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Volume 2 Issue 1 | Spring 2009

LETTERS

Volume 2 Issue 1 | Spring 2009 L E T T E R S March 2009

March 2009

Dear Harvard Community,

It is a true delight for me to introduce this issue of e Harvard Undergraduate Research Journal.

At a time when the college re-commits itself to the importance of hands-on learning and research through the new program in General Education, it is wonderful to see undergraduates already well advanced in their e orts as researchers. As important as books and journals are to the educational enterprise, there is no substitute for hands-on experience, especially in the world of science. One successful—or even unsuccessful—original experiment can bring students to a much deeper understanding of scienti c principles than can reading about or listening to descriptions of the experiments of others. is is a position that has been repeatedly rea rmed by many curricular committees, and is the central conviction energizing the wonderful Program for Research in Science and Engineering, in which the College has invested so deeply.

e Harvard Undergraduate Research Journal demonstrates that our e orts in the sciences have combined with the remarkable skills and passion of our undergraduates to produce impressive results that will contribute not only to the formation of the next generation of investigators and innovators, but also to a more scienti cally literate society.

Sincerely,

and innovators, but also to a more scienti cally literate society. Sincerely, Jay M. Harris www.thurj.org

Jay M. Harris

LETTERS

Volume 2 Issue 1 | Spring 2009

e Harvard Undergraduate Research Journal

March, 2009

Dear Harvard Community,

We are honored to share with you Volume 2, Issue 1 of e Harvard Undergraduate Research Journal (THURJ), a biannual publication that features the research and writing endeavors of Harvard undergraduates. is issue has a number of unique features, and we hope you will nd reading it both enjoyable and intellectually stimulating. e work contained in these pages showcases the talented intellectual inquiry taking place daily on Harvard’s campus. It also emphasizes the importance of research in the undergraduate experience. Our research articles feature subjects ranging from neuro lament networks to priming e ects as related to bingo. ey represent undertakings in biomechanics, materials science, psychology, health and medicine, and evolutionary and molecular biology. Our prize winning manuscript, “Elasticity in ionically cross-linked neuro lament networks,” represents in its discussion of the mechanical properties of neuro laments the type of cross-cutting query that both THURJ and Harvard are so proud of. We also continue in this issue our commitment to science writing. Our writers have delved into micro uidic chips, the origins of life, and even robotic ies. eir pieces are essential to our mission of sharing science with the larger Harvard community.

Our journal has grown tremendously in the past year. With an expanded sta of over y, we have broadened our research focus into the social sciences and solidi ed our ties with many of the depart- ments on Harvard’s campus. Our members have been trained by professionals from Cell, the New England Journal of Medicine, and the National Association of Science Writers. Yet, we are constantly looking for new partners, new directions, and new ideas.

We hope this issue provides a taste of the Harvard undergraduate community’s intellectual vigor. We would like to thank the people who made publication of this issue possible. Firstly, thanks to our Peer Review Board and the Harvard faculty, graduate students, and associates who reviewed our manuscripts and ensured their scienti c quality. Next to our Content, Design, Business, Social and Public Relations, and Strategic Planning and Operations Boards for their tireless work and creativity. Perhaps most importantly, this issue would not have been possible without the generous support of HMS Dean Je rey Flier, Professor Steven Freedman, Provost Steven Hyman, Faculty of Arts and Sciences (FAS) Dean Michael Smith, FAS Dean for the Physical Sciences Jeremy Bloxham, Professor Xiao-li Meng, Harvard University, and Harvard College. And of course, a special thank you to the authors whose work is showcased in these pages for sharing their inquiries with THURJ and the Harvard Community. Enjoy.

Sincerely,

with THURJ and the Harvard Community. Enjoy. Sincerely, John Zhou Co-Editor-in-Chief Lisa Rotenstein

John Zhou Co-Editor-in-Chief

Community. Enjoy. Sincerely, John Zhou Co-Editor-in-Chief Lisa Rotenstein Co-Editor-in-Chief ii The Harvard

Lisa Rotenstein Co-Editor-in-Chief

Volume 2 Issue 1 | Spring 2009

CONTENTS

Summaries

Preview the research articles with summaries before reading them.

1

Research

Features

Biomechanics

32

Elasticity in ionically cross-linked neuro lament networks

Evolutionary Biology

38

Evolution of marine cyanobacteria in the Red Sea

Health and Medicine

44

Biomechanical response of the in situ primate lens in its natural versus empty state as assessed with an ex vivo accommodation simulator

Materials Science

49

Properties of silk III broin at the air-water interface

Molecular Biology

56

Tandem repeats in promoter regions of S. cerevisiae generate variability in gene expression with phenotypic consequences

Searching for life’s origins, on Earth and beyond 7 Quantum dots, vacuum energy, and micro
Searching for life’s origins, on Earth
and beyond
7
Quantum dots, vacuum energy, and
micro uidic chips
10
A window into humanity
13
It’s a bird! It’s a plane! It’s a robotic y!
17

CONTENTS

Research

Psychology

66

Young people play bingo, too:

Reducing priming e ects through mindfulness

Cover Image

is issue’s cover image comes from work done by the Lieber group, mentioned in the article “Quantum dots, vacuum energy, and micro uidic chips.” It features a SEM image of hybrid measurement chip where neurons are interfaced with multiple independently-addressable nanowire devices.

