 Select study type(s) for this group of animals:
Collection of Blood/Tissue
Surgical Survival
Blood/Tissue Procedures
1.0 List any blood/tissue procedures that will be performed on this group of animals:
Procedure Description Pain Category

Collection of Blood D
Collection of Heart C
Collection of Kidney(s) C
Collection of Spleen Spleen will be
collected after
euthanasia
2.0 Is toe clipping indicated in the Breeding Colony details

No
Blood/Tissue Information
1.0 Total number of animals estimated for this group:
664
Out of the total number of animals for this group, how many are estimated to undergo blood/tissue procedures:
664
2.0 Indicate methods for the prevention of anemia:

When blood is drawn from live animals, no more 10% of the animal’s blood volume is taken. Most often, this is done only
once, but when multiple draws are necessary, they are performed no more frequently than once every two weeks. The
volumes and schedule are in compliance with the institutional SOP for blood sampling, and should not induce anemia. (Us-
ing the figure of 5% of body weight as the total blood volume, our 3.5-kg rabbits have ~175 ml of blood and our 250-g rats
have 12.5 ml.) Note that we have listed the maximum number of animals from which blood will be drawn. We will likely per-
form far fewer blood draws than are listed, but all animals will have blood drawn, tissues harvested postmortem, or both.
472 Appendix IV
3.0 Blood/Tissue Collection Info:
Blood/Tissue Amount/Size Frequency

Blood 10mL 1-6 times
Blood 10-60mL Once, at Termination
Heart Infected area Once, at Termination
Kidneys Whole organ Once, at Termination
Spleen Whole organ Once, at Termination
4.0 Blood/Tissue Collection Location(s):

Location
04-039A
08-049A
B2-025
Surgical Procedures
1.0 List any surgical procedures that will be performed on this group of animals:

Aortic Valve/Left An incision is made in the neck above the sternum. The right carotid artery is D
Ventricle Catheterization gently dissected away from surrounding tissue and exposed. The artery is tied
off with suture at the head end, and clamped at the base of the neck or
occluded with a forceps. A bent needle is used to introduce a catheter into the
artery. The clamp or forceps is loosened, and the catheter threaded through the
artery until resistance is met, indicating contact with the aortic valve or the
ventricle wall. Sutures are tied around the artery and catheter at the base of the
neck in order to secure the catheter and prevent bleeding. The short remaining
head end of the catheter is tucked under the subcutaneous tissue of the neck,
and the incision closed with skin clips. The animal is returned to its cage or
carrier, and placed upon bench paper covering a warmed isothermal heat pad
until fully recovered.
Surgical Information
664
Out of the total number of animals for this group, how many are estimated to undergo surgical procedures:
664
2.0 Select pre-operative drugs:
Drug Dose Route Frequency Duration

Acetylpromazine ~2mg/kg SC Once 1 day
Select surgical anesthetic/analgesic drugs:

Ketamine HCl 50mg/kg or up to 25mg/kg SC Once pre-op then supplemental Supplemental
Xylazine 5mg/kg or up to 2.5mg/kg SC Once pre-op then supplemental Supplemental
Buprenorphine 0.0075mg/kg or up to SC Once pre-op then supplemental Supplemental
0.00375mg/kg
Glycopyrrolate 0.1mg/kg or up to 0.05mg/kg SC Once pre-op then supplemental Supplemental
Bupivacaine (0.5%) 0.5mL or up to 0.5mL SC Once pre-op then supplemental Supplemental
4.0 Describe the expected duration of anesthesia:

Surgeries typically last 20 minutes, but may range from 15 to 45 minutes. Animals are anesthetized just prior to surgery.
Rabbits typically require 2 to 4 hrs to recover completely from anesthesia.
5.0 Describe the expected duration of surgery:

6.0 Describe pre-operative care:

Animals are examined visually the week of arrival for appearance, food intake, and urine and feces production. Animals
are weighed prior to surgery to determine anesthesia dosage. No fasting is required.
7.0 Will gas/inhalation anesthesia be used:

 Yes ● No
8.0 Will paralytic drugs be used:

 Yes ● No
9.0 How will the level of anesthesia be monitored and how often:
The surgeon will continuously monitor respiratory rate and rhythm, and will monitor the level of anesthesia during the
procedure by checking for absence of pedal reflexes at least every 15 minutes.
10.0 What method will be used to prevent dehydration and hypothermia:

Rabbits will be protected from the surgical table by a “space drape,” an absorbent pad, and a bottom drape. All animals
are also covered with a top drape, which helps prevent heat loss. Animals are placed on warmed Delta-thermal pads
during recovery. Dehydration is not expected to occur, since fluids will not be withheld prior to or following the proce-
dure, blood loss is normally minimal, and the surgery lasts less than an hour (usually 15-30 minutes).
11.0 Surgical Procedures Location(s):

Location
04-039A
Surgical Information—Description
1.0 Describe surgical procedures:
Surgeries are performed in the surgical suite in room 4-051. For both species, anesthesia is given in the outer room. Once
animals are fully anesthetized, their necks are shaved using an electric clipper attached to the shop-vac. For rabbits, the
ears and abdomen are shaved as well to facilitate later injections and necropsy, and ophthalmic ointment is applied to the
eyes. For both species, betadyne is swabbed onto the shaved area and bupivacaine injected subcutaneously at the inci-
sion site. Animals are carried to the surgery room and placed on a sterile bottom drape. Surgeons don surgical gowns and
wear appropriate PPE, including sterile surgical gloves, shoe and head covers, mask, and goggles.
For rabbits, a sterile pack containing all surgical instruments, skin clips, sutures, and a sterility indicator is assembled
for each animal. Catheters and scalpels are supplied in individual, pre-sterile packaging. For rats, several sterile packs
are created. After each set is used, it is cleaned with disinfectant, rinsed with water, and placed in a “Germinator 500”
glass bead sterilizer for 2-10 seconds, as recommended by the manufacturer. The instruments are then removed and
placed in between top and bottom sterile drapes to cool for at least one minute prior to use. (The manufacturer states that
30 seconds is sufficient.) Handles will be oriented in the same direction to avoid contamination. Catheters for rats are cut,
pre-sealed, soaked in a high-level disinfectant, rinsed, and stored in a container of sterile water or PBS before use.
head end, and clamped at the base of the neck or occluded with a forceps. A bent needle is used to introduce a catheter
into the artery. The clamp or forceps is loosened, and the catheter threaded through the artery until resistance is met,
indicating contact with the aortic valve or the ventricle wall. Sutures are tied around the artery and catheter at the base
of the neck in order to secure the catheter and prevent bleeding. For rabbits, the catheter is crimped, tied, and trimmed,
whereas the rat catheters are pre-cut to size and pre-sealed. With either animal, the short remaining head end of the
catheter is tucked under the subcutaneous tissue of the neck, and the incision closed with skin clips. The animal is re-
turned to its cage or carrier, and placed upon bench paper covering a warmed isothermal heat pad until fully recovered.
474 Appendix IV
Post-Surgical Procedures
1.0 List any post-surgical procedures that will be performed on this group of animals:

Blood Sampling Draw blood for labs D
Post-Surgical Information
664
Out of the total number of animals for this group, how many are estimated to undergo post-surgical procedures:
640
2.0 Select post-surgical drugs:

Buprenorphine 0.03m/kg SC Twice daily 48 hours, then PRN
3.0 Survival surgeries require sterile instruments and aseptic surgical techniques. Indicate how instruments
will be sterilized for each surgery:
For rabbits, a sterile pack containing all surgical instruments, skin clips, sutures, and a sterility indicator is assembled for
each animal. Catheters and scalpels are supplied in individual, pre-sterile packaging. After each set is used, it is cleaned
with disinfectant, rinsed with water, and placed in a “Germinator 500” glass bead sterilizer for 2-10 seconds, as recom-
mended by the manufacturer. The instruments are then removed and placed in between top and bottom sterile drapes to
cool for at least one minute prior to use. (The manufacturer states that 30 seconds is sufficient.) Handles will be oriented
in the same direction to avoid contamination.
4.0 Describe post-operative recovery from anesthesia, including frequency and type of observations. Also list
any lab tests, observations and management of potential experimental related disease, wound care, parenteral
fluids, special diet, etc.:
After surgery, animals are returned to the outer room of the surgical suite. They are placed in a carrier, which contains a
warmed isothermal pad underneath a sheet of absorbent paper.
At least every 15 minutes, animals are monitored for the following: respiration occurring at a normal, regular rate; lack
of bleeding from the incision site; normal color; movement of the head or other body parts; movement about the cage and
position within the cage; and posture. We have observed that it is especially important to prevent rabbits from burying
their noses in the corner of their carrier upon initial waking, which can result in suffocation. Assuming other parameters
are normal, when rabbits have achieved sternal recumbency, the thermal pads and papers are removed and animals are
returned to their room. At the end of the surgical day, animals are given buprenorphine injections.
5.0 Describe criteria for the assessment of post-surgical pain:

Criteria for pain assessment are those found at https://www.univ.edu/Assessing_pain_and_distress.pdf for each
species.
Animals will be assessed every 12 hrs from surgery until euthanasia. Rabbits will be assumed to be in pain if they are
hunched, drag their hind legs, squeal, or face the back of the cage. Pain will be treated with injections of buprenorphine
every 12 hrs. If any of the signs listed above do not resolve after administration of buprenorphine, the animal will be euth-
anized. In addition, animals will be euthanized if found to be unresponsive or to demonstrate signs of stroke (a possible
complication of endocarditis).
6.0 Describe the management of post-operative pain in compliance with the institution’s post-operative
analgesia policy:
No special diet is required. Animals are assessed and provided additional buprenorphine injections every 12 hrs for 48
hrs. Activity level, posture, responsiveness, and presence of urine and feces are observed at each assessment. The neck
wound is assessed for signs of infection or hematoma. Most experiments end <18 hrs after the last required buprenor-
phine dose is administered. For experiments lasting longer, twice-daily assessment continues until euthanasia. If species-
appropriate signs of pain are observed, additional doses of buprenorphine will be provided every 12 hrs. If this does not
have the desired effect, or if the animal shows other signs of distress, such as labored breathing or abnormal movement
or responsiveness, it will be euthanized.
7.0 Describe the expected duration of post-surgical analgesia:

Surgeries typically last 20 minutes, but may range from 15 to 45 minutes. Animals are anesthetized just prior to surgery
with a cocktail that includes buprenorphine as an analgesic. Rabbits typically require 2 to 4 hrs to fully recover. Post-
operative analgesia is provided every 12 hrs for 48 hrs, and then as needed until the animal is euthanized.
8.0 Describe the length of time the animal will be kept alive post-operatively:
2-7 days
9.0 Describe long-term care of chronically instrumented animals:

N/A
10.0 Will multiple major survival surgeries be performed:

 Yes ● No
11.0 Personnel responsible for records:

Name E-Mail Office
12.0 Location of post-surgical records:

Location
04-039A
13.0 Post-surgical procedure location(s):

Location
04-039A
Biological Hazard Information

Biosafety
Drug Dose Route Frequency Duration Level
Complete Freund’s Adjuvant 1mL of 50%, no more SC Once 7 weeks ABSL-1
(CFA) (+ purified protein) than 0.1mL per site
Live bacteria, possibly up to 10e8 IV Once 2 hours to 5 days ABSL-1
containing rDNA
TiterMax (+ purified protein) 1mL SC 3 times 7 weeks ABSL-1

664
Out of the total number of animals for this group, how many are estimated to undergo biological hazard
procedures:
640
2.0 Indicate the role of each biohazardous material or agent in the proposed study:
Complete Freund’s Adjuvant (CFA) and TiterMax are used as adjuvants for immunization in experiments designed to test
the efficacy of proteins for prevention of endocarditis. Our current study uses a pool of 10 proteins for each vaccine, re-
quiring a strong adjuvant. Thus, we expect to continue to need CFA for most of our vaccination experiments rather than
TiterMax. If new studies employing new individual test antigens are initiated, we will begin by trying TiterMax.
Immunization is followed by injection of animals with live bacteria. Lack of infection or lower bacterial loads in vacci-
nated animals compared to control, mock-vaccinated animals indicates vaccine efficacy. In other experiments designed
to test the role of selected bacterial genes in endocarditis causation, bacteria containing mutations in the genes of
476 Appendix IV
interest are injected into animals either singly or along with the parental or other mutant strains. These experiments re-
veal the relative virulence of the mutant strains.
Notes on compounds:
The purified proteins pose no known or suspected risks to the animals. The Freund’s complete adjuvant may produce in-
flammation at the site of injection. Animals will be monitored daily after injection. Any animal that shows signs of distress
will be given buprenorphine as an analgesic until the lesion resolves, following consultation with animal resource per-
sonnel. If the lesion does not resolve, the animal will be euthanized.
Freund’s incomplete adjuvant and Titermax list no known risks. However, animals will be monitored daily for inflam-
mation at injection sites. The CFA and TiterMax are alternative treatments, so animals will receive one or the other, not
both. The live bacteria used in these studies (usually Streptococcus sanguinis, but possibly strains of Streptococcus
mutans, Streptococcus mitis, Streptococcus salivarius, Streptococcus gordonii, Streptococcus parasanguinis, Strep-
tococcus bovis, Streptococcus pneumoniae, Aggregatibacter [Actinobacillus] actinomycetemcomitans, Kingella kin-
gae, or enterococci) are normally present in the mouth or GI tract of all humans, possess low virulence, and are
categorized as Biosafety level 1 or 2. At the high doses injected, the animals may develop fever. All animals will be
provided with buprenorphine before and after injection. Animals will be euthanized 2 hrs-5 days following injection of
bacteria and will be monitored daily. If an animal showed signs of unalleviated distress even after buprenorphine ad-
ministration, it would be euthanized earlier. Further, if we find that significant mortality occurs at 5 days post-inoculation,
a shorter period will be adopted for these experiments.
3.0 Describe potential adverse health effects on laboratory personnel, animal caretakers and/or animals and
indicate the degree and nature of the risk to the personnel:
Although listed above, the purified proteins and TiterMax pose no known or suspected risks to lab personnel, animal
caretakers, or the animals. The Freund’s complete adjuvant that may be used in the first vaccination can induce inflam-
mation if introduced intradermally or into the eyes, and can lead to a positive reaction to the standard TB skin test. Limited
risk to animal care workers is posed by possible exposure to residual CFA on animals and in bedding materials during
initial hours following administration.
The live bacteria used in these studies are normally present in the mouth or GI tract of all humans, possess low viru-
lence, and are categorized as Biosafety level 1 or 2. All bacterial strains and related rDNA manipulations will be handled
under BSL-2 conditions. Preparation of doses will be conducted within a certified biological safety cabinet (BSC) while
donning proper personal protective equipment. Following inoculation, contact with infected animals is unlikely to cause
disease. Euthanasia usually occurs less than 24 hrs after infection, so animals will likely develop fever, but will usually not
have time to develop other, more serious complications.
Rabbits will be monitored daily following injection of Freund’s complete adjuvant for signs of excessive inflammation at
the site of injection. Any animal that shows signs of distress will be euthanized or will be given buprenorphine as an anal-
gesic until the lesion resolves following consultation with animal resources personnel. All animals are euthanized 2 hrs-5
days following injection of bacteria.
4.0 Describe the containment procedures to be followed to protect other animals, personnel and the
environment from the hazardous agents; include monitoring methods, frequency, the name of the person
responsible for monitoring and biosafety assigned by the IBC:
Syringes are filled with bacteria or adjuvant in BSL2 conditions a biosafety hood in the lab using a 3-way stopcock. After
filling, capped needles are placed on each syringe; thus, there is no recapping of needles, only attachment of capped
needles to the filled syringes. Used syringes will be placed in approved sharps containers without recapping of the nee-
dle. Unused (extra) syringes will be placed in the sharps container without removing the cap.
Injection of Freund’s adjuvant or live bacteria will be performed while wearing eye protection and other PPE.
Animals will be injected with bacteria or CFA in a separate part of the room, away from other animals. During the
period prior to completion of first change of bedding workers will don PPE to include N-95 respirator, eye protection,
disposable coveralls, and gloves. Following completion of first bedding change significant exposure threats in relation
to this agent should be eliminated and animal care workers may follow standard Animal Resources Division
precautions.
Live Bacterial Strains and rDNA may be handled under ABSL-1 precautions in accordance with conditions established
in the Division’s SOP.
5.0 Describe waste and animal storage and disposal requirements:

1. Animal carcasses are to be placed in red bags, managed as regulated medical waste (RMW), and disposed of via
incineration through the Animal Resources Division.
2. Complete Freunds Adjuvant: Bedding and other waste materials generated through first bedding change will be
managed as regulated medical waste (RMW) and disposed of via incineration (red-bagging) only. Following the
first bedding change special handling of bedding is not required.
3. Bedding and other materials contaminated with live bacterial strains and/or pEMCat plasmid/rDNA materials are to
be managed as regulated medical waste (RMW) and disposed of via incineration (red-bagging).
4. Bacterial Proteins: Special waste handling procedures are not required for animals exposed to bacterial proteins
in the absence of live bacteria, pEMCat plasmid, and CFA hazards.
5. Unwanted surpluses/stocks or waste material contaminated with greater than trace amounts of CFA will be dis-
posed of as hazardous chemical waste through OEHS.
Recombinant DNA Information

Drug Dose Route Frequency Duration Biosafety Level
Live Bacteria: S. sanguinis, S. mutans, S. 500mg SC Once 7 weeks ABSL-2
mitis, S. salivarius, S. gordonii, S.
parasanguinis, S. bovis, S. pneumoniae,
Kingella kingae, A.
actinomycetemcomitans, E. faecalis +
Plasmid DNA/promoter pEMcat rDNA

664
Out of the total number of animals for this group, how many are estimated to undergo rDNA procedures:
640
2.0 List known MUA number(s):

MUA #
123456
3.0 Indicate sources of DNA:

Streptococcus sanguinis bacteria that have been genetically modified by introducing antibiotic resistance cassettes. It is
also possible that similar experiments could be performed with other indigenous oral or GI tract bacteria, including S.
mutans, S. salivarius, S. gordonii, S. mitis, S. parasanguinis, S. bovis, S. pnuemoniae, Enterococcus faecalis, Kingella
kingae, or Aggregatibacter actinomycetemcomitans.
4.0 Describe nature of the inserted DNA sequence, i.e., what does the insertion code for and what are you
trying to accomplish:
Antibiotic resistance genes encoding resistance to chloramphenicol, kanaymycin, erythromycin, spectinomycin, or tetra-
cycline, and which are already found in nature in these species. These genes have one or two purposes. In all experi-
ments, the genes serve as markers to identify the bacteria that we introduce into the animal. In some cases, the antibiotic
resistance genes are also used to disrupt or “knock out” certain bacterial genes in order to determine the importance of
these genes for disease causation.
5.0 Describe vectors and hosts and their potential hazards to lab personnel, animal caretakers and/or animals
and indicate the degree and nature of the risk to the personnel:
The vectors are standard E. coli cloning vectors and plasmids found naturally in streptococci. In many instances, the an-
tibiotic resistance genes are inserted into the bacterial chromosome and no vector remains. The antibiotic resistance
genes were chosen because they are found in nature in the bacteria being studied. Because of this, the corresponding
antibiotics are not normally used clinically for the treatment of rare infections caused by these bacteria. If a lab worker
478 Appendix IV
were accidentally injected with these bacteria, he would be provided prophylactic antibiotics—normally a single dose of
amoxicillin. If the worker were allergic to that antibiotic, then he should avoid the use of erythromycin or tetracycline until
it is determined whether the inoculated strain carries a gene for resistance to one of these drugs.
There is no danger to workers in handling inoculated animals, since the bacteria are present at low or undetectable
levels in the animal’s blood 30 minutes after inoculation. Also, the disease under study (infective endocarditis) is non-
contagious, and therefore cannot be spread to workers or other animals.
The bacteria are normal inhabitants of the human mouth, are introduced into the bloodstream in small numbers and
swallowed in large numbers on a daily basis by all humans.
6.0 Will a deliberate attempt be made to obtain expression of a foreign gene:

● Yes  No
7.0 Describe safety precautions per NIH guidelines and IBC assigned biosafety levels:
For purposes of the recombinant DNA work, the Biosafety level is specified as Risk group 1. The streptococcal bacteria
would be classified as BSL1 or possibly BSL2. Work in the laboratory proceeds according to BSL2 guidelines, with han-
dling occurring in Class IIA hoods in rooms 407 and 409. The animal work is classified as ABSL-1. These studies have
been reviewed and approved by OEHS, most recently under MUA 123456, dated 12/06/07.
8.0 Describe procedures for storage and/or transport of genetically modified material or animals, both within
and outside of the institution, and their ultimate disposal:
The recombinant DNA is contained within the bacteria inoculated into the animals. The bacteria are handled and loaded
into syringes in Biosafety hoods in rooms 407 or 409, then carried in a closed container to the research building for injec-
tion. Injection occurs in the research building vivarium. Used syringes are placed in sharps containers for incineration.
Remaining bacteria are autoclaved.
9.0 Are volumes in excess of 10 liters:

 Yes ● No
Recombinant DNA—Foreign Gene Info

1.0 Provide the name and biological function, if known, for each protein to be produced:
Antibiotic resistance genes will be expressed in most of the bacteria that are inoculated into the animals. Expression of
the resistance genes in the bacteria should have no effect on the animals.
Group Details
1.0 List strain(s) in this group of animals:
Strain
Sprague-Dawley
2.0 Age at final disposition (sacrifice or transfer) for this group of animals:
1 (select any that apply)
Adult
3.0 Will this group of animals be fasted (food and/or water) or placed on a limited/special diet:
 Yes ● No
4.0 Will this group of animals need single housing:

● Yes  No
5.0 Will the Animal Resources Division provide environmental enrichment for this group of animals:
● Yes  No
6.0 What amount of time, if any, will this group of animals be held outside of the vivarium:
0 -11 Hours
USDA Determination
1.0 Group Species: Rats
Single Housing Justification
1.0 Provide a justification for single housing:

It might confound experiments if differently vaccinated and inoculated animals were housed together.
Group Drugs/Compounds
1.0 List ALL drugs/compounds used for this group of animals:
Drug Dose Route Frequency Duration Hazard Biosafety Level

Complete Freund’s Adjuvant 0.2mL of 50%, no SC Once 7 weeks Biological ABSL-1
(CFA) (+ purified protein) more than 0.1mL
per site
Live bacteria, possibly up to 10e8 IV Once 4 hours to 1 day Biological ABSL-1
containing rDNA
S. sanguinis, S. mutans, S. ~10^8 cells IV Once 2 hours to 5 days Biological ABSL-2
mitis, S. salivarius, S.
gordonii, S. parasanguinis,
S. bovis, S. pneumoniae,
Kingella kingae, A.
actinomycetemcomitans, E.
faecalis + plasmid DNA/
promoter pEMcat rDNA
providing antibiotic
resistance
Complete Freund’s Adjuvant 0.2mL of 50%, no SC Once 7 weeks Chemical ABSL-1
(CFA) more than 0.1mL
per site
Buprenorphine 0.05mg/kg SC Twice daily 48 hours, then
PRN
Ketamine HCl 100mg/kg or up to SC Once pre-op Supplemental
50mg/kg then
supplemental
Midazolam 2.5mg/kg or up to SC Once pre-op Supplemental
1.25mg/kg then
supplemental
Buprenorphine 0.01mg/kg or up SC Once pre-op Supplemental
to 0.005mg/kg then
supplemental
Bupivacaine (0.5%) 0.1mL SC Once pre-op Supplemental
then
supplemental
Group Euthanasia Methods

1.0 Select euthanasia method(s) for this group of animals:
(select all that apply)
CO2 without Physical Method
480 Appendix IV
2.0 Describe euthanasia method(s) for this group of animals and how carcasses will be disposed:
Euthanasia will be by CO2 inhalation using the chamber in the necropsy room. The recommended procedure will be used
and heartbeat will be monitored by touch prior to removal of rats from the chamber. No more than two animals will be
euthanized at the same time.
Group Study Type(s)

1.0 Select study type(s) for this group of animals:
Collection of Blood/Tissue
Surgical Survival
Blood/Tissue Procedures
1.0 List any blood/tissue procedures that will be performed on this group of animals:
Procedure Description Pain Category Justification

Collection of Blood D
Collection of Heart C Tissues will be collected
after euthanasia.
Collection of Kidney(s) C Tissues will be collected
after euthanasia.
Collection of Spleen Spleen will be collected C
after euthanasia.
2.0 Is toe clipping indicated in the Breeding Colony details:

No
Blood/Tissue Information
300
Out of the total number of animals for this group, how many are estimated to undergo blood/tissue procedures:
300
2.0 Indicate methods for the prevention of anemia:

When blood is drawn from live animals, no more 10% of the animal’s blood volume is taken. Most often, this is done only
once, but when multiple draws are necessary, they are performed no more frequently than once every two weeks. The
volumes and schedule are in compliance with the Standard Operating Procedure for blood sampling, and should not in-
duce anemia. (Using the figure of 5% of body weight as the total blood volume, our 3.5-kg rabbits have ~175 ml of blood
and our 250-g rats have 12.5 ml.) Note that we have listed the maximum number of animals from which blood will be
drawn. We will likely perform far fewer blood draws than are listed.
3.0 Blood/Tissue Collection Info:
Blood/Tissue Amount/Size Frequency

Blood 1mL Once
Blood 10mL Once, at Termination
Heart Infected area Once, at Termination
Kidneys Whole organ Once, at Termination
Spleen Whole organ Once, at Termination
4.0 Blood/Tissue Collection Location(s):

Location
04-039A
08-049A B2-025
Surgical Procedures
1.0 List any surgical procedures that will be performed on this group of animals:

Aortic Valve/Left A incision is made in the neck above the sternum. The right carotid artery is D
Ventricle Catheterization gently dissected away from surrounding tissue and exposed. The artery is tied
off with suture at the head end, and clamped at the base of the neck or occluded
with a forceps. A bent needle is used to introduce a catheter into the artery. The
clamp or forceps is loosened, and the catheter threaded through the artery until
resistance is met, indicating contact with the aortic valve or the ventricle wall.
Sutures are tied around the artery and catheter at the base of the neck in order
to secure the catheter and prevent bleeding. The short remaining head end of
the catheter is tucked under the subcutaneous tissue of the neck, and the
incision closed with skin clips. The animal is returned to its cage or carrier, and
placed upon bench paper covering a warmed isothermal heat pad until fully
recovered.
Surgical Information
300
Out of the total number of animals for this group, how many are estimated to undergo surgical procedures:
300
2.0 Select pre-operative drugs:

N/A
3.0 Select surgical anesthetic/analgesic drugs:

Ketamine HCl 100mg/kg or up to SC Once pre-op then Supplemental
50mg/kg supplemental
Midazolam 2.5mg/kg or up to SC Once pre-op then Supplemental
Buprenorphine 0.01mg/kg or up to SC Once pre-op then Supplemental
Bupivacaine (0.5%) 0.1mL SC Once pre-op then Supplemental
supplemental
4.0 Describe the expected duration of anesthesia:

Rats are typically fully recovered from anesthesia in 1 to 2 hrs.
5.0 Describe the expected duration of surgery:

Rats are typically fully recovered from anesthesia in 1 to 2 hrs.
6.0 Describe pre-operative care:

Animals are examined visually the week of arrival for appearance, food intake, and urine and feces production. Animals
are weighed prior to surgery to determine anesthesia dosage. No fasting is required.
7.0 Will gas/inhalation anesthesia be used:

 Yes ● No
482 Appendix IV
8.0 Will paralytic drugs be used:

 Yes ● No
9.0 How will the level of anesthesia be monitored and how often:
The surgeon will continuously monitor respiratory rate and rhythm, and will monitor the level of anesthesia during the
procedure by checking for absence of pedal reflexes at least every 15 minutes.
10.0 What method will be used to prevent dehydration and hypothermia:

Surgery boards used for rats are fitted with a warmed isothermal pad to prevent hypothermia. All animals are also cov-
ered with a top drape, which helps prevent heat loss. Animals are placed on warmed isothermal pads during recovery.
Dehydration is not expected to occur, since fluids will not be withheld prior to or following the procedure, blood loss is
normally minimal, and the surgery lasts less than an hour (usually 15-30 minutes).
11.0 Surgical Procedures Location(s):