Volume 2 Issue 1 | Spring 2009

Features

Statistics: Your chance for happiness (or misery) 21 A Marxist utopia in your backyard? 28
Statistics: Your chance for happiness
(or misery)
21
A Marxist utopia in your backyard?
28

Visit http://www.thurj.org for news, details about the organization, guidelines for submission, and other information on research at Harvard

for news, details about the organization, guidelines for submission, and other information on research at Harvard

Volume 2 Issue 1 | Spring 2009

Boards

Business Hua Szu Yang ‘12

Design Lisa Chen ‘12 - Associate Design Chair Francis Deng ‘12 - Associate Design Chair Ritchell van Dams ‘11 Evelyn Park ‘11 Yan Yan Mao ‘10 Lauren Kaye ‘10 Katie Goldin ‘11 Ingrid Pierre ‘12 Kathleen Tang ‘12 Joyce Yang ‘12

Content Alissa D’Gama ‘11 - Associate Managing Editor Sophie Wharton ‘11 - Associate Managing Editor Jen Jian Gong ‘12 Isha Jain ‘12

Social and Public Relations Alyssa Blaize ‘12 Roshane Campbell ‘12 Angela Primbas ‘12 Shoshana Tell ‘10

Peer Review and Submissions Meng Xiao He ‘11 - Associate Manager Monica Liu ‘12 -Associate Manager Charlotte Seid ‘10 - Associate Manager Jessica Zeng ‘12 - Associate Manager Helen Yang ‘11 - Head Copy Editor Lisa Chen ‘12 - Copy Editor Darius Li ‘12 - Copy Editor Jacob Cedarbaum ‘12 Eric Chen ‘12 Sway Chen ‘12 Hyunje (Grace) Cho ‘12 Francis Deng ‘12 Ben Dobkin ‘12 Kelly Fitzgerald ‘10 Eva Gillis-Buck ‘12 Jen Jian Gong ‘12 Johnny Hu ‘11 Edward Kogan ‘12 David Levary ‘12 Shravani Mikkilineni ‘12 Briana Prager ‘12 Abby Schi ‘11 Nicholas Tan ‘12 Jacob Weatherly ‘12 Vanisha Yarbrough ‘10 Chi Zhang ‘12

Strategic Planning and Operations Eric Lin ‘12 Anne Polyakov ‘12

CONTENTS

About Us

e Harvard Undergraduate Research Journal (THURJ) showcases peer-reviewed undergraduate student research from all science and quantitative social science disciplines. As a biannual publication, THURJ familiarizes students with the process of manuscript submission and evaluation. Moreover, it provides a comprehensive forum for scienti c discourse on the cutting-edge research that impacts our world today.

At its core, THURJ allows students to gain insight into the peer review process, which is central to modern scienti c inquiry. All THURJ manuscripts are rigorously reviewed by the Peer Review Board (consisting of Harvard undergraduates), and the top manuscripts that they select are further reviewed by Harvard graduate students, post-doctoral fellows, and professors. is process not only stimulates faculty-student collaboration and provides students with valuable feedback on their research, but also promotes collaboration between the College and Harvard’s many graduate and professional schools. In addition to publishing original student research papers, THURJ is also an important medium for keeping the Harvard community updated on science research-related news and developments.

Contact

General Email: contact@thurj.org

Advertising Email: advertising@thurj.org

Subscriptions Email: subscriptions@thurj.org

Submissions Email: submissions@thurj.org

Website

http://www.thurj.org

Copyright 2009 The Harvard Undergraduate Research Journal.

No material appearing in this publication may be reproduced without written permission of the publisher, with the exception of the rights of photographs which may only be granted by the photographer. e opinions expressed in this magazine are those of the contributors and are not necessarily shared by the editors. All editorial rights are reserved.

Executive Board

Co-Editors-in-Chief John Zhou ‘10 Lisa Rotenstein ‘11

Business Manager Alexander Piñero ‘11

Managing Editor of Content Fernando Racimo ‘11

Managing Editor of Peer Review and Submissions John Liu ‘11

Design Chair John Mei ‘12

Co-Managers for Social and Public Relations Hyunje (Grace) Cho ‘12 Gordon Bae ‘12

Manager for Strategic Planning and Operations Tengbo Li ‘12

CONTENTS

Faculty Advisory Board

Alán Aspuru-Guzik, Ph.D

Assistant Professor of Chemistry and Chemical Biology

Paul Bamberg, Ph.D

Senior Lecturer on Mathematics

Michael Brenner, Ph.D

Glover Professor of Applied Mathematics and Applied Physics

Myron Essex, D.V.M., Ph.D

Mary Woodard Lasker Professor of Health Sciences in the Faculty of Public Health

Brian Farrell, Ph.D

Professor of Biology

Je rey Flier, M.D.

Dean, Harvard Medical School, and George C. Reisman Professor of Medicine

Nicole Francis, Ph.D

Associate Professor of Molecular and Cellular Biology

Steven Freedman, M.D., Ph.D

Associate Dean for Clinical and Translational Research and Associate Professor of Medicine

Guido Guidotti, Ph.D

Higgins Professor of Biochemistry

David Haig, Ph.D

George Putnam Professor of Organismic and Evolutionary Biology

Marc Hauser, Ph.D

Professor of Psychology

Dudley Herschbach, Ph.D

Frank B. Baird Jr. Professor of Science

John Hutchinson, Ph.D

Abbott and James Lawrence Professor of Engineering and Gordon McKay Professor of Applied Mechanics