Location
04-039A
Surgical Information—Description
1.0 Describe surgical procedures:
Surgeries are performed in the surgical suite in. Anesthesia is given in the outer room. Once animals are fully anesthe-
tized, their necks are shaved using an electric clipper attached to the shop-vac. The ears and abdomen are shaved as
well to facilitate later injections and necropsy, and ophthalmic ointment is applied to the eyes. Betadyne is swabbed onto
the shaved area and bupivacaine injected subcutaneously at the incision site. Animals are carried to the surgery room
and placed on a sterile bottom drape. Surgeons don surgical gowns and wear appropriate PPE, including sterile surgical
gloves, shoe and head covers, mask, and goggles.
A sterile pack containing all surgical instruments, skin clips, sutures, and a sterility indicator is assembled for each
animal. Catheters and scalpels are supplied in individual, pre-sterile packaging. For rats, several sterile packs are cre-
ated. After each set is used, it is cleaned with disinfectant, rinsed with water, and placed in a “Germinator 500” glass
bead sterilizer for 2-10 seconds, as recommended by the manufacturer. The instruments are then removed and placed in
between top and bottom sterile drapes to cool for at least one minute prior to use. (The manufacturer states that 30 sec-
onds is sufficient.) Handles will be oriented in the same direction to avoid contamination.
head end, and clamped at the base of the neck or occluded with a forceps. A bent needle is used to introduce a catheter
into the artery. The clamp or forceps is loosened, and the catheter threaded through the artery until resistance is met,
indicating contact with the aortic valve or the ventricle wall. Sutures are tied around the artery and catheter at the base
of the neck in order to secure the catheter and prevent bleeding. The catheter is crimped, tied, and trimmed. The short
remaining head end of the catheter is tucked under the subcutaneous tissue of the neck, and the incision closed with skin
clips. The animal is returned to its cage or carrier, and placed upon bench paper covering a warmed isothermal heat pad
until fully recovered.
Post-Surgical Procedures
1.0 List any post-surgical procedures that will be performed on this group of animals:

Blood sampling Draw blood for labs D
Post-Surgical Information
300
Out of the total number of animals for this group, how many are estimated to undergo post-surgical procedures:
300
2.0 Select post-surgical drugs:

Buprenorphine 0.05mg/kg SC Twice daily 48 hours, then PRN
3.0 Survival surgeries require sterile instruments and aseptic surgical techniques. Indicate how instruments
will be sterilized for each surgery:
Several sterile packs containing all surgical instruments, skin clips, sutures, and a sterility indicator are assembled. Cath-
eters and scalpels are supplied in individual, pre-sterile packaging. After each set is used, it is cleaned with disinfectant,
rinsed with water, and placed in a “Germinator 500” glass bead sterilizer for 2-10 seconds, as recommended by the man-
ufacturer. The instruments are then removed and placed in between top and bottom sterile drapes to cool for at least one
minute prior to use. (The manufacturer states that 30 seconds is sufficient.) Handles will be oriented in the same direction
to avoid contamination. Catheters for rats are cut, pre-sealed, soaked in a high-level disinfectant, rinsed, and stored in a
container of sterile water or PBS before use.
4.0 Describe post-operative recovery from anesthesia, including frequency and type of observations. Also list
any lab tests, observations and management of potential experimental related disease, wound care, parenteral
fluids, special diet, etc.:
After surgery, animals are returned to the outer room of the surgical suite. They are placed in a cage, which contains a
warmed isothermal pad underneath a sheet of absorbent paper.
At least every 15 minutes, animals are monitored for the following: respiration occurring at a normal, regular rate; lack
of bleeding from the incision site; normal color; movement of the head or other body parts; movement about the cage and
position within the cage; and posture. Assuming other parameters are normal, when rats are moving about normally, the
thermal pads and papers are removed and animals are returned to their room. At the end of the surgical day, animals are
given buprenorphine injections.
5.0 Describe criteria for the assessment of post-surgical pain:

Criteria for pain assessment are those found at https://www.univ.edu/Assessing_pain_and_distress.pdf for each
species.
Animals will be assessed every 12 hrs from surgery until euthanasia. Rats will be assumed to be in pain if they squeak
or squeal, run in circles, exhibit rounded backs, or are ataxic. Pain will be treated with injections of buprenorphine every
12 hrs. If any of the signs listed above do not resolve after administration of buprenorphine, the animal will be euthanized.
In addition, animals will be euthanized if found to be unresponsive or to demonstrate signs of stroke (a possible complica-
tion of endocarditis).
6.0 Describe the management of post-operative pain in compliance with the institution’s post-operative
analgesia policy:
No special diet is required. Animals are assessed and provided additional buprenorphine injections every 12 hrs for 48
hrs. Activity level, posture, responsiveness, and presence of urine and feces are observed at each assessment. The neck
wound is assessed for signs of infection or hematoma. Most experiments end <18 hrs after the last required buprenor-
phine dose is administered. For experiments lasting longer, twice-daily assessment continues until euthanasia. If species-
appropriate signs of pain are observed, additional doses of buprenorphine will be provided every 12 hrs. If this does not
have the desired effect, or if the animal shows other signs of distress, such as labored breathing or abnormal movement
or responsiveness, it will be euthanized.
7.0 Describe the expected duration of post-surgical analgesia:

Surgeries typically last 20 minutes, but may range from 15 to 45 minutes. Animals are anesthetized just prior to surgery
with a cocktail that includes buprenorphine as an analgesic. Animals are typically fully recovered from anesthesia in 1 to
2 hrs. Post-operative analgesia is provided every 12 hrs for 48 hrs, and then as needed until the animal is euthanized.
484 Appendix IV
8.0 Describe the length of time the animal will be kept alive post-operatively:
2-7 days
9.0 Describe long-term care of chronically instrumented animals:

Rat records are stored in room 8-049.
10.0 Will multiple major survival surgeries be performed:

 Yes ● No
11.0 Personnel responsible for records:

Name E-Mail Office
12.0 Location of post-surgical records:

Location
08-049A
13.0 Post-surgical procedure location(s):

Location
08-049A
Biological Hazard Information

Complete Freund’s Adjuvant 0.2mL of 50%, no SC Once 7 weeks ABSL-1
(CFA) (+ purified protein) more than 0.1mL per
site
Live bacteria, possibly up to 10e8 IV Once 4 hours to 1 day ABSL-1
containing rDNA
S. sanguinis, S. mutans, S. ~10^8 cells IV Once 2 hours to 5 days ABSL-2
mitis, S. salivarius, S. gordonii,
S. parasanguinis, S. bovis, S.
pneumoniae, Kingella kingae,
A. actinomycetemcomitans, E.
faecalis + plasmid DNA/
promoter pEMcat rDNA

300
Out of the total number of animals for this group, how many are estimated to undergo biological hazard procedures:
300
2.0 Indicate the role of each biohazardous material or agent in the proposed study:
Complete Freund’s Adjuvant (CFA) and TiterMax are used as adjuvants for immunization in experiments designed to test
the efficacy of proteins for prevention of endocarditis. Our current study uses a pool of 10 proteins for each vaccine, re-
quiring a strong adjuvant. Thus, we expect to continue to need CFA for most of our vaccination experiments rather than
TiterMax, especially for rats. If new studies employing new individual test antigens are initiated, we will begin by trying
TiterMax.
Immunization is followed by injection of animals with live bacteria. Lack of infection or lower bacterial loads in vacci-
nated animals compared to control, mock-vaccinated animals indicates vaccine efficacy. In other experiments designed
to test the role of selected bacterial genes in endocarditis causation, bacteria containing mutations in the genes of inter-
est are injected into animals either singly or along with the parental or other mutant strains. These experiments reveal the
relative virulence of the mutant strains.
Notes on compounds:
The purified proteins pose no known or suspected risks to the animals. The Freund’s complete adjuvant may produce in-
flammation at the site of injection. Animals will be monitored daily after injection. Any animal that shows signs of distress
will be given buprenorphine as an analgesic until the lesion resolves, following consultation with animal resources per-
sonnel. If the lesion does not resolve, the animal will be euthanized. Freund’s incomplete adjuvant and Titermax list no
known risks. However, animals will be monitored daily for inflammation at injection sites.
The CFA and TiterMax are alternative treatments, so animals will receive one or the other, not both.
The live bacteria used in these studies (usually Streptococcus sanguinis, but possibly strains of Streptococcus mu-
tans, Streptococcus mitis, Streptococcus salivarius, Streptococcus gordonii, Streptococcus parasanguinis, Streptococ-
cus bovis, Aggregatibacter [Actinobacillus] actinomycetemcomitans, or enterococci) are normally present in the mouth
or GI tract of all humans, possess low virulence, and are categorized as Biosafety level 1 or 2. At the high doses injected,
the animals may develop fever. All animals will be provided with buprenorphine before and after injection. Animals will be
euthanized 2 hrs-5 days following injection of bacteria and will be monitored daily. If an animal showed signs of unallevi-
ated distress even after buprenorphine administration, it would be euthanized earlier. Further, if we find that significant
mortality occurs at 5 days post-inoculation, a shorter period will be adopted for these experiments.
Although listed above, the purified proteins and TiterMax pose no known or suspected risks to lab personnel, animal
caretakers, or the animals.
The Freund’s complete adjuvant that may be used in the first vaccination can induce inflammation if introduced intra-
dermally or into the eyes, and can lead to a positive reaction to the standard TB skin test. Limited risk to animal care
workers is posed by possible exposure to residual CFA on animals and in bedding materials during initial hours following
administration.
The live bacteria used in these studies are normally present in the mouth or GI tract of all humans, possess low viru-
lence, and are categorized as Biosafety level 1 or 2. All bacterial strains and related rDNA manipulations will be handled
under BSL-2 conditions. Preparation of doses will be conducted within a certified biological safety cabinet (BSC) while
donning proper personal protective equipment. Following inoculation, contact with infected animals is unlikely to cause
disease. Euthanasia usually occurs less than 24 hrs after infection, so rats will likely develop fever, but will usually not
have time to develop other, more serious complications. Rats will be monitored daily following injection of Freund’s com-
plete adjuvant for signs of excessive inflammation at the site of injection. Any animal that shows signs of distress will be
euthanized or will be given buprenorphine as an analgesic until the lesion resolves following consultation with animal
resources personnel. All animals are euthanized 2 hrs-5 days following injection of bacteria.
4.0 Describe the containment procedures to be followed to protect other animals, personnel and the
environment from the hazardous agents; include monitoring methods, frequency, the name of the person
responsible for monitoring and biosafety assigned by the IBC:
Syringes are filled with bacteria or adjuvant in BSL2 conditions a biosafety hood in the lab using a 3-way stopcock. After
filling, capped needles are placed on each syringe; thus, there is no recapping of needles, only attachment of capped
needles to the filled syringes. Used syringes will be placed in approved sharps containers without recapping of the nee-
dle. Unused (extra) syringes will be placed in the sharps container without removing the cap. Injection of Freund’s adju-
vant or live bacteria will be performed while wearing eye protection and other PPE.
Animals will be injected with bacteria or CFA in a separate part of the room, away from other animals. During the pe-
riod prior to completion of first change of bedding workers will don PPE to include N-95 respirator, eye protection, dispos-
able coveralls, and gloves. Following completion of first bedding change significant exposure threats in relation to this
agent should be eliminated and animal care workers may follow standard Animal Resources Division precautions.
Live Bacterial Strains and rDNA may be handled under ABSL-1 precautions in accordance with conditions established
in Animal Resources Division SOP.

incineration through Animal Resources Division.
486 Appendix IV
3. Bedding and other materials contaminated with live bacterial strains and/or pEMCat plasmid/rDNA materials are to
be managed as regulated medical waste (RMW) and disposed of via incineration (red-bagging).
4. Bacterial Proteins: Special waste handling procedures are not required for animals exposed to bacterial proteins
in the absence of live bacteria, pEMCat plasmid, and CFA hazards.
Chemical Hazard Information

Selected chemical hazard(s):

Complete Freund’s 0.2mL of 50%, no SC Once 7 weeks ABSL-1
Adjuvant (CFA) more than 0.1mL per
site

300
Out of the total number of animals for this group, how many are estimated to undergo chemical hazard procedures:
300
2.0 Indicate the role of each hazardous chemical in the proposed study:
CFA may be used as an adjuvant for immunization in experiments designed to test the efficacy of proteins for prevention
of endocarditis. Our most recent study used a pool of 10 proteins for each vaccine, requiring a strong adjuvant. We may
need to use CFA for future vaccination experiments as well, although it will not be our first choice.
The Freund’s complete adjuvant that may be used in the first vaccination can induce inflammation if introduced intrader-
mally or into the eyes, and can lead to a positive reaction to the standard TB skin test. Limited risk to animal care workers
is posed by possible exposure to residual CFA on animals and in bedding materials during initial hours following
administration.
Rats and rabbits will be monitored daily following injection of Freund’s complete adjuvant for signs of excessive inflam-
mation at the site of injection. Any animal that shows signs of distress will be euthanized or will be given buprenorphine
as an analgesic until the lesion resolves following consultation with animal resources personnel.
4.0 Describe the containment procedure to be followed to protect other animals, personnel, and the
environment from the hazardous chemicals including monitoring methods and frequency and the name of the
person responsible for monitoring:
Syringes are filled with CFA in BSL2 conditions a biosafety hood in the lab using a 3-way stopcock. After filling, capped
needles are placed on each syringe; thus, there is no recapping of needles, only attachment of capped needles to the
filled syringes. Used syringes will be placed in approved sharps containers without recapping of the needle.
Injection of CFA will be performed while wearing eye protection and other PPE. Animals will be injected with CFA in a
separate part of the room from other animals. During the period prior to completion of first change of bedding workers will
don PPE to include N-95 respirator, eye protection, disposable coveralls, and gloves. Following completion of first bedding
change significant exposure threats in relation to this agent should be eliminated and animal care workers may follow
standard Animal Resources Division precautions.
The investigator performing the study will be responsible for monitoring.

incineration through the Animal Resources Division.
Print Animal Arms

1.0 Total Study Animals:
964
2.0 Animal Groups:
Group Name Species # Yr 1 # Yr 2 # Yr 3 Pain Category USDA

Rabbit Pain Category D Rabbits 221 221 222 D yes
Rat Pain Category D Rats 100 100 100 D No
4. Resources
Research universities and research institutions typically maintain websites that are rich in information and resources
important to the conduct of research that uses either human or animal subjects. So checking your institution’s website is
a recommended first step. Content typically includes:
• Guidelines for obtaining approval and authorization to use human or animal subjects in research, including links to
institutional requirements, regulatory agencies, funding agencies, and applicable laws.
• Information on and access to training that is required prior to conducting research involving humans or animals.
Such training may involve online programs, lecture series, workshops, or courses. There also may be training
modules that deal with the review process, especially if submission and review of the protocol is electronic.
• Links to institutional forms needed to seek authorization to do subjects-based research.
• Policies and procedures of the IRB and the IACUC including review schedules and general logistics.
• Standard operating protocols that apply to the conduct of research involving human or animal subjects.
• Instructions and materials needed to address issues of noncompliance arising during the course of the research,
including inappropriate use of animals or unexpected or adverse events associated with the use of humans.
• Information on protocol development and preparation to assist you in skill building. Samples of approved protocols
may be posted as models for writing your own protocol. Some institutions offer the services of office staff to assist
in protocol development or protocol prereview. Similar types of assistance may include prereview services pro-
vided by the IRB or the IACUC.
• Information, policies, and forms on topics that may have relevance to human or animal subjects research including
conflict of interest, safety and biohazards, and issues of privacy and confidentiality.
Federal policy, guidance, compliance oversight, and other useful information may be found at the websites of the Office
for Human Subjects Research and the Office of Laboratory Animal Welfare. Both of these offices fall under the authority
of the U.S. Department of Health and Human Services.
http://www.hhs.gov/ohrp/humansubjects/index.html
http://grants.nih.gov/grants/olaw/olaw.htm
Selected examples of institutional websites dealing subjects protections may be found at the following URLs.
Vanderbilt University
https://www4.vanderbilt.edu/irb/
University of Pittsburgh
http://www.iacuc.pitt.edu/
488 Appendix IV
University at Buffalo
http://www.research.buffalo.edu/rsp/default.cfm
University of California, San Francisco

http://www.research.ucsf.edu/chr/Index.asp
http://or.ucsf.edu/larc/home.html
University of Wisconsin
http://www.grad.wisc.edu/respolcomp/hrpp/
appendix V
Example of a U.S. Patent Specification
A s a postdoctoral trainee at the University of Illinois in the late 1960s,

Al Chakrabarty was intrigued with the extraordinary nutritional di-
versity of microorganisms. The pioneering work of Chakrabarty, his post-
doctoral mentor I.C. Gunsalus, and their lab colleagues helped define the
genetic basis of hydrocarbon degradation in species of the bacterium Pseu-
domonas. Their research revealed that pseudomonad bacteria often carried
genes on extrachromosomal elements (plasmids) that encoded enzymes
able to degrade complex hydrocarbons. Such gene ensembles were found
on specific plasmids: for example, one plasmid encoded the enzymatic
pathway for the degradation of n-octane, another encoded the instructions
for camphor degradation, and so on. Equally important was that many of
these plasmids could be moved between bacterial cells by a genetic transfer
mechanism called conjugation. So it was possible to construct pseudomo-
nad strains that contained multiple plasmids and, thus, the genetic infor-
mation encoding multiple degradative pathways.
In 1971, Chakrabarty joined the research and development center of the
General Electric Company in Schenectady, NY. Although his initial work at
GE involved the study of bacterial degradation of lignocellulosic com-
pounds, he continued to think about the hydrocarbon-degrading capabili-
ties of the pseudomonads. Chakrabarty reasoned that it should be possible
to bring together by conjugation several different plasmids into the same
Pseudomonas strain. He further believed that selection of specific plasmids to
ensure a variety of degradative capabilities would create a “superstrain” able
to degrade components of crude oil, for example. Chakrabarty did the
doi:10.1128/9781555818487.AppV
489
490 Appendix V
experiments to test these ideas and demonstrated that a multi-plasmid-

containing pseudomonad strain that he constructed was able to degrade an
oil spill in a fish tank.
On June 7, 1972, GE on behalf of Chakrabarty sought patent protec-
tion for the oil-eating pseudomonad and the process of bacterial crude oil
degradation. As noted in chapter 9, the eventual issuance of this patent had
a major impact on biotechnological intellectual property. However, once
submitted, this patent was almost 9 years in the making, finally being
granted on March 31, 1981. This extended period was considerably longer
than it takes most patent applications to be considered and acted upon. In
large part, the reason for this was that the Chakrabarty invention stirred
much controversy and debate once it was filed for consideration. In 1974,
the U.S. Patent and Trademark Office (PTO) rejected the claims related to
the oil-eating bacterium but allowed the claims related to the degradation
process. GE appealed the rejection, beginning a 6- year legal odyssey.
During this period, the application moved multiple times between the
PTO, the PTO Board of Appeals, the U.S. Court of Customs and Patent
Appeals, and the U.S. Supreme Court. At the center of the legal delibera-
tions was the historic conception that living organisms— products of
nature—were unpatentable. At times the arguments became sidetracked
over issues like the possible threats of genetic engineering research and the
deliberate release of engineered organisms into the environment. On June
16, 1980, the U.S. Supreme Court voted 5 to 4 to uphold the patentability
of Chakrabarty’s oil-eating bacterium. In effect, this decision said that a
nonhuman life form could be patented if its creation could be attributed in
some way to human intervention. The Court’s ruling marked a sea change
in the intellectual property and biotechnology worlds.
In the parlance of intellectual property law, Chakrabarty’s experiments
at GE “reduced his invention to practice.” First, he showed that strains
with multiple-degradative capability could be constructed in the labora-
tory. A novel, nonhuman life form had been created by a scientist. Second,
he demonstrated that a proposed use of this new life form—cleanup of
environmental oil spills—was possible in a controlled, laboratory setting.
In doing so, Chakrabarty met important legal criteria critical to obtain-
ing a patent. First, he demonstrated his invention—a genetically modified
Pseudomonas bacterium—to be a new composition of matter that was useful
for oil spill cleanup by biological means. Second, his invention was novel,
not having been previously described or known to exist in nature or in the
laboratory. Last, he could show that the claimed bacterium was not obvi-
ous compared with reports of other bacterial cultures.
The full text of the Chakrabarty patent specification is presented in this
appendix. “Specification” is the term used to identify the document describ-
ing the invention for which the patent protection is being sought. Attached
to the specification are one or more drawings that are necessary to support
Example of a U.S. Patent Specification 491
or help understand the invention. These are like figures in a scientific paper.
Another similarity to scientific papers is that a patent specification usually
contains data and information presented in the form of tables.
The specification begins with a descriptive title. It then lists the inven-
tor and may list the assignee, if the inventor has assigned or transferred
ownership in the invention to another. The inventor is the person or per-
sons who conceived and reduced the invention to practice either by the
filing of a patent application or by developing and testing the invention.
The assignee is the organization (or person) to which the property rights
of the patent are granted. In a university setting, the inventor and the
assignee have usually worked out an agreement for the sharing of profits
associated with the use or licensing of the patent. The inventor and the
assignee could be one and the same. Patents, like scientific publications,
have a brief abstract summarizing the invention and how it works.
The “Background” section of the specification is what we might call an
extended version of the “Introduction” in a scientific paper. This section
contains a discussion of the relevant literature to the field or area of “art.”
A variation of this latter terminology is “prior art,” which strictly means
references or other documentation that the PTO or a court (or possibly
the patent applicant) considers to be a barrier to the patentability of the
claimed invention. In the Chakrabarty specification, a glossary was in-
cluded in the “Background” section to aid in understanding the rest of the
specification. Next, there is a brief summary of the invention. Then there
is a description of the invention, referred to as the “preferred embodi-
ment.” This is the section where the inventor explains how the invention
works or operates. The description here must be detailed and thorough.
The presentation must be precise enough that someone “skilled in the art”
can practice the invention. A patent specification must fully disclose every-
thing needed to replicate and use the invention. This section ends with a
summation of the invention, emphasizing its advantages and use.
A patent specification concludes with a description of the claims associ-
ated with the invention. These numbered sentences or sentence fragments
precisely define the nature of the invention and its uses. In other words,
the claims are what others will be prevented from making, using, selling, or
importing should the patent be granted. Only the inventor (or assignee)
will have the right to exclude others from carrying out the actions listed in
the claims once patent protection is awarded. Even the inventor and
assignee may be excluded from practicing the claimed invention, if it is
dominated or considered to be within the claims of a broader invention in
a patent to another party.
To fulfill the requirements for a patent application, the patent applicant
must also pay a filing fee and provide a signed oath that the inventor(s) is
the original and first true inventor of the claimed invention.
492 Appendix V
494 Appendix V
496 Appendix V
498 Appendix V
500 Appendix V
appendix VI
Laboratory Notebook Instructions
The following instructions for keeping laboratory notebooks are used by the re-
search division of a company.
The primary purpose of this lab notebook is to protect your and the com-
pany’s patent rights by keeping clear, complete, and legible records of all
original work in a form acceptable as evidence if any legal conflict arises.
The laboratory notebook is the exclusive property of the company and
must not leave the premises. Laboratory notebooks must be stored away
from risk of damage by chemicals, heat, water, etc. Notebooks not in use
are stored in a locked fireproof cabinet with authorized access by person-
nel. Their contents are not to be disclosed to anyone without written au-
thorization by an officer of the company. You are responsible for the safe
keeping and maintenance of the notebook. Report immediately its damage
or loss to your supervisor. It is a legal document which is valuable in estab-
lishing invention dates. As such, it must be signed and dated daily by the
contributing scientist, and then signed weekly by another scientist who has
witnessed the experiment and/or reviewed the data. These records may be
crucial in determining dates of invention on which a patent claim may
depend.
It is essential to document the progress of an experiment, beginning
with the objective, explanation of the method and materials, results and
discussion, and conclusion. This should be written in a clear and concise
manner so that it can be followed by another scientist with duplication of
results at a later date. The laboratory notebook is also a permanent record
doi:10.1128/9781555818487.AppVI
503
504 Appendix VI
of original ideas, future steps, observations, and discussions with others as

well as graphs, photos, computer printouts, etc. Specific instructions are
given below to help you meet the requirements outlined above.
1. Use permanent, waterproof ink when making entries. Write clearly

and legibly.
2. Have a table of contents in the front of the notebook to show a
chronological record of work that is kept up-to-date.
3. When starting a page, enter the project name, number, title, note-
book number, and date, which should be in agreement with the ta-
ble of contents.
4. If you are working on different projects, use one notebook for re-
cording all the projects and keep entries in chronological order.
Refer to previously recorded methods, data, and information re-
lated to the same project by the notebook and page number.
5. Use your notebook as a diary of all your work, so that one reading
the notebook can follow the progress of your work.
6. State the objective, purpose, and plan of each experiment clearly
and concisely.
7. Record your work clearly and completely so that a coworker can
repeat your experiment based on your description and reproduce
the same observations as originally recorded by you.
8. Give a complete description of your experiment in the chronologi-
cal order in which it was conducted.
9. Record all operating details and conditions, including calculations,
yields, product or compound names, lot numbers of standards and
reference materials, solvents, buffers, suppliers, and any expiration
dates. Record cell line information, animal order number, species,
strain, sex, number, and vendor (see specific instructions pertaining
to chemistry in appendix 1).
10. Record the raw data, both negative and positive results, and your
observations. Include diagrams, photos, data plots, plans, and pro-
cedures.
11. Attach supporting records where practical; where volume and size
prohibit this action, store such records, after properly referencing
and cross-indexing in an orderly form that is readily retrievable.
For HTS (high-throughput screening), attach summary of each
run and cross-reference the source and date of electronic data. Sign
and date the summary. Document Testsets in summary to link to
original data in ActivityBase.
12. Avoid making notes on loose paper for later recopying. If you take
notes or draw a schematic diagram or the like on loose-leaf paper,
or have a drawing made and you prefer not to copy it into your
Laboratory Notebook Instructions 505
notebook, tape it to a notebook page. Sign and date. Signature

should cross both the attached material and the notebook page.
Tapes, photographs, computer printouts, and other records should
be handled in the same manner.
13. Avoid stating opinions; be factual and let the results speak for
themselves.
14. Make entries in your notebook immediately when you have an idea,
and concurrently with the progress of your work. Sign and date
each entry. The inventing scientist should enter “inventions” in the
notebook. If the idea is tested by others, these people should cross-
reference the inventor’s notebook and page number.
15. Do not use correction fluid nor erase; draw a single line through
incorrect entries so that the entries are still readable. Sign and date
each change.
16. Do not skip or remove pages; make all entries on consecutive pages.
Any unused portion of a page or pages should be crossed through
diagonally and signed and dated across the line.
17. If abbreviations or code names or numbers are used, give their
meanings or definitions or identify the compound or trademark,
trade name, and source.
18. Include all ideas, conceptions, suggestions to others, calculations,
objects, plans or experiments, tests, results, observations, the field
of usefulness, and the details of any discussions with suppliers or
others outside the company, including dates of discussions. Also,
specify the person or persons who originated each new idea, and to
whom the idea was disclosed and the date of disclosure.
19. Do not make new notations on entries previously made. Instead,
make such notations on a new page and sign and date them, making
cross-references to the earlier related pages.
20. When it is helpful to supplement your entries, you should cross-
reference related pages of your notebook, the notebooks of others,
normal drawings, logs, etc.
21. Explain each entry to at least one witness who is not your project
leader or supervisor or colleague working on the same project, and
have him or her sign and date the pages. This should be done within
1 week after the entry is made.
22. Record the names of other scientists and witnesses present during
any experiment, test, or demonstration and have them sign your
notebook. If no witness is present during an important test, repeat
it in the presence of a witness. In any case where someone witnesses
a test, as distinguished from merely witnessing test data that has
been entered into your notebook, he or she should so indicate in
the notebook. In other words, he or she should state, “Witnessed
506 Appendix VI
the test of . . .” to clearly indicate that the person not only reviewed
the data but actually saw the test performed.
23. Some notes on signing and dating the notebook:
• Sign and date each entry, such as new ideas or inventions, at the
end of each day.
• Sign and date each page at the bottom as it is completed.
• Have a witness and/or scientist not working on the project read
and understand the entries; sign and date each page weekly.
24. Do not disclose the notebook and its contents to anyone outside the
company unless you are authorized by the organization. You must
return the notebook when you have finished with it, upon request, or
upon termination of your employment. It should be kept in a pro-
tected place. If loss occurs, notify your supervisor immediately and
prepare a written report describing the circumstances of the loss.
25. The departmental head or his or her designee may perform unan-
nounced auditing of notebooks in circulation if necessary.
Appendix 1
Specific Instructions Regarding
Chemistry Notebooks
The following information is required in the chemistry notebook.