David Jeruzalmi, Ph.D

Associate Professor of Molecular and Cellular Biology

E himios Kaxiras, Ph.D

Gordon McKay Professor of Applied Physics and Professor of Physics

George Lauder, Ph.D

Professor of Biology and Alexander Agassiz Professor of Zoology

Richard Losick, Ph.D

Maria Moors Cabot Professor of Biology

L. Mahadevan, Ph.D

Lola England de Valpine Professor of Applied Mathematics

David Mooney, Ph.D

Associate Dean for Applied Chemical/Biological Sciences and Engineering and Gordon McKay Professor of Bioengineering

Hongkun Park, Ph.D

Professor of Chemistry and Chemical Biology

Steven Pinker, Ph.D

Johnstone Family Professor of Psychology

Tobias Ritter, Ph.D

Assistant Professor of Chemistry and Chemical Biology

Eugene Shakhnovich, Ph.D

Professor of Chemistry and Chemical Biology

Irwin Shapiro, Ph.D

Timken University Professor

Zhigang Suo, Ph.D

Allen E. and Marilyn M. Puckett Professor of Mechanics and Materials

David Weitz, Ph.D

Mallinckrodt Professor of Physics and of Applied Physics

Volume 2 Issue 1 | Spring 2009

Special Thanks to Our Reviewers

Daniel Lieberman, Ph.D

Professor of Anthropology

Andrew Murray, Ph.D

Herchel Smith Professor of Molecular Genetics

David Mooney, Ph.D

Gordon McKay Professor of Bioengineering

L. Mahadevan, Ph.D

Lola England de Valpine Professor of Applied Mathematics

James McCarthy, Ph.D

Alexander Agassiz Professor of Biological Oceanography

Yundan Pi

Ph.D Candidate in Earth and Planetary Sciences

Robin Greenwood, Ph.D

Associate Professor of Business Administration

Maxine Isaacs, Ph.D

Adjunct Lecturer in Public Policy, Harvard Kennedy School

Matt Chingos

Ph.D Candidate in Government

Ellen Langer, Ph.D

Professor of Psychology

Phyllis Kanki, Ph.D

Professor of Immunology and Infectious Diseases, Harvard School of Public Health

Marty Hirsch, Ph.D

Professor of Immunology and Infectious Diseases, Harvard School of Public Health

Katharine Jensen

Ph.D Candidate in Physics

Volume 2 Issue 1 | Spring 2009

SUMMARIES

Biomechanics: Elasticity in ionically cross-linked neuro lament networks

e mechanical response of cells depends in large part on the structure and elasticity of their cytoskeleton. e cytoskeleton is composed of a variety of biopoly- mers, ranging from microtubules and lamentous actin to inter- mediate laments and binding proteins. While both individual micro- tubules and actin, as well as their networks, have been extensively studied in vitro and in vivo, much less is known about the properties of intermediate lament networks. is stems, in part, from their sheer diversity: while microtubules and actin are essentially the same in

all eukaryotic cells, intermediate laments are highly specialized, e.g., with speci c neuro laments in neurons, and desmin laments in muscle. Nevertheless, these la- ments generally play a key role in the stable organization of the cy- tosol and in giving cells enhanced compliance to external stress. us, understanding intermediate lament assemblies and their me- chanics represents an important biophysical challenge. By examining both the me- chanical properties of in vitro neuro lament networks, the authors are able to determine that multivalent ions act as e ective

cross-linkers for these networks. ey are then able to propose a model which accounts for the physical origins of neuro lament elasticity. is model, based on thermal stretching, quantitatively explains the network’s remark-

able resilience and also allows for the extraction of microstructural parameters. ese microstruc- tural network parameters, which include the polymer’s e ective length and the average distance between cross-links are extremely

di cult to measure directly.

p. 32

Evolutionary Biology: Evolution of marine cyanobacteria in the Red Sea

Each and every day, ecosystems around the world are being trans- formed by global climate change. Soon, the planet’s environments may no longer be inhabitable by their current residents. Among the rst to feel these e ects will be the most ancient organisms adapted speci cally to their habitats, including cyanobacteria. e Prochlorococcus and Synecho- coccus strains of these microscopic organisms are the smallest photo- synthetic organisms on Earth, yet they account for two-thirds of the oceans’ photosynthetic reactions.

By taking carbon compounds out of the atmosphere and convert- ing them into nutrients usable by other aquatic species, cyanobacte- ria allow bodies of water to act as ‘carbon sinks’ and slow the e ects of global warming. is research studied the genetic compositions of Prochlorococcus and Synechococcus cyanobacteria to understand how they have adapted to the speci c nitrogen- stressed environment of the Red Sea. By sequencing, analyzing, and comparing their DNA se- quences, the investigator tried

to determine how each strain has adapted to unique environ- mental conditions. Synechococcus sequences showed 26 genes related to nitrogen processing, suggesting

that they have adapted genetically to their environment. Prochloro- coccus, however, showed only one nitrogen-related gene. It is possible that, while Synechococcus evolved genetically to survive in

a nitrogen-stressed environment,

Prochlorococcus made physical or behavioral changes instead. ese two di erent approaches dem- onstrate that cyanobacteria have

SUMMARIES

Volume 2 Issue 1 | Spring 2009

Photo by Lamiot/Wikipedia multiple ways to adapt to changing marine environments, but their speci c
Photo by Lamiot/Wikipedia
multiple ways to adapt to changing marine environments, but their speci c evolutionary mechanisms should
be further investigated.
p. 38

Health and Medicine: Biomechanical response of the in situ primate lens in its natural versus empty state as assessed with anex vivo accommodation simulator

Near vision, or presbyopia, is the most common refractive disorder of the elderly. It is characterized by the loss of accommodation, the ability to focus distant to near objects. Lens and capsule-based theories of presbyopia assert that the decrease in accommoda- tive ability can be attributed to increased hardening of the lens

substance and decreased elastic- ity of the lens capsular bag with age. One novel technique in the restoration of accommodation is Phaco-Ersatz, or lens re lling. e promise of Phaco-Ersatz can be assessed by characterizing the bio- mechanical properties of the lens in its natural versus empty state. Postmortem cynomolgus monkey,

rhesus monkey, and human eyes of varying ages were stretched in their natural and empty states in an ex vivo Accommodation Simulator in eight, 0.25mm steps, mimicking the changes that occur in vivo when focusing objects. e diameter-force relationship of the natural and empty lens were characterized and compared.

Illustration by Evelyn Park/THURJ Staff

Illustration by Charlotte Seid/THURJ Staff

Volume 2 Issue 1 | Spring 2009

SUMMARIES

ere was no relationship between the empty-bag diameter slope and age, indicating that the lens

ere was no relationship between the empty-bag diameter slope and age, indicating that the lens cap- sule’s mechanical properties do not change the setting of accom- modation. Moreover, the ratio of the empty capsule to natural lens

load-diameter slope decreased sig- ni cantly with age, showing that it is the lens material, and not the elasticity of the capsular bag, that contributes to presbyopia. e re- sults con rm the postulation that accommodation can be e ciently

conducted as long as the lens contents have proper viscoelastic properties. us, Phaco-Ersatz is a viable future treatment for presbyopia.

p. 44

Materials Science: Properties of silk III broin at the air-water interface

e macromolecule broin, found in the silk of silkworms, is found in the silk I and II confor- mations, which have well charac- terized structures and properties. Since ancient times, these materi- als have lent themselves to a variety of applications, and now that their sturctures are fully apprehended, they can be used for increasingly complex biomedical applications, including the rapid repair of torn anterior cruciate ligaments (ACL). It was hypothesized that the broin crystalline structure silk III could also have applicable properties, such as high tensile strength, biocompatibility, and liquid crystallinity. Silk III is not yet fully under-

and liquid crystallinity. Silk III is not yet fully under- stood due to its relatively recent

stood due to its relatively recent discovery and the lack of an es- tablished manufacturing process for it. is research assessed key

properties of silk III broin at the air-water interface in order to facilitate future manufacturing and biomedical applications. A

Illustration by Evelyn Park/THURJ Staff

SUMMARIES

Volume 2 Issue 1 | Spring 2009

procedure was rst determined for

at such an interface. A successful

the physical integration of silk III

p. 49

the

consistent production of silk

preliminary biocompatibility

in hybrid materials. Overall, the

III

at the interface. Mechanical

assessment a rmed possible fu-

investigator evaluated the novel

strength and tensile properties were measured and analyzed to t a mathematical model. e data indicated which concentrations are optimal if silk III is manufactured

ture use of silk III in humans for biomedical applications. Imaging tests also revealed important struc- tural features of the silk III lm, important for applications such as

material of silk III and its capacity for use in biological and physical applications of interest.

Molecular Biology: Tandem repeats in promoter regions ofS. cerevisiae generate variability in gene expression with phenotypic consequences

Most genomes are made

up of substantial portions of

repetitive DNA. In humans, for example, as much as 49% of the

genome consists of such repeats. Tandem repeats, sequences which are repeated head-to-tail at one speci c locus within the genome, are especially interest-

ing because of their high level

of variability. e focus of this study is on tandem repeats which occur in the promoter regions of genes in Saccharomyces cer-

evisiae (brewer’s yeast). Here, the investigator shows that repeats in promoters are indeed hyper- variable and o en di er between evolutionarily closely related sub-populations of yeast (natural yeast strains). Studies conducted concerning the e ect of repeat size on the transcriptional activ- ity of the candidate genes SDT1

and YKL071w found that changes

in the number of repeat units

in the genes corresponded to

in the number of repeat units in the genes corresponded to variation in transcriptional activ- ity.

variation in transcriptional activ- ity. Growth assays were conducted with SDT1 strains in the presence of 6-azauracil, which yielded dif- ferences in the length of the lag

phase that corresponded with the gene expression of the respective strain, suggesting that changes in transcription levels result in a phenotypic change. In YKL071w,

Volume 2 Issue 1 | Spring 2009

SUMMARIES

bindingsitesforthestress-response transcription factor Yap1 overlap with the variable tandem repeats. Together, these results indicate

that just as variable repeats located within coding regions allow swi evolution of protein function, repeats in promoters may allow

quick evolution of gene expression levels to changing environments and selective pressures. p. 56

Psychology: Young people play bingo, too: Reducing priming e ects through mindfulness

In psychology, the concept of mindfulness refers to making

a conscious e ort to be “in the moment” and aware of one’s environment, which allows for

more thoughtful decision-making. In this study, the researchers examined how the concept of mindfulness might inform our understanding of another concept in psychology: priming. Priming

is the idea that exposing people

to certain stimuli can a ect their subsequent behavior by increasing the accessibility of other informa- tion even without them being aware of it. For example, research- ers in one study found that chil- dren who watched a violent police

lm displayed more aggressive behaviors in a subsequent hockey game than did those who instead watched a nonviolent lm about bike racing. In one well-known study on priming, researchers investigated how being exposed to words asso- ciated with the elderly stereotype a ected how quickly participants walked down a hallway at the conclusion of an experiment. ey found that participants who were exposed to words related to the elderly stereotype walked more slowly than did those who were exposed to neutral words. In the current study, the re- searchers replicated the study by