• Title: “Preparation of . . . ,” “Solubility testing of compound # . . . ,”
etc.
• Top of page: date when experiment was started.
• Structural formulas or common abbreviations (such as EDC, HOBt).
• Molecular weight, amount of compound used in both g and mmol; if
a reactant is measured by volume, then its density must also be listed.
• Source of reactants and solvents (vendor; notebook page; if someone
else’s notebook, then also give that person’s name).
• Reference to literature procedure or other notebook pages and pur-
pose of the experiment, if appropriate.
• Detailed description of the experiment (ask yourself: can someone
else repeat the procedure without asking you for details?); reference
to other pages is okay if the reaction is conducted in about the same
way (e.g., “procedure as described on p. 56 except that reaction time
is increased to 2 h”); referring to a procedure on 10-mg scale when
the reaction itself is conducted on a 5-g scale is not acceptable.
Points that need to be clear:
• Order of mixing the reactants.
• Mixing temperature.
Laboratory Notebook Instructions 507
• Temperature of reaction: is it the temperature of the heating/cooling

bath or is it measured inside the reaction mixture?
• How is the reaction monitored? Reaction time?
• Workup: if it involves extraction, how much solvent was used?
• Chromatography: medium (silica gel?), column dimensions, eluents.
If a gradient is used, it must be clear what combinations (“mixture of
DCM and MeOH” alone is not acceptable). If prep. high-
performance liquid chromatography is used, the conditions can also
be printed and filed together with the analytical data. If TLC is used
for monitoring the reaction or the elution from a column, then the
TLC sheets must be copied into the notebook together with the elu-
ents used.
• If material is submitted, list information necessary for compound
registration (compound #, vial bar code, etc.).
Additional Resources
Links to scientific record-keeping guidance published by selected universi-

ties, government, and private organizations may be found on this text’s
companion website:
http://www.scientificintegrity.net
Examples include those published by the National Institutes of Health:

http://sourcebook.od.nih.gov/ethic-conduct/RECORDKEEPING.pdf
Available recommended reading includes a chapter on data management

and laboratory notebooks in the Howard Hughes Medical Institute publi-
cation Making the Right Moves: A Practical Guide to Scientifıc Management for
Postdocs and New Faculty, 2nd ed:
Management/Making%20the%20Right%20Moves/moves2_ch8.pdf
appendix VII
Laboratory Safety Resources
Overview
W orking in research laboratories, especially those in the biomedical,

life, and physical sciences, carries the risk of harm to both people
and property. A brief inventory of things found in research laboratories
supports that assertion. To illustrate with examples, consider the possible
dangers associated with working with high-voltage instrumentation, pow-
erful magnetic fields, toxic chemicals including mutagens and carcinogens,
radiation, infectious agents, and animals capable of biting or scratching.
Policies, laws, and required training and inspections dealing with labora-
tory safety have long been part of the research environment. However,
despite a legacy of safety awareness and prescribed practices, laboratory
accidents continue to occur, capture headlines, and in some cases, result in
tragic consequences. Failure of scientists to promote laboratory safety
through education and training, to ignore policies and best practices, or to
avoid sanctioning transgressions is irresponsible behavior. Furthermore,
failure to meet the responsibilities associated with creating and maintain-
ing a safe laboratory environment erodes the trust of the public, who—as
discussed elsewhere in this book—are investors and stakeholders in the
research enterprise.
In early 2013, Nature published the results of a survey administered to
approximately 2,400 scientists. The survey was the collaborative effort of
the Nature Publishing Group, BioRAFT (a provider of safety compliance
software), and UCLA’s Center for Laboratory Safety. It aimed to gain
doi:10.1128/9781555818487.AppVII
509
510 Appendix VII
knowledge about attitudes and behaviors related to laboratory safety. The

survey respondents represented an international cross section, with most
coming from the United States and the United Kingdom and other oth-
ers coming from Europe, China, and Japan. The survey data published in
Nature were both illuminating and provocative.
Responses to broad-based items dealing with general beliefs about the
climate of laboratory safety were positive and encouraging. For example:
• 95% rated laboratory safety as being very or quite important.
• 86% indicated that their laboratory was a safe place to work.
• 91% indicated they were aware of and understood training
requirements.
But in contrast to these data, responses to more specific items in the
survey gave a disparate picture of the respondents’ attitudes and knowl-
edge related to laboratory safety. Examples included the following.
• 45% indicated that overall laboratory safety could be improved.
• 64% reported working alone in the lab multiple times per week.
• 54% reported not wearing lab coats at all times.
• 46% reported sustaining some type of injury in the laboratory set-
ting; among the more common injuries were lacerations, needle
pricks, thermal and chemical burns, and chemical inhalation.
• 30% reported the awareness of at least one laboratory accident in
their career that resulted in major injury requiring medical attention.
• 40% reported not having received safety training on specific agents
or hazards with which they worked.
• 40% of junior and supervised respondents indicated that their super-
visor failed to regularly check their performance in terms of safety.
Comments on the results of this survey have offered various kinds of cau-
tionary observations. This survey is arguably the first of its kind. Interpret-
ing and drawing conclusions from the results may be premature in the
absence of comparative data. Nevertheless, the data at face value suggest a
disparity that some have argued bespeaks a false sense of security about
safety in their laboratories. As seen above, the generally held beliefs about
the importance of lab safety, its existence in practice, and the implementa-
tion of associated training seem to be at odds with the reported realities of
day-to-day practice. Additional analyses and interpretations of these data
are likely, as are follow-up survey instruments. For example, some suggest
that collecting survey data from laboratory safety professionals and research
administrators—in addition to researchers themselves—is also needed.
Clearly more information gathering and research on the realities of
safety in the research workplace are needed. In this vein, the National Re-
search Council—chartered by the U.S. government to provide independent
Laboratory Safety Resources 511
scientific advice—set up a commission in 2013 to examine laboratory safety

and to provide recommendations for improving it on university campuses.
The 13-member commission was charged with examining laboratory safety
in chemical research in nonindustrial settings. The commission will make
recommendations aimed to improve safety in chemistry research laborato-
ries specifically, as well as other research laboratories. The commission in-
cludes several behavioral scientists. In this connection, the commission will
“examine knowledge from the behavioral sciences, and experience with
safety systems from other sectors (such as industrial research facilities, nu-
clear energy, aviation and medical) for key attributes of successful safety
systems and cultures.” The intent is to apply information learned from
these sectors to nonindustrial laboratory research. Ultimately, the commis-
sion hopes to “provide guidance on systems (such as training and reporting)
that might be established, maintained, and utilized to raise the overall safety
performance of US chemistry research laboratories.” The commission’s re-
port is expected to be published in the summer of 2014.
New developments related to the survey published in Nature and the
National Research Council commission’s progress and report will be
posted on this book’s companion website: www.scientificintegrity.net.
Resources
Creating a culture of safety in the laboratory environment is vitally depen-

dent on you, your supervisor, and the relationship that exists between the
two of you. Together, both of you must be cognizant of what training you
need to successfully complete in order to work safely on your research.
Besides knowing what training you need, you must know when you need
to complete it as well as when you must complete continuing education or
recertification training. And this applies to your supervisor, too. First and
foremost, doing this is about the ensuring the safety of you and those who
work around you. It’s simply the right thing to do. But safety training often
fulfills legal requirements that, if not met, can create institutional exposure
to investigation and prosecution for noncompliance. In fact, for some
kinds of noncompliance you may be personally responsible for your ac-
tions, and this may lead to criminal prosecution. Your supervisor must en-
sure that you complete the training in a timely fashion, and he or she must
be prepared to intervene if training requirements are not met. Once ap-
propriate training has been completed for whatever specific areas are
needed, it’s up to you to habitually practice what you have learned. Cutting
corners is not allowed. You need to model safe laboratory practices in all
that you do. The entire research team must work together to create a cul-
ture of laboratory safety. The role of the laboratory supervisor—usually
the principal investigator—merits reemphasis. He or she is responsible for
512 Appendix VII
making sure all trainees, investigators, and staff complete training that al-
lows them to understand and deal with the hazards associated with their
work. And staff includes administrative personnel who handle hazardous
materials for nonexperimental purposes such as shipping, receiving, stock-
ing, and inventorying.
Another player in laboratory safety is the institution itself, specifically the
administrative infrastructure responsible for the oversight of the workplace
environment. The form and substance of safety training is determined by
the institution at which you work. The responsibilities associated with safety
training, compliance, inspections and monitoring, investigations, and acci-
dent remediation generally rest in a single office or division. Names of these
vary, but common constructs are “Occupational Health and Safety” and
“Environmental Health and Safety.” They ensure that the government-
sponsored safety polices are in place, monitored, and enforced. They also
produce safety manuals and guidance materials, develop and deploy
institution-specific safety policies, and deliver training in person or provide
various training platforms (e.g., online training modules) to meet safety
needs. Sometimes training modules are “homegrown,” while other types of
instructional delivery are outsourced to vendors who provide all the needed
materials, usually via an electronic interface or electronic media. Many insti-
tutions keep their online training on secure servers, accessible only to insti-
tutional members by electronic ID and password. Some allow their training
to be in the public domain, allowing open access.
Compiled below are a variety of resources that deal with laboratory
safety topics and training. This compilation is intended to familiarize you
with the kinds of resources that may be useful in allowing you to maintain
the highest standards of safety when working in the research laboratory.
However, it is important that you complete whatever training is specifi-
cally prescribed and required by your institution. Rely on your supervisor
to help guide you to these resources. And never assume that completion of
a training module that you have discovered in the public domain may be a
substitute for the requirements of your institution’s training programs.
General resources
The Centers for Disease Control and Prevention (CDC) provides a num-
ber of publications and resources that deal with workplace safety.
Chemical safety
http://www.cdc.gov/niosh/topics/chemical-safety/
Biosafety
http://www.cdc.gov/biosafety/publications/index.htm
National Select Agent Registry

http://www.selectagents.gov/
Fleming D, Hunt D (ed). 2006. Biological Safety: Principles and Practices,

4th ed. ASM Press, Washington, DC.
Moran L, Masciangioli T (ed). 2010. Chemical Laboratory Safety and Secu-

rity: A Guide to Prudent Chemical Management. National Academies Press,
Washington, DC. http://dels.nas.edu/resources/static- assets/bcst/miscel
laneous/Chemical-Laboratory-Safety-and-Security.pdf.
National Research Council. 2011. Prudent Practices in the Laboratory:

Handling and Management of Chemical Hazards, updated version. National
Academies Press, Washington, DC. http://www.nap.edu/catalog.php?
record _id=12654.
Occupational Safety and Health Administration. 2011. Laboratory

Safety Guidance. Occupational Safety and Health Administration, Wash-
ington, DC. https://www.osha.gov/Publications/laboratory/OSHA3404
laboratory-safety-guidance.pdf.
The United States Nuclear Regulatory Commission website offers re-

sources on medical, industrial, and academic uses of nuclear materials.
http://www.nrc.gov/materials/miau/regs-guides-comm.html
World Health Organization. 2004. Laboratory Biosafety Manual, 3rd ed.

World Health Organization, Geneva, Switzerland.
http://www.who.int/csr/resources/publications/biosafety/Biosafety7.pdf?ua=1.
Resources on lab surveys

Van Noorden R. 2013. Safety survey reveals lab risks. Nature 493:9–10.
http://www.nature.com/news/safety-survey-reveals-lab-risks-1.12121.
The survey also appears in Scientific American: http://www.scientificameri
can.com/article/safety-survey-reveals-lab-risks/.
The Topline Edition of the 2012 UC, BioRAFT and NPG Lab Safety Sur-
vey Data:
http://figshare.com/articles/THE_TOPLINE_EDITION_OF_THE_2012_UC
_BIORAFT_AND_NPG_LAB_SAFETY_SURVEY_DATA/105431
For coverage of the survey on the BioRAFT website, see:

http://www.bioraft.com/blog/laboratory-safety-culture-survey-lifting-veil
514 Appendix VII
National Research Council Commission on Establishing and Promoting a

Culture of Safety in Academic Laboratory Research:
http://sites.nationalacademies.org/DBASSE/BOHSI/CurrentProjects
/DBASSE_082715
Examples of institutional safety resources

The mission of the UC Center for Laboratory Safety, located at UCLA, is
to sponsor and support research in laboratory safety, develop and translate
research into applied best practices, and facilitate implementation and op-
timization of laboratory safety practices. Although this site contains a sig-
nificant amount of material that is password protected for use by
institutional members, it also is a rich source of public domain information
on laboratory safety with a resource library, links to relevant organizations
and institutions, and an archive of relevant media stories.
http://cls.ucla.edu/
Some institutions publish comprehensive safety manuals addressing the

full array of safety issues: biological, chemical, radiation, and other areas.
Yet others publish safety manuals that address a specific area. Below is a
small sampling of institutional safety manuals.
You should be familiar with your own institution’s safety manual(s).
These are usually easy to find on your institution’s website. They may be
behind a firewall that will require you to access them using your institu-
tional electronic ID and password. Also look for information on training
requirement completion deadlines. Many institutions post easy-to-read
charts or matrices that describe training requirements needed by specific
categories of personnel (e.g., graduate students, postdocs, and staff and
faculty).
Duke University
http://www.safety.duke.edu/safetymanuals/Lab/default.htm
Harvard University
http://vpr.harvard.edu/pages/environmental-health-safety
National Cancer Institute

http://home.ncifcrf.gov/ehs/uploadedFiles/STANDARD%20OPERATING%20
PROCEDURE%20GUIDELINES021810final.pdf
Princeton University
http://web.princeton.edu/sites/ehs/index.html
University of California, Los Angeles

http://www.ehs.ucla.edu/LabSafetyManual.pdf
University of California, San Diego

http://blink.ucsd.edu/safety/research-lab/index.html
University of California, San Francisco

http://ehs.ucsf.edu/laboratory-safety-manual
University of North Carolina

http://ehs.unc.edu/manuals/laboratory/
University offices that oversee environmental health and safety

Massachusetts Institute of Technology
http://ehs.mit.edu/site/
Penn State University

http://www.ehs.psu.edu
Purdue University
https://www.purdue.edu/rem/index.htm
Stanford University
http://www.stanford.edu/dept/EHS/prod/
University of Georgia
http://esd.uga.edu
University of Washington
https://www.ehs.washington.edu/
Training modules
Lab Safety Workspace offers an ensemble of online safety training courses
that are free but require registration.
http://labsafetyworkspace.org/
BioRAFT provides commercial training modules covering a wide selection

of safety topics relevant to research.
http://www.bioraft.com/bioraft-modules
Index
A politics of, 192–194