Bargh and colleagues and extend- ed it by introducing the concept of mindfulness, to see whether by making participants mindful, they could reduce the priming e ects. Although non-signi cant, the study’s results showed an interaction in the expected direc- tion with decreased walk-time for participants in the elderly-mindful condition, lending tentative sup- port to the researchers’ hypothesis. is concept has important impli- cations for social issues such as stereotyping, as the results imply that mindfulness may be an e ec- tive means of reducing stereotype activation.

p. 66

Features

Volume 2 Issue 1 | Spring 2009

FEATURES

!!"#$%&'()*!+,%!-(+#./ !!!!,%(*()/0!,)!1$%2' Illustration by Katherine Goldin/THURJ Staff
!!"#$%&'()*!+,%!-(+#./
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Illustration by Katherine Goldin/THURJ Staff
!!!!!!!!!!$)3!4#5,)3
By Sophie Wharton, THURJ Sta

! ince the beginning of recorded history, the

questions “How did life begin?” and “Are we

alone in the universe?” have mysti ed humans,

dominating religious and political debate. Today, Harvard scientists from across four major disciplines have united to grapple with the same age-old ques- tions, using innovative new technologies. Biologists, chemists, earth and planetary scientists, and astronomers together comprise the Harvard Origins of Life Initiative, a grassroots project o cially formed in 2005 a er recommendations from the Task Force on Science and Technology. e Task Force had

recognized the need to bring together researchers working on separate pieces of the same puzzle, to form a bridge between the physical and life sciences. As Dimitar Sasselov, director of the initiative, puts it, “ e big issues faced by humanity today and in the near future can only be solved by combining exper- tise from the life sciences and the physical sciences.” Sasselov is an astronomer whose research has focused on the diversity of planetary environments. e collaborative and interdisciplinary nature of the initiative are helping him gain new perspectives on his own work: “ is project is allowing me to

FEATURES

follow a path in the discovery and study of distant planets which is much richer in what I look to nd on them.” Just as discoveries on a micro-level are guiding the theoretical and observational work of the astrophysicists and planetary scientists, so too are the laboratory experiments conducted by chemists and

“Across all levels of inquiry – from the cosmic to the cellular – enormous and often unanticipated strides have been made since the project was launched.”

molecular biologists informed, via their setup and initial conditions, by the macro-level work of the other team members. us, across all levels of inquiry – from the cosmic to the cellular – enormous and o en unanticipated strides have been made since the project was launched. e research conducted by Jack Szostak, a professor of genetics at Harvard Medical School and a researcher at Massachusetts General Hospital, has helped advance the scienti c understanding of how the very rst cell may have formed and evolved. His lab developed

Illustration by Katherine Goldin/THURJ Staff
Illustration by Katherine Goldin/THURJ Staff

Volume 2 Issue 1 | Spring 2009

primitive cell membranes and is studying their dynamic nature and the conditions necessary for them to spontaneously enlarge and divide. e chemists in George Whitesides’ Research Group

– also involved in the Origins Team – are trying to

nd out how energy was available to drive the earliest chemical reactions on pre-biotic Earth. ey have made progress in explaining how cells became able to harness the potassium and sodium potentials created by the di erent concentrations of these compounds outside and inside the cell, and use them as a source of free energy. Another group in the Initiative – Scot T. Martin’s lab – managed to demonstrate that in prebi-

otic conditions, a reverse version of the Krebs cycle (a key biochemical process in cellular respiration) might have produced the rst biomolecules. e reaction may have been catalyzed by sunlight combining with

a particular mineral that is thought to have existed in

Earth’s early waters. On a di erent front, astronomers on the Origins Team developed a new laser that dramatically improves our ability to measure the size of a star’s “wobble”: a type of oscillation caused by the gravita- tional pull of orbiting bodies around it, and a proxy for the existence of extrasolar planets that might be

“As Sasselov notes, ‘We are uniquely positioned to o er Harvard students an opportunity to combine projects in the intersection of life sciences and physical sciences.’”

capable of harboring life. Until now, only the wobble of giant, gaseous planets with very noticeable e ects on stars could be detected. However, with this new laser technology, the sensitivity of detection has increased by about a hundred times, and it is now possible to detect smaller, rockier planets, which are better candi- dates for sustaining life. Such exciting ndings are evidence that the Initia- tive is successfully tackling key questions about life’s origins. But research is only one part of its mission:

Volume 2 Issue 1 | Spring 2009

FEATURES

education and outreach are two of the most important goals. Carol Knell, Program Coordinator for the Initiative, has been on board since the beginning and remarks on how publicity and outreach events have

taking one of the eight undergraduate courses given by Origins team members at Harvard, including the core course Science A-54 “Life as a Planetary Phenomenon,” which is taught by Sasselov.

“This interdisciplinary enterprise… boldly confronts some of the most fundamental questions about our existence and our universe.”

progressed since the project’s infancy: “so many more people, nonscientists and scientists, have become aware and excited about the initiative.” Knell helps to organize the Origins Forums, monthly events aimed at giving the University community a taste of the current research undertaken by the Initiative. Large audiences regularly come to hear presentations from researchers from Harvard, other universities, or international speakers. During the more informal monthly “Chalk Talks,” graduate students and post docs discuss excit- ing advances made in their research. Undergraduates are encouraged to attend all such events, but those interested in a more hands-on experi- ence are welcome to apply for research fellowships to work on a particular project in a team member’s lab. Fellowships are available for Harvard undergraduates during the academic year (wage stipends are provided) and summer fellowships are open to undergraduates at other colleges as well. Knell reports that feedback from students involved in research has been fantastic across the board. As Sasselov notes, “We are uniquely positioned to o er Harvard students an opportunity to combine projects in the intersection of life sciences and physical sciences.” Students can also learn about the astrophysics and biochemistry of life’s origins by

A er the $8 billion hit that Harvard’s endowment took a few months ago, there is fear that funding to the Origins of Life Initiative may su er too. e progress of the Initiative is hindered by the lack of a dedicated space for labs, which are currently scattered through- out the University. Nevertheless, the development of a new science campus in Allston – on the other side of the Charles River – o ers a promising solution. Certainly, this interdisciplinary enterprise is one that merits Harvard’s support, as it boldly confronts some of the most fundamental questions about our existence and our universe. And although this team of scientists does not embark upon scienti c inquiries with the intention of contributing to philosophical or religious debate, Sasselov holds that one cannot deny that such “new fundamental knowledge is always bound to shape humans’ total worldview.” And that fundamental knowledge cannot come about without scienti c collaboration across many elds. e questions of whether we are alone in the universe or how we came to be here will most likely not be answered by a team composed solely of biolo- gists or solely of astronomers. It will be up to teams of scientists from a variety of disciplines – like the Origins of Life Initiative – to take on that challenge.

FEATURES

Volume 2 Issue 1 | Spring 2009

Quantum dots, vacuum energy, microfluidic chips:

and

By Isha Jain, THURJ Staff

Bridging the sciences at the nanoscale level

Illustration by Katherine Goldin/THURJ Staff

Volume 2 Issue 1 | Spring 2009

I n the past, the sciences were o en regarded as

a hierarchy. Professor Federico Capasso – from

Harvard’s School of Engineering and Applied

Sciences – describes society’s original outlooks:

e elds that are more theoretical, more far from reality, particularly in science and technology, by some ill-conceived argument were viewed as superior intellectually.” But for Capasso, “this mentality is a total disaster: we create the di erences between these elds.

FEATURES

questions through a nanoscale lens. Rather than simply considering single units at the nanoscale level, the Center strives to understand systems built from nanoscale components. In addition, CNS serves as a technological melting pot. Supported by grants from the NSF, the o ers the Harvard research community access to a myriad of technological resources for imaging, nanofabrication and materials synthesis.

“The advantage of CNS is that you have a lot of interdisciplinary activity, because the lines between biology, chemistry and physics are being blurred at the nanoscale level.”

Nature does not distinguish whether a phenomenon is chemistry, physics or biology…it is a completely arti cial thing.” Recently, we have come to appreciate science as more of a coplanar playing eld. Every sub eld exists to serve its own purpose as well as to augment progress in other sub elds. One of the newest embodiments of this mantra is Harvard’s very own Center for Nanoscale Systems (CNS). e term “nano” tends to conjure up an image of the unknown, the mysterious that resides in a parallel world, see-sawing reality and science ction. But the groundbreaking research being conducted in the CNS seeks to conquer such ambiguities in the form of applicative innovations. It is o en di cult to conceptualize orders of magnitude that deviate from our day-to-day encounters. A nanometer is 10 -9 of a meter. A human hair is approximately 100 microns or 100,000 times a nanometer in width. A typical covalent bond is approximately one-tenth of a nanometer. So, what truly lies behind all the hype of this esoteric nano-world? e primary motivation driving this eld of study is the increased importance of minute forces we tend to disregard on larger scales. ese forces drastically alter the classical laws of physics. We enter a realm of phenomena such as quantum-tunneling, carbon nanotubes and quantum dots. e Center for Nanoscale Systems is an endeavor by the Harvard faculty to approach multidisciplinary

Why here? Why now? What next?

W hen it comes to the life sciences, Harvard’s research is in many ways unparalleled. But when it comes

to engineering, more technically focused institutions like MIT tend to be seen as at the forefront of scienti c e orts. With such a distinctive reputation, the Center faced the challenges of establishing an engineering and physics based institution in the midst of a largely biology-oriented community. As Professor Capasso explains, “ e advantage of CNS is that you have a lot of interdisciplinary activity, because the lines between biology, chemistry and physics are being blurred at the nanoscale level. A number of professors had the wisdom to propose a service center, a facility. ese elds have developed so much that you need a centralized facility. It cannot be done in the old style garden variety manner.” CNS is now at the forefront of competitive nanotech research due to the collaborative e orts of its faculty and to the top-notch technology it houses.