Abortion, fetal tissue research and, 156–157 utilitarianism and, 173–174, 176–178
Abstract, evaluation of, in peer review, 110 case studies of, 44, 197–203
Academic freedom, protection of, 226–227 ethical issues in, 173–174.176–181
Accidents, laboratory, 509–515 historical practices in, 173–175
Accountability humane care in, 187–192
in collaborative research, 250–251 institutional committees for, 183–190
as core value, 37 legislation on, 182–184
Accuracy, 37 moral judgments in, 176
Acknowledgment section, of publications, 105 political realities of, 192–194
Active listening, in collaborative research, 262 protocols for
Adolescents, research on, 152–153 review of, 187–189
Advising, vs. mentoring, 54 sample of, 464–487
Advocacy, in mentoring, 56–57 resources for, 487–488
Affordable Care Act of 2010, 372 security in, 195–196
Agreements, in collaborative research, 251–254, 257 standards for, 441–442
Alzheimer’s Disease Sequencing Project, 374 survey form for, 391, 404–405
America Invents Act of 2011, 305, 307, 309, 313– Animal Liberation, 176–177
314 Animal Welfare Act, 182–189, 364
American Association for Cancer Research, cell line Antivivisectionism, 173–174
policy of, 97 arXiv archives, 116–117
American Association of University Professors, 224 Asilomar conference, on DNA technology, 366,
American Chemical Society, preprints of, 117 368–371
American Phytopathological Society, 96 Assertive behavior, in conflict resolution, 269–271
American Society for Cell Biology, on impact Association of American Medical Colleges, on
factors, 120–121 mentoring, 63–64
American Society for Microbiology, biosecurity Atlas, Ronald, on biosecurity, 377
guidelines of, 95 Authorship, 83–105
Anesthesia, for animals, 184, 187–188 biosecurity and, 95–96
Animal Care and Use Committee, 93–94 case studies of, 43, 123–129
Animal experimentation, 173–208 coauthors, 86, 88, 101–104, 300–301
animal rights in, 174–176, 178–181, 192–194 in collaborative research, 267
activists in, 192–194 conflict of interest in, 92–93
birth of movement, 173–174 contribution to, 88, 99
deontology and, 178–181 copyright for, see Copyright(s)
517
518 Index
Authorship (continued) Birenbaum Carmeli, Daphna, on human subject

criteria for, 86–88 research, 152
definition of, 88, 97–98 Blogs, postpublication, 118
digital image integrity in, 94–95 Books, data, see Record keeping, data books for
dispute handling in, 90–91 BRCA gene testing, 372–373
electronic data manipulation in, 92 Brenner, Sydney
first (principal) author, 103 on cheating, 17
ghost writers, 87, 104–105 on reporting research results, 8
guest, 104–105 Bulger, Ruth, on scientist responsibility, 363
honorary, 87, 105 Burch, Rex, on animal experimentation, 190–191
inappropriate, 104–105 Burroughs Wellcome Fund, record-keeping
instructions for, 87–97 guidelines of, 330
manuscript preparation in, 87–88 Business
manuscript review in, 89 collaborative research with, 271–273
multiple, 86, 88, 101–104, 300–301 consultation for, 221–222
peer review and, 105–113, 109 equity interests in, 229–230
postpublication comments and, 119 methods used in, patents for, 313
pressure to publish and, 85–86 preferential information access agreements with,
prior publication and, 90–91 226
responsibility in, 101–103 research funding from, 211–212, 219–220
senior (primary) author, 101–103 scientist interactions with, 211–212, 221–222
shared research materials in, 92
standards for, 431, 436–437 C
submitting author, 103 Calculus-based trust, 256–257
survey forms for, 390, 399–400 Caplan, Arthur, on lying, 16
unpublished information citations in, 91–92 Career counseling, in mentoring, 56–57, 67
Autoradiographs, in data books, 333 Carmeli, Yoram, on human subject research, 152
Avian influenza virus, genetic engineering of, 378– Carmichael, Emmett, on scientist responsibilities,
380 262–263
Carruthers, Peter, on animal rights, 178, 181
B Casadevall, Arturo, on retracted papers, 122
Bacterial restriction enzymes, 367 Case studies, see specific subjects
Barker, Kathy, on record keeping, 330 Categorical imperative principle, 34–35
Barner, Dionne, on dual-use review policy, 96 Cell lines
Bauer, Henry, “myth of the noble scientist,” 5–7 disclosure of, 97
Bayh-Dole Act, 219, 307, 309 origin of, 97
Bebeau, Muriel, on moral reasoning, 40 patents for, 310–312
Beckwith, Jon Center for Strategic International Studies, on
lactose operon isolation by, 365 bioterrorism, 381
on rDNA, 370 Chakrabarty patent, 489–501
on reporting research results, 9 Children, research on, 152–153
Belmont Report, 137 Chimeras, patents for, 309–310
“Bench to bedside” research, 361–362 Citations, in journals, 120
Beneficence, 137 Clinical and Translational Science Awards, 245, 362
Bentham, Jeremy, utilitarianism theory of, 32–34, Clinical trials registry, 94
176–177 Clinton, Bill, on Tuskeegee syphilis study, 136
Berg, Paul, on rDNA, 365, 367–370 Cloning, 310–311
Bethesda Statement, on open-access publication, Coauthorship, 86, 88, 101–104, 300–301
114–115 Codes
Biological specimens, noninvasive, collection of, of ethics, of professional societies, 29
148–149 for research, 10–11, 13
BioRAFT, laboratory safety survey of, 509–510 Coercion, for consent, 138–139, 139–142
Biosecurity, in publication, 95–96 Cohen, Carl, on animal rights, 178, 181
Bioterrorism, dual-use research of concern and, Cohen, Stanley, on DNA technology, 367
376–381 “Coin of the realm,” publication as, 83
Index 519
Cold Spring Harbor, rDNA discovery at, 366 Commitment, moral, 40

Cold Spring Harbor Laboratory Press, manuals of, Communication, see also Publication
339 in collaborative research, 253–254, 261–263
Collaborative Electronic Notebook Systems in mentoring, 59–60, 67
Association, 350 of research implications, 362
Collaborative research, 243–285 Compensation
accountability in, 250–251 conflict of interest and, 221–222, 229–230
agreements in, 251–254, 257 from different sources, 215
authorship issues in, 267 multiple pay for one job, 222
case studies of, 45, 276–283 Competence, recommendations for, 48
centers for, 244–246 Competence-based trust, 256–257
challenges of, 247–249 Competing interests, 209–241
choosing personnel for, 248–249 case studies in, 235–239
communication in, 261–263 conflict of conscience, 215–217
conflict in, 269–271, 274–275 conflict of effort, 213–215
custody issues in, 267–269 management of, 231–232
data sharing in, 253–254, 261–263, 267–269 overview of, 209–213
disagreement in, 269–271 terminology of, 209–210
diversity in, 266–267 Competition, patents and, 314
drivers of, 244–245 Compromise, in collaborative research
example of, 245–247, 249–250 disagreement, 269–271
expectations of, 260–261 Computers
goals of, 257–258 for record keeping, 346–347
grants in, 251, 254–255 software for
inclusion in, 266–267 copyright and copy protection, 302–303, 313–
with industry, 271–273 314
institutes for, 244–246 licensing of, 295, 302–303
institutional positions on, 249 Concluding, in collaborative research, 256
intellectual property resulting from, 251 Conduct, see also Misconduct
interdisciplinary, 244–246 recommendations for, 48
international, 262–263, 273–274 standards of, 429–443
involving different research sectors, 271–273 Conferences, reimbursement for, 220
joint appointments in, 254–255 Confidentiality, 29
language differences in, 262–263 in collaborative research, 272
meetings in, 262 of genetic information, 374–376
mentoring in, 265–266 in human subject research, 145, 153–156
nature of, 249–251 insider trading and, 227
new members of, 258–260 in patents, 308
offer letter in, 253–254 in peer review, 108–109
ownership of, 267–269 standards for, 437–438
power in, 263–265 Conflict, 209–241; see also Competing interests
publications in, 274 causes of, 211–212
responsibilities in, 250–251, 254 of conscience, 215–217
standards for, 438 of effort, 213–215
survey form for, 391, 406–407 of interest, 217–231
team dynamics in, 255–265 academic, 226–227
time frame for, 261 business relationships and, 211–212
trust in, 256–257 case studies of, 44–45, 235–239
vision for, 257–258 circumstances favoring, 219–220
Coller, Barry, on diversity, 266 in collaborative research, 269–271
Collins, Francis S., on DNA testing, 374–375 compensation and, 221–222
Colon cancer genes, collaborative research on, 245– vs. conflict of effort, 213
247 in courseware, 223
Commercialization, of inventions, conflict of entrepreneurial climate and, 219–220
interest and, 212, 230–231 equity interests, 229–230
520 Index
Conflict (continued) Council of Canadian Academies Expert Panel on

family and, 211–212 Research Integrity report, 38–39, 48–50
financial, 214–215 Council of Science Editors, 90
gifts and gratuities and, 220–221 Courseware, conflict of interest and, 223
guidelines for, 224–225 Creative Commons, 117–118
insider trading, 227 Crick, Francis, 103
institutional, 228–230 Critical thinking, 38–39
intramural, 217–218 Critique, in mentoring, 56
levels of, 210 Cultural issues
managing, 231–232 in biotechnology patents, 312
in mentoring, 66 in collaborative research, 266–267, 273–274
multiple pay for one job and, 222 Culture, of practice, 28–29
nepotism, 223–224
orientation of, 217 D
in publication, 92–93 Data
reasons for, 215 definition of, 289
recommendations for, 48 documentation of, see Record keeping
scientific, 224–225 evaluation of, in peer review, 109–110
survey forms for, 391, 405–406 legal protection of, 294–295; see also types of
zero tolerance in, 210 protection
managing, 231–232 noninvasive collection of, 149
recommendations for, 48 ownership of, see Ownership, of data and
scientific, in collaborative research, 269–271 intellectual property
Conscience, conflict of, 215–217 release into public domain, 290–291
Consent, informed, in human subject research, 139– retention period of, 291
142, 461–463 Data and Safety Monitoring Board, in human
Consequentionalist ethical theories, 32 subject research, 145–146
Consultantships, 214, 221–222 Data sharing, 291–294
Consumers, direct genetic testing to, 372–373 in collaborative research, 253–254, 261–263,
Contributorship, in publication, 88, 99 267–269
Copyright(s), 298–304 policies for, 291–294
assignment of, 88–89, 301 publication-related, 92
coauthor rights in, 300–301 survey forms for, 391–392, 407–409
of computer software, 302–303, 313–314 Databases, for laboratory record keeping, 350
of courseware, 223 Day, Robert, on publication, 83–84
definition of, 298 Declaration of Helsinki, on human subject research,
of derivative works, 299 164–170, 364
of electronic publications, 114 Deontology, animal rights and, 34–35, 174, 178–181
fair use of, 301–302 Department of Energy, on human subject research,
infringement of, 302–304 371–373
originality requirement of, 299–300 Dependence, in mentoring, 57–58
owner rights in, 300–301 Design patents, 309
vs. patents, 299 Digital image integrity, 94–95
of preprint material, 117 Digital Millennium Copyright Act, 303–304
renewing, 299 Digital technology, in publication, 113–122
of research papers, 88–89 Digital Theft Deterrence and Copyright Damages
restrictive language in, 300 Improvement Act, 303–304
review articles and, 299 Dilemmas, ethical, 31, 373–376
symbol for, 300 Dinse, Gregg, on dual-use review policy, 96
term of protection under, 298–299 Directory of Open-Access Journal, 115
website material and, 303–304 Disagreement, in collaborative research, 269–271
work for hire, 298, 301 Dissertation, mentoring for, 59
Copyright Damages Act, 303–304 Diversity
Cornell University, arXiv at, 116–117 in collaborative research, 266–267
Correspondence, in record keeping, 345 in mentoring, 69–91
Index 521
DNA, storage of case study approach to, 38–39

for future reference, 374–376 codes of, 28, 35–39
informed consent concerning, 147 in collaborative research, 273–274
DNA technology conflict of conscience and, 215–217
Asilomar conference on, 366, 368–371 core values of, 37–38
debate over, 365–369 critical thinking and, 38–39
decisions about, 365–369 decision making in, 26–27, 38–39
discovery of, 365–369 definition of, 25
history of, 364–365 dilemmas in, 31, 373–376
lactose operon isolation and, 365 in fetal tissue research, 156–157
social considerations and, 364–371 in gene therapy, 311–312
Documentation, see Record keeping in human subject research, 135–137, 156–157
Dual-use research of concern (DURC), 95–96, 376– vs. metaethics, 30–31
381 moral reasoning in, 40
nepotism and, 223–224
E normative, 30–31
Economic Espionage Act, 296–297 overview of, 25–27
Editor, responsibilities in peer review, 113–120 philosophical issues in, 30–32
Editorial board, peer review by, 224 in publication, 86
Edmonson, Amy, on teamwork, 265 for scientists, 27
Education situational (utilitarianism), 32–34, 173–174, 176–
conflict of interest in, 226–227 178
courseware for, conflict of interest and, 223 theories in, 32
human subject research on, 147–148 deontology, 34–35, 174, 178–181
leaves for, 226–227 evaluation of, 31
mentoring in, see Mentoring teleological, 32–34
for profession, 28 utilitarianism, 32–34, 173–174, 176–178
strategies for, human subject research on, 141– Ethics Collaborative Online Resource
142 Environment, 35–36
Effort, conflict of, 213–215 Europe PubMed Central, 85
Egghe’s g-index, 121 European Bioinformatics Institute, 375
Electronic Lab Notebook Project, 350 Euthanasia, in animal experimentation, 184, 187–
Electronic publication, 85, 113–122 188
ELN culture, 350 Experiments of concern, 377
Embryonic stem cell research, 156–157 Expert testimony, conflict of interest in, 225
Embryos, patents for, 310–311
Entrepreneurship, conflict of interest and, 229–230 F
Environmental health and safety issues, 19, 509–515 F1000Prime and related services, 118
Equipoise principle, in human subject research, 144 Fabrication, in scientific misconduct, 13, 15–17, 20,
Equity interests, conflict of interest and, 229–230 112, 212–213
Errors Fairness, 37
correction of, 96–97 Falsification, in scientific misconduct, 13, 15–17, 20,
in data recording, 344 112, 212–213
vs. misconduct, 20 Family
postpublication, 119 coercion by, in informed consent, 140–141
retraction of, 121–122 conflict of interest and, 217–218
types of, 96 in human subject research, 140–141
Ethical, Legal and Social Implications Working nepotism and, 223–224
Group, of Human Genome Project, 371–373 two-career, 223–224
Ethics, 25–52 Fanelli, Daniele, on misconduct, 15
in animal experimentation Fang, Ferric C., on retracted papers, 122
deontologic, 174, 178–181 Federal Select Agent Program, 380
protocols for, 187–189 Federal Technology Transfer Act, 219
utilitarian, 173–174, 176–178 Federal Trade Commission, on patent system
case studies of, 42 changes, 314–315
522 Index
Federal Trade Secrets Act, 296 Global Research Council, on open-access