Projects through a Peephole

D r. Federico Capasso exudes a love of science. With a distinctive Italian accent, he remarks, “I like to

think of myself as an engineer. I work in a number of interlocked, interdisciplinary areas. I like to bridge the

gap between so called fundamental stu , basics and

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applications.” In one of its projects, Capasso’s group seeks to understand a newly discovered phenomenon. Contrary to what one may believe, a vacuum is a

surprisingly dynamic condition. Speci c materials pos- sess intrinsic properties at the nanoscale level. In the mid 1900s, a theory known as the Casimir e ect rst highlighted the existence of attractive forces between macroscale objects. Now, the Capasso group has found the rst evidence of repulsive forces caused by a so called “vacuum energy.” Two plates made of special materials can now be engineered to have a levitating

e ect. e weight of the upper weight can be countered

by the repulsive force between the two plates. e group is also pioneering development in laser technology. “Last year our group developed a tiny laser spectrometer on a chip, something like a nger nail. e Holy Grail is to go to the longest possible wavelength. At this wavelength, light can penetrate non metallic enclosures, so it could be a substitute to x-rays. It could be used in security check points to detect weapons.” Robert Westervelt – a Professor of Physics and Applied Physics at the CNS – works to engineer circuitry using quantum dots. It was originally believed that the number of microprocessors able to t on a chip would double every three years. However, physical laws place an upper limit on this prediction. en came the revolutionizing idea of quantum computers, based on quantum dots. Quantum dots contain a speci c number of electrons (each with an up or down spin). is is analogous to the binary system currently utilized in common computers. Westervelt has led the pioneering research of connecting quantum dots, which in turn could be used to build nanoscale

Illustration by Katherine Goldin/THURJ Staff
Illustration by Katherine Goldin/THURJ Staff

Volume 2 Issue 1 | Spring 2009

circuits. In the biotech realm, the Westervelt group has con- structed a “hybrid integrated circuit and micro uidic chip.” is fusion of technologies enables researchers to trap and move thousands of small droplets and living biological cells in speci c con gurations. is biological etch-a-sketch has been used to move yeast and mammalian cells at speeds in the tens of microns per second.

“The future lies in lowering the barrier between science, engineering and technology.”

At the forefront of integrative bio-nanotechnology at the CNS is the work of Dr. Charles Lieber. ere are two approaches generally used by nanotechnologists:

top-down and bottom-up. e Lieber lab focuses on the bottom-up approach to design nanoscale building blocks and then eventually build complex and elabo- rate systems. For example, the Lieber group devises sensory technology to detect speci c protein-protein interactions or the presence of bio-hazardous materials in trace amounts. e basis of this technology is the manner in which the presence of a particular molecule can be translated into an electrical signal. In another project, Lieber attempts to model engineering at the nanoscale level o the architecture of the brain. Today’s computers have to be restricted to the concept of the 2-dimensional at chip. Dr. Lieber has been cra ing the foundation for branching nanowires, to overcome this restriction.

The Future of the CNS

C apasso, Westervelt, Lieber and many other faculty at the CNS are paving the path for integrative

research in the study of nanoscale systems. As Capasso asserts, “the future lies in lowering the barrier between science, engineering and technology.” e Center for Nanoscale Systems combines all three: studying, modifying, and creating new connections between the basic particles that make up our world.

Illustration by Kathleen Tang/THURJ Staff

Volume 2 Issue 1 | Spring 2009

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Online collaboration and its implications

by Jen Jian Gong, THURJ Sta

R ecent years have seen the massive rise of

web-based social networking , blogs, and

free data sharing through websites like

Project Gutenberg and Wikipedia. Not surprisingly, the way scientists look at social interactions is now changing dramatically. Professor Yochai Benkler, the Jack N. and Lillian R. Berkman Professor of Entrepre- neurial Legal Studies of the Harvard Law School, has made human behavior his primary research focus and is now helping to lead the e ort in introducing social implications to the study of the Internet. Professor Benkler started his career at Harvard as a Teaching Fellow, worked as an associate at the Ropes & Gray law rm in Boston and then as a law clerk to Justice Stephen Breyer of the United States Supreme Court. He later became a professor of law at the New York University School of Law, continu- ing his teaching career at Yale, and nally coming back to Harvard in 2007, where he became faculty co-director of the Berkman Center for Internet and Society. His book, e Wealth of Networks: How Social Production Transforms Markets and Freedom, has won many awards, including an award from the American

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Sociological Association in 2008 and the 2007 Don K. Price award from the American Political Sci- ence Association for the best book on science, technology, and politics

“How does the internet a ect democracy? And what does collaboration online mean to society and human relationships in general?”

in the last 3 years. Benkler’s research aims to answer two fundamental questions: how does the Internet a ect democracy? And what does collaboration online mean to society and human rela- tionships in general? In the 1990s, the Internet was regarded as “a new frontier,” where “everyone could say what they wanted.” However, there was not enough real data to back up this idealism. But now, “the physical capital means in our hands – computers, mobile phones – are as necessary as the physical capital in the core economic activities of the most advanced economies” and in recent years have started to a ect “behaviors we’ve always had as social beings.” Benkler is currently studying the same process, but in reverse. Originally the puzzle was, “‘why do we see so much cooperation online?’ and the answer had to do with things we’ve always been doing

Volume 2 Issue 1 | Spring 2009

Illustration by Kathleen Tang/THURJ Staff
Illustration by Kathleen Tang/THURJ Staff

Volume 2 Issue 1 | Spring 2009

FEATURES

becoming economically important.” But now that we’ve been exposed to so much online cooperation, the

real question is: “what can we learn about human motivation or inter- action from that very exposure?” Professor

Benkler

is also

questioning

the “basic,

dominant

assump-

tion,” that

“everybody is more or less the same, we’re all rational and we’re all self- interested.” Instead, he posits that perhaps all the networking and social interactions occurring online can show us “deviations from sel shness.” An important aspect of Benkler’s research deals with the perspective we take when looking at the data about di erent sites and practices on the Internet. While the current tendency is to “look at every single blog as though it is the same thing,”

he proposes that “one of the big challenges now is to try and zoom in on what is happening within the blogs, within the text itself.” Instead of integrating all the blogs and then recording the data, Benkler

text from a variety of sources in order to use machine analysis, in

collaboration with other groups in the University, such as the Institute for Quantitative Social Science at Harvard, to nd out “where ideas come from,