Federation of American Societies for Experimental publication, 116
Biology, mentoring guidelines of, 68 Good Laboratory Practices, in collaborative
Fetal tissue research, 156–157 research, 272–273
Financial support, see Funding Goodstein, David
Fink, Gerald R., biosecurity report of, 376–377, 381 on cheating, 16–17
Fiscal accountability, 19 “myth of the noble scientist,” 4, 6–9
Food and Drug Administration on reporting research results, 10
on human subject research, 143, 145, 155–156 Gordon Research Conference of 1973, 367
23andMe test and, 372–373 Graduate training programs, mentoring in, see
Formal organization, of professionals, 28 Mentoring
Forming team, in collaborative research, 255–256 Grants
Four-Component Model of Morality, Rest’s, 40 for collaborative research, 245, 251, 254–255
Francione, Gary, on animal experimentation, 193– data ownership and, 289–294
194 record keeping for, 334
Fraud, 7, 9–11, 112–113 research for, 60
Frederickson, Donald S., on recombinant DNA Grants Policy Statement, 292–294
controversy, 366 Grinnel, Frederick, on reporting research result, 9
Freedom of Information Act, 290–291 Guarantors, of published papers, 88, 102
Frey, R. G., on animal rights, 181 Guardian, informed consent from, 152
Frontier science, vs. textbook science, 5–6 Guatemala penicillin study, 136–137
Funding, research; see also Grants Guest authorship, 104–105
appropriate use of, 19 Guidance, see Mentoring
business involvement in, 211–212, 219–220 Guide for the Care and Use of Laboratory Animals,
collaborative, 267 182–184, 195–196
conflict of interest in, 226 Guidelines
data ownership and, 289–290 for animal experimentation, 181–196
data storage requirements for, 334 for authors, 87–97
data witnessing requirements for, 331 for conduct, 431–443
by federal agencies, 219–220 for conflict-of-interest management, 231–232
patents and, 309 for fetal tissue research, 156–157
publication pressure and, 85–86 for human subject research, 135–137
recommendations for, 48 for mentoring, 64
transfer to another institution, 289–290 for peer review, 113–120
Guidelines for Research Involving Recombinant or
G Synthetic DNA Molecules, 368–369
Garfield, Eugene, on impact factor, 120–122
Gastel, Barbara, on publication, 84 H
Gene therapy, patents for, 310–311 Handler, Philip, on rDNA technology, 367
Genetic disease, patents and, 311 Harmful consequences, of research, 362
Genetic Information Nondiscrimination Act, 372 Haslam, Robert, 152
Genetic sequences, patents for, 311–312 Hazardous materials and equipment, safety and,
Genetic technology, 371–376 509–515
case studies of, 46–47 Health insurance
Human Genome Project, 245–247, 371–373 discrimination in, genetic information and, 371–
patents for, 309–315 372
Genetic testing, 373–376 lack of, human subject research participation and,
Genome-wide association studies, 374 141
Genotype testing, 374 Health Insurance Portability and Accountability Act
Ghost writers, 87, 104–105 (HIPAA), 153–156, 372
Gifts and gratuities, as conflict of interest, Health Research Extension Act of 1985, 183
220–221 HeLa cells, ethical concerns about, 375
g-index, Egghe’s, 121 Helsinki Declaration, on human subject research,
Ginsparg, Paul, server-based archive of, 116–117 135–137, 164–170, 364
Glass, H. Bentley, on scientist responsibility, 363 Herzog, Harold, on animal rights, 192
Index 523
High-impact journal, 120 Identity-based trust, 256–257

h-index, 121 Impact factor, journal, 120–122
HIPAA (Health Insurance Portability and Impartiality, 37–38
Accountability Act), 153–156, 372 Implementation, moral, 40
Hirsch, Jorge, h-index of, 121 Incarcerated population, research on, 150–152
Homeland Security and Counterterrorism, Federal Inclusion, in collaborative research, 266–267
Select Agent Program of, 380 Incompetent persons, human subject research on,
Honesty, 37 150
Honorary authorship, 87, 105 Independence, as core value, 37–38
Hosselet, Stephen, on ELNs, 350 Individual development plan, in mentoring, 68–69
Howard Hughes Medical Institute, 64, 72, 330 Industry, see Business
Huang, Franklin, on rDNA, 370 Influenza H5N1 virus, genetic engineering of, 378–
Hudson, Kathy, on HeLa cells, 375–376 380
Human Genome Project, 245–247, 371–373 Information management, see Record keeping
Human subject research, 135–172 Informed consent, in human subject research, 139–
case studies of, 43, 159–163 142, 146–148, 461–463
on children, 152–153 Inherent value, of humans and animals, 179–180
confidentiality in, 153–156 Insider trading, using proprietary information,
without consent, 155–156 227
definition of, 138–139 Institute for Scientific Information, impact factor,
ethics of, 135–137 120–122
exempt from federal regulations, 147–148 Institutional Animal Care and Use Committee
federal regulations on, 137 (IACUC), 183–190, 214
on fetal tissue, 156–157 Institutional commitment, to mentoring, 63–64
historical chronology, 135–137 Institutional review boards/committees
on incompetent persons, 150 for animal experimentation, 183–190
informed consent for, 139–142, 146–148, 461– for human subject research, 137
463 expedited review processes in, 148–149
institutional review boards for function of, 142–146
expedited review process by, 148–149 informed consent and, 146–148
function of, 142–146 personnel on, 143
informed consent and, 146–148 small study considerations by, 143–144
personnel on, 143 special population considerations by, 150–153
small study considerations by, 143–144 Insurance, health
special population considerations, 150–153 discrimination in, genetic information and,
legal issues in, 137, 153–156 372
overview of, 135–137 lack of, human subject research participation and,
pilot studies in, 144 141
on prisoners, 150–152 Integrity
Privacy Rule in, 153–156 definition of, 1–2
protected health information in, 154–156 research, 18–19
recommendations for, 49 Intellectual property
resources for, 487–488 from collaborative research, 251
risks of, 139, 142 definition of, 287–288
sample protocols for, 447–461 ownership of, see Ownership, of data and
standards for, 364, 439–441 intellectual property
survey form for, 390, 403–404 Interest, conflict of; see Conflict, of interest
Waiver of Authorization in, 155–156 International aspects
World Medical Association Declaration of of collaborative research, 262–263, 273–274
Helsinki, 137, 164–170 of patents, 305–306
Hypothesis, in scientific method, 3, 5–7 International Committee of Medical Journal
Editors, manuscript publication
I requirements of, 94, 98–100, 105
IACUC (Institutional Animal Care and Use International Committee of Medical Journal
Committee), 183–190, 214 Editors, 94
524 Index
Internet record keeping, 331

copyrighted material on, 303–304 trade secrets, 296–297
mentoring information on, 60–61 Legislation
Interview, of new team members, 259–260 on animal experimentation, 182–189
Intuition, in scientific method, 6 expert testimony for, 225
Inventions, patents for; see Patent(s) Lerman, Michael, on collaborative research, 247
Letter of recommendation, 57
J Licensing, conflict of interest and, 228–229
Jackson, David, on rDNA, 366 Linehan, Marston, on collaborative research, 246–
Jacob, François, on reporting research results, 8 247
Jail population, research on, 150–152 Listening, in collaborative research, 262
Jamison, Wesley, on animal rights, 193 Lunch, William, on animal rights, 193
Johnson, Deborah, on computer ethics, 27–29 Luria, Salvador, on cheating, 16
Joint appointments, in collaborative research, 254– Lying
255 deontologic view of, 31–35
Journal Editors and Authors Group, on biosecurity, utilitarian view of, 32–34
381
Journal impact factor, 120–122 M
Justice, 137 Manuals, laboratory, 338–339, 514–515
Manuscript review, 89
K Manuscripts
Kanare, Howard, on record keeping, 317, 330–331, preparation of, 87–88
335–336 review of, 89; see also Peer review
Kant, Immanuel, categorical imperative principle senior author responsibility for, 101–103
of, 34–35 unpublished information cited in, 91–92
Kennedy, Donald, on publication, 84 Marcus, Adam, on postpublication comments, 119–
Kilmann, Ralph, on conflict, 269–271 120
Knowledge, new, translating, 361–362 Master log book, 338
Koren, Gideon, on human subject research, 152 McClintock, Barbara, 244
Material transfer agreement, in collaborative
L research, 273
Laboratory animals, see Animal experimentation Medawar, Sir Peter, on scientific papers, 7, 9, 16
Laboratory manuals, 338–339, 514–515 MEDRAD Electronic Lab Notebook Project, 350
Laboratory safety, 509–515 Meetings, in collaborative research, 262
overview of, 509–511 Mental disorders, human subject research and, 150
resources for, 511–515 Mentoring, 53–82
survey of, 509–510 vs. advising, 54
Lacks, Henrietta, HeLa cells of, 375 career counseling in, 56–57, 67
Lactose operon, isolation of, 365 case studies of, 42–47, 73–79
Language differences, in collaborative research, in collaborative research, 254, 265–266
262–263 communication in, 59–60, 67
Lavoisier, Antoine, on collaborative research, 243 conflict of effort in, 213–215
Leadership, in collaborative research, 261, conflict of interest in, 66
263–265 critiquing in, 56
Leahy, Michael, on animal rights, 181 current status of, 53–55
Leahy-Smith America Invents Act of 2011, 305, definition of, 53
307, 309, 313–314 dependence in, 57–58
Legal issues diversity in, 69–91
in collaborative research, 273 duty changes in, 57
conflict of interest, 217–218 dynamic nature of, 57
copyrights, see Copyright(s) exclusive nature of, 57–59
data ownership, see Ownership, of data and foundations for, 63–69
intellectual property historical origin of, 53
in human subject research, 137, 153–156 individual development plan in, 68–69
patents, see Patent(s) information resources for, 71–72
Index 525
institutional comittment to, 63–64 Mistakes

Internet sources for, 60–61 in data recording, 344
meetings in, 59 vs. misconduct, 20
mentor assignment in, 65 Monographs, 90
mentor-trainee relationship in, 55–60 Moral commitment, 40
on methodology, 55–56 Moral judgment, in animal experimentation, 176
overview of, 53–55 Moral perseverance (implementation), 40
peer-to-peer, 64 Moral reasoning, 39–41
performance evaluation in, 67–69 Moral rights, animal experimentation and, 178–181
personal characteristics of mentors and trainees Moral sensitivity, 40
for, 64–65 Morality
of postdoctoral candidates, 62 of animal experimentation, 173, 178–181
problems in, 57–59 conflict of conscience and, 215–217
ratio of mentor to trainees, 66 definition of, 25
recommendations for, 50 deontologic ethics and, 34–35
on record keeping, 329 ethics agreement with, 32
relationships in, 65–66 of human genetic material patents, 310–313
secondary network in, 66 vs. legality, 25
selection of mentor for, 60–63 of software copyrights, 303
seminars for, 72 utilitarianism and, 32–34
skills for, 71–72 “Myth of the scientific method,” 4–5, 9
socialization aspects of, 56
standards for, 433–434 N
styles of, 55 National Academies Press, DURC report of, 376–
supervisory role of, 66 377
survey forms for, 389–390, 396–398 National Academy of Sciences
trainee responsibilities in, 65 on bioterrorism, 381
transient, 59 on patent system changes, 314
trust in, 59–60 on prior publication, 91
Merton, Robert K., “coin of the realm,” 83 proceedings of, 99–100
Meselson, Matthew, on reporting research results, 8 National Cancer Institute, 245
Metaethics, 30–31 National Center for Advancing Translational
Methodology Science, 245, 362
evaluation of, in peer review, 109–110 National Center for Biotechnology Information,
mentoring on, 55–56 85, 97
notebooks for, 338–339 National Commission for the Protection of Human
Metrics, postpublication, 120–122 Subjects, 137, 156–157
Midgley, Mary, on animal rights, 178 National Institute of Standards and Technology
Mill, John Stuart, utilitarianism, 32–34 (NIST), 97
Millikan, Robert, reporting research results by, National Institutes of Health
9–10 animal experimentation guidelines of, 182–184
Misconduct, scientific, 9–18 Clinical and Translational Science Awards of, 245,
definitions of, 12–13 362
historical perspective of, 9–11 collaborative research promoted by, 245
incidence of, 13–17 conflict-of-interest guidelines of, 225
institution conflict of interest and, 230–231 on data ownership, 289–290, 292–293, 295–296
investigation of, 19–21 data sharing policy of, 292–293
media coverage of, 2–3 data storage requirements of, 331, 334
perpetrators of, 16–17 ethics code of, 36
prosecution for, 7, 10 funding from, 219
public perceptions of science and, 2–4 grants for, 60
recommendations for, 50 Guatemala penicillin study of, 136–137
record keeping and, 331–332 Human Genome Project, 371–373
survey forms for, 389, 395–396 mentoring guidelines of, 70
types of, 20 Office of Biotechnology Activities, 377–380
526 Index
National Institutes of Health (continued) Openness, 37

PubMed, 113, 115–116 Oransky, Ivan, on postpublication comments, 119–
Recombinant DNA Molecule Program Advisory 120
Committee, 368 Originality, of copyrighted material, 299–300
record-keeping guidelines of, 334 Orphan diseases, human subject research on, 143
scientific misconduct definition of, 10–12 Ownership, of data and intellectual property, 287–
standards of conduct of, 431–443 327
National Library of Medicine, 113, 115–116 case studies of, 45, 318–323
National Postdoctoral Association, mentoring in collaborative research, 267–269
guidelines of, 63, 68–69 copyrights, see Copyright(s)
National Research Council definition of, 287–289
on animal experimentation, 189 legal protection of, 295–296, 309–315
laboratory safety commission of, 509–510 overview of, 287–289
National Science Advisory Board for Biosecurity patents, 299, 304–317
(NSABB), 377–380 record keeping and, 331
National Science Foundation trade secrets, 296–297
collaborative research promoted by, 245 trademarks, 297–298
data sharing policy of, 292–293
ethics code of, 35–36 P
funding from, 219 Pasteur, Louis, 9
grants for, 60 Patent(s), 304–317
mentoring guidelines of, 68–71 application for, 307–308, 315–317
record-keeping guidelines of, 334 assignment of rights in, 306–307
scientific misconduct definition of, 12–13, 15, 19– on biotechnology, 309–315
21 on business methods, 313
Natural disasters, animal experimentation facilities on cloning, 310–311
and, 196 computer software, 313–314
Nature vs. copyrights, 299–300
laboratory safety survey of, 509–510 description of, 304–306
preprints of, 117–118 design, 309
Nature Publishing Group, 119 development rights under, 305–306
laboratory safety survey of, 509–510 example of, 489–501
online journal of, 339 “first-to-file” policy of, 317
Nepotism, 223–224 on gene therapy, 310–311
Noncompliance, with regulations, as scientific historical origin of, 304–305
misconduct, 12–13 international aspects of, 308–309
Noninvasive procedures, expedited approval laws on, 305–306
involving, 149 ownership of, 306–307
Normative ethics, 30–31 plants, 312
Norming, in collaborative research, 256 prior use rights in, 308
Novelty, of patents, 299–300 provisional, 308, 315
NSABB (National Science Advisory Board for record keeping for, 317, 331
Biosecurity), 377–380 reduction to practice, 306
Nuremberg Principles, on human subject research, review of, 227
135–137, 364 shop right laws for, 307
term of, 305
O from translational research, 362
Oat bran health claims, 3–4 types of material patentable, 308–309
Objectivity, 37 Patent Act of 1790, 294
Offer letter, in collaborative research, 253–254 Pediatric patients, research on, 152–153
Office for Human Research Protections, 138, 143 Peer review, 84–85, 105–113
Office for Protection from Research Risks, on ad hoc, 105–106
human subjects, 138 appointment of, 105–106
Office of Research Integrity, 11, 15–16 case studies of, 43, 123–129
Open-access publication, 89, 113–115 in collaborative research, 248
Index 527
confidentiality in, 108–109 Prisoners, research on, 150–152

conflict of interest in, 107–108, 224–225, 227 Privacy Rule, in human subject research, 153–156
debating, 111–113 Procedure notebooks, 338–339
by editorial board members, 105–106 Profession, concept of, 27–29
electronic handling of, 113 Property, personal vs. real, 295–296
evaluation criteria for, 109–110 Proprietary information, insider trading using, 227
goals of, 108 Protected health information, in human subject
philosophy of, 108 research, 154–156
postpublication, 118–120 Protégés, see Mentoring
process of, 106–108 Pseudomonas, degredative capability of, patent for,
reassignment of, 107–108 489–501
recommendations for, 49 Psychiatric disorders, human subject research and,
standards for, 437–438 150
survey form for, 390, 401–403 Psychological safety, in collaborative research, 264
writing results, 110–111 Public disclosure embargo, 90–91
People for the Ethical Treatment of Animals Publication, 113–122; see also Authorship;
(PETA), 193–194 Manuscripts; Peer review
Performance evaluation, in mentoring, 67-69 benefits of, 85–86
Performing, in collaborative research, 256 changing landscape of, 113–122
Perseverance, moral, 40 collaborative research and, 248, 267, 274
Personal Genome Service, 372–373 conflict of interest in, 92–93
Personal property rights, 295–296 copyrights for, see Copyright(s)
Personal views, conflict of conscience and, 215–217 disclosures in, 211–212
PETA (People for the Ethical Treatment of dispute resolution in, 96–97
Animals), 193–194 electronic, 113–122
Philosophy enhanced review of, for bioterrorism information,
of animal rights, 173–174, 176–181 377
ethics and, 30–32 ethics in, 86
of peer review, 108 metrics in, 120–122
Photocopying, copyrights and, 302 online, 113–114
Photographs, in data books, 333, 340 open-access, 113–115
Physical Sciences and Oncology Center, 245 options for, 85–86
Pigman, Ward, on scientist responsibilities, 262–263 postpublication review in, 118–120
Pilot studies, in human subject research, 144 preprint servers in, 116–118
Placebo studies, 144 pressure for, 85–86
Plagiarism, in scientific misconduct, 12–13, 20, 96, primary, definition of, 90–91
112 prior, definition of, 90–91
Plants, patents for, 308–309, 312 repositories in, 115–116
Politics, of animal experimentation, 192–194 retraction in, 121–122
Pollack, Richard, involvement in recombinant DNA sharing credit in, 275
discovery, 366 standards for, 431, 435–436
Position papers, on mentoring, 64 survey form for, 390, 398–399
Post, Stephen, on animal rights, 178 PubMed
Postpublication review, 118–120 for checking prior publication, 90
Power, in collaborative research, 263–265 electronic archives of, 85, 113, 115–116
Predoctoral programs, mentoring in; see Mentoring retracted papers in, 122
Pregnancy PubMed Central Canada, 85
fetal tissue research and, 156–157
human subject research in, 145–146 Q
Preprint servers, 116–118 Quality of life, with genetic diseases, 310–311
Pretenure agreement, 253–254, 273
Primary scientific publication, definition of, 90 R
Principles for the Utilization and Care of Rattan, Anil, on ELNs, 350
Vertebrate Animals Used in Testing, RCR (responsible conduct of research), 18–21
Research, and Training, 187 Reasoning, moral, 38–41
528 Index
Recombinant DNA Molecule Program Advisory Respect for Persons principle, 137
Committee, 368 Responsibility, scientist, 361–364
Record keeping, 329–359 Responsible conduct of research, 18–21
case studies of, 45–46, 351–357 Rest, James, on moral reasoning, 40
data books for, 335–336 Rest’s Four-Component Model of Morality, 40
chemistry, 506–507 Retraction, in publication, 121–122
correspondence in, 345 Review
definition of, 332–334 institutional boards for, see Institutional review
electronic, 346–347, 350 boards/committees
format for, 340–344 of manuscript, see Peer review
instructions for, 503–507 Risk(s), of research, 362
master log book, 338 Risk-to-benefit ratio
organization of, 338–339 for animal experimentation, 177–178
sample pages from, 348–349 for human subject research, 144
tangible data in, 332, 339–340 Rockefeller University Press, 94–95
witnessing, 344–346 Rubacha, Michael, on ELNs, 350
data in Russell, William, on animal experimentation, 190–
definition for, 332–334 191
forms of, 332–334 Ryan, Kenneth J., report on misconduct, 11
ownership of, see Ownership, of data and
intellectual property S
storage and retention of, 335 Safety
electronic, 346–347, 350 of genetic tests, 372
importance of, 329 laboratory, 509–515
interactions with other people, 344–346 psychological, in collaborative research, 264
legal issues in, 331 Salami science, 85
methodology notebook, 338–339 San Francisco Declaration on Research Assessment,
for patent application, 317 120–121
policies for, 336–337 Schachman, Howard, on responsible science, 6
publications on, 330 Science, definition of, 1
reasons for, 330–332 Scientific conflict, in collaborative research, 269–
recommendations for, 49 271
sources for, 506 Scientific method, 5–7
standards for, 434–435 Scientist responsibility, 361–364
survey forms for, 392, 409–410 Secrecy, in business-sponsored research, 212–213
tools for, 335–336 Security
writing instruments for, 336 in animal experimentation facilities, 195–196
Reduction, in animal experimentation guidelines, in publication, 95–96
191 Senior (primary) author, 101–103
Referees, see Peer review Sensitivity, moral, 40
Refinement, in animal experimentation guidelines, Seok, Junhee, on animal rights, 186
191 Serial advancement, of research, 288
Regan, Tom, on animal rights, 30, 174, 178–181 Server-based archives, 116–117
Regulations, noncompliance with, as scientific Service marks, vs. trade marks, 297–298
misconduct, 12–13 Shamoo, Adil, on responsible conduct, 28
Reiser, Stanley, on scientist responsibility, 363 Sharing
Reliability, 37 of data, see Data sharing
Replacement, in animal experimentation guidelines, of research materials, 92
190–191 Shop right laws, for patents, 307
Reporting science, 7–9, 49 Singapore Statement on Research Integrity, 38, 48–50
Repositories, in publication, 115–116 Singer, Maxine, at Gordon Conference, 367
Research, integrity in, 18–19 Singer, Peter, on animal rights, 30, 173–174, 176–
Research Councils UK, 115–116 177
Resnick, Davis Site license, for software, 303
on dual-use review policy, 96 Situational ethics (utilitarianism), 32–34, 176–178
on responsible conduct, 28 Skloot, Rebecca, on confidentiality, in testing, 375
Index 529
“Sloppy science,” 2 publication, 390, 398–399

Social considerations record keeping, 392, 409–410
in animal experimentation, 192–194 Symons, Robert, on rDNA, 366
dual use research of concern and, 376–381 Syphilis study, ethical questions in, 136
genetic testing and, 371–376
rDNA technology and, 364–371 T
recommendations for, 50 Tangible personal property rights, to data, 295
science research impacts on, 361–386 Task Force on Genetic Information and Insurance,
scientist responsibility in, 361–364 371–373
surveys for, 391, 411–412 Team development and dynamics, in collaborative
Social media comments, postpublication, 118 research, 255–265
Socialization, of trainees, 56 Teleological ethical theories, 32–34
Society for Neuroscience, 109 Terrorism, publications used in, 95–96, 376–381
Software, computer Textbook science, vs. frontier science, 5–6
copyright and copy protection of, 302–303, 313– Thinking, critical, 38–39
314 Third Reviewer, The, 118
licensing of, 295, 302–303 Thomas, Kenneth, on conflict, 269–271
Soll, Dieter, at Gordon Conference, 367 Thomson Reuters, impact factor, 120–122
Speciesism, animal rights and, 177, 179 Toussaint, Henri, 9
Standards Trade secrets, ownership of, 296–297
for authors, 87–97 Trademarks, 297–298
of conduct, 429–443 Trainees, mentoring of, see Mentoring
information sources for, 429–431 Transforming, in collaborative research, 256
National Institutes of Health, 431–443 Transgenic animals and plants, patents for,
of professional societies, 429 309–315
for genetic testing, 372 Translational research, 361–362
for research, 10–11, 13 Transplantation, fetal tissue, 156–157
Steen, R. Grant, on retracted papers, 122 Trust
Stem cells, research on, 156–157 in collaborative research, 256–257
Steneck, Nicolas, on misconduct, 14 as core value, 37
Stewardship, 37 in mentoring, 59–60
Sticky ends, on DNA, 367 Tuckman, Bruce, on team development, 255–256
Storming, in collaborative research, 255–256 Tuskegee Institute, human subject research at, 136
Suber, Peter, on open-access publications, 114 23andMe test, 372–373
Subjects, see also Animal experimentation; Human
subject research U
definition of, 18 United States Public Health Service
protection of, 93–94 animal experimentation guidelines of, 182–184
Suffering, of animals, 177, 187, 188 scientific misconduct and, 12–13, 15, 19–21
Supervisors University of Southern California LA, laboratory
mentoring by, 66 safety survey of, 509–510
safety responsibilities of, 511–512 Unpublished information, cited in manuscripts, 91–
Survey(s) 92
laboratory safety, 509–510, 513–514 Utilitarianism, 32–34, 176–178
social considerations, 391, 411–412 Utility Examination Guide, for patents, 312
Survey forms, 147, 387–412
animal experimentation, 391, 404–405 V
authorship, 390, 399–400 Vaccines, rendering ineffective, 377
collaborative research, 391, 406–407 Values
conflict of interest, 391, 405–406 inherent, of humans and animals, 179–180
data sharing, 391–392, 407–409 of scientific community, 35–38
general, 393–395 Venture corporations, conflict of interest and, 229–
human subject research, 390, 403–404 230
mentoring, 389–390, 396–398 Veterinarians, role of, in animal experimentation,
misconduct, 389, 395–396 184–185, 189
peer review, 390, 401–403 Vision, for collaborative research, 257–258
530 Index
Volker, Joseph, on moral reasoning, 40 World Health Organization, on avian influenza

von Hippel-Lindau disease, collaborative research virus genetic engineering, 378–380
on, 246–247 World Medical Association Declaration of Helsinki,
on human subject research, 136, 164–170,
W 364
Waiver of Authorization, in human subject research, Writing, of scientific results, 7–9
155–156
Watson, James, 103 Y
Weaponization, of agents, 377 Yamamoto, Keith, on responsible science, 6
Web of Science, Thomson Reuters, 120–122
Weston, Anthony, on ethics, 27 Z
Witnessing, of data, 344–346 Zbar, Berton, on collaborative research, 246–247

Scientific Integrity - Text and Cases in Responsible Conduct of Research-Francis L. Macrina

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Scientific Integrity - Text and Cases in Responsible Conduct of Research-Francis L. Macrina

Uploaded by

Copyright:

Available Formats

Scientific

Text and Cases in Responsible Conduct of Research

Printed in the United States of America

Laurel, Mike, Dylan, and Megan

My colleague, and pioneer in research ethics education

chapter 1 Methods, Manners, and the Responsible

chapter 2 Ethics and the Scientist 25

chapter 4 Authorship and Peer Review 83

chapter 5 Use of Humans in Biomedical Experimentation 135

chapter 6 Use of Animals in Biomedical Experimentation 173

chapter 7 Competing Interests in Research 209

chapter 8 Collaborative Research 243

chapter 9 Research Data and Intellectual Property 287

chapter 10 Scientific Record Keeping 329

chapter 11 Science, Technology, and Society 361

appendix I Surveys as a Tool for Training in Scientific Integrity 387

appendix II Student Exercises 413

appendix III Standards of Conduct 429

appendix IV Sample Protocols for Human and Animal

appendix V Example of a U.S. Patent Specification 489

appendix VI Laboratory Notebook Instructions 503

appendix VII Safe Laboratory Practices Resources 509

L. Michelle Bennett, Ph.D. Thomas D. Mays, Ph.D., J.D.

Teaching Responsible Conduct

L ike Frank Macrina, the author of this outstanding textbook, we have

Teaching RCR: how, who, and when?

We all learned at an early age to pay more attention to what people do

Issues in the Graduate Education of Scientists and Engineers. They found

The Role of Federal and Institutional

mentioned. Nor does NSF indicate the acceptability of exclusively relying

The role of professional societies and research institutions

A Final Thought: How the Behavior

voters to write their government representatives to tell them not to fund

1. Moonesinghe R, Khoury MJ, Janssens AC. 2007. Most published

T he first edition of Scientific Integrity: Text and Cases in Responsible Con-

responsibility and accountability of authorship. A significant revision of

conduct. But equally important, it provides tools to apply that knowledge.

A ssistance in preparing this updated edition came in many forms and

T his text contains multiple means to facilitate learning by applying

How To Use End-­of-­Chapter Case Studies

intense. However, dialogue should never be allowed to become insulting

A Website Companion for Scientific

Methods, Manners, and the

W hat do we mean by “integrity in science”? The word “integrity”

incredulous when a scientist admits to falsifying or fabricating research

Perceptions of scientists and science

cannot understand how scientific facts can be disputed. Yet definitions of

Work in this area continues to yield new and sometimes surprising

this process as the result of the systematic implementation of a single, pre-

the increasing complexity and collaborative nature of scientific research

years later, Goodstein’s perspective on the scientific paper is captured in his

The research writings and scientific memoirs of François Jacob further

Defining research misconduct

The appearance of such a definition signaled a response to concerns

In 2000 (Federal Register, December 6, 2000), the United States Office of

Innovation, creative expression, intuition, and other subjective activities do

scientists, trainees, and technicians. Although we may debate how to calcu-

hypothesis—if the corresponding author’s state was identified as being

Impact of research misconduct

certain activities like submission of proposals to funding agencies or ser-

Responsible Conduct of Research

Today, we speak of “RCR courses,” “RCR training,” and “RCR require-

publication practices. Guidelines that describe proper or expected

How To Use End-of-Chapter Case Studies

M any of the decisions that scientists make in their day-to-day activ-

2.2 Ashton Malone is a second-year graduate student conducting her

2.4 An institutional review board (IRB)-approved clinical trial of a new

2.10 Jacob Moscowitz is a 66-year-old English professor at State Uni-

Funds 5. Use research funds responsibly: Individuals and organizations

Subjects 9. Treat everyone involved with research fairly and with

Society 10. Public Communication: Researchers should limit

14. Societal Considerations: Researchers and research

Misconduct 11. Reporting Irresponsible Research Practices: Researchers