“Benkler is also questioning the ‘basic, dominant assumption’ that ‘everybody is more or less the same, we’re all rational

and we’re all self-interested.’”

hopes to maintain the integrity of the individual nature of each blog and then search for similar characteristics between them. For example, political a liations de ne interesting di erences in the blogosphere. “We’ve been looking at the organization of technologies adopted by blogs, and we’re nding very interesting di erences between the le and right wings of the blogosphere, with the le adopting technologies that allow for much more participation: people who are not the primary authors can quite easily nd a place on the front page of a site, whereas the right tends to be much more solo and hierarchical in the sense that users can’t contribute that much.” Following this line of thought, Benkler is currently associated with MediaCloud, a scienti c project that attempts to take in massive quantities of online

how they move through the network public sphere so that we can actu-

ally begin to get a map of ideas and statements.” Instead of staying away from the content of each blog, MediaCloud’s goal is “zooming in, both by human coding of what the actual practices are, and by a large-scale text analy- sis to look at what it is that people are doing.” e research spearheaded by Professor Benkler taking place at the Berkman Center investigates what all the collaborative e orts on the Internet mean to society’s un- derstanding of human nature and human motivation: “How do we construct a new model for human behavior that takes into account the reality that we’re observing in lots of di erent disciplines, that people don’t behave in practice according to the predictions of sel shness?” e Center’s research on human cooperation focuses on free so ware and Web 2.0 websites like Wikipedia and Facebook, investigating the evolution of social behaviors evidenced and enabled by the Internet. In questioning our current economic assumptions about human nature (that we are fully rational and sel sh), Benkler also joins with others in “a great group that meets weekly with people from evolutionary dynamics and com-

Professor Benkler Photo by Jen Jian Gong/THURJ Staff
Professor Benkler
Photo by Jen Jian Gong/THURJ Staff

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Volume 2 Issue 1 | Spring 2009

puter science and political science

and the business school – all sorts of people who are interested in this question of how we understand the micro-foundations of cooperation.” David Rand, a member of the Program of Evolutionary Dynamics at Harvard, coordinates these meet- ings. He works with Benkler on the

cooperation

group project,

investigating

how the

collaborative

e orts that

have appeared

online question our current beliefs about human nature. Rand believes that “in the face of changing con icts and shi ing alliances, it is essential for group identities to be exible,” rather than centered on individual sel sh interests. If human nature is indeed di erent, as cooperation over the Internet seems to suggest, then “solidarity is a force that can potentially be harnessed to help groups work together if institutions are designed in a way that prevents the negative and discriminatory aspects of such behavior.” Another study at the Berkman Center seeks to analyze a couple of thousand online collaboration

communities and tries to see what typi es them: “What are the kinds of things they’re doing? What are the kinds of motivations? How much do people rely on money, how much do people rely on moral implications, how much do people rely on just creating person to person interactions and com-

could understand how cooperation works online, not only could you play a part in creating institutions that support working in cool things online, you could also take part in a broader trend we’ve been seeing in the past few years: internet culture manifesting itself in the mainstream. If you understood it

“If human nature is indeed di erent, as cooperation over the Internet seems to suggest, then ‘solidarity is a force that can potentially be harnessed to help groups work together’”

munications?” ese observations, Benkler notes, provide the perfect contrast with experimental work, “[combining] both greater preci- sion and tractability and greater realism in terms of looking at the way humans are actually behaving.” Tim Hwang, a recent Harvard College graduate, worked part-time at the Berkman center during his undergraduate years. He is now a research associate there, and works with Benkler on many projects, pursuing his interest in online communities. Hwang’s enthusiasm for the cooperation project and these studies on online communi- ties arises from the idea that “if you

on this level, you could generalize it to the larger societal space.” Professor Benkler’s work and the related research happening at the Berkman Center and all across Harvard demonstrate the impor- tance of interdisciplinary study. “[T]he net provides a breathtaking expanse where you can actually go and look at lots of di erent things without physically traveling to a thousand di erent places.” is research links a variety of depart- ments and subjects, pooling knowl- edge and using technology and networking as windows into human nature and social interactions.

Volume 2 Issue 1 | Spring 2009

FEATURES

It’s a bird! It’s a plane! It’s a robotic fly! !"#$%%"&'($)*"+'(,-
It’s a bird!
It’s a plane!
It’s a robotic fly!
!"#$%%"&'($)*"+'(,- ('"/(#"0((*1."
!"#$%$%&%'#()*+&
Photo by John Mei/THURJ Staff

!"#$%&''(#)*+(,(-#

!"#$%&'()*

P rofessor Robert Wood’s cre-

ations have been featured in

an exhibit at the Museum

of Modern Art, on two Discovery Channel series, and in Time Magazine. When you walk into his Harvard lab at 60 Oxford Street—a building beyond the boundary of

most undergaduates’ travels—you nd yourself amid the hustle and bustle of undergraduates, graduate students, and postdocs peering through microscopes at actuators, using lasers to create air frames, and tweaking mechanical wings and transistors. Yet the most excited of all is Professor Wood himself, walking around and peering over the shoulders of his students, making

suggestions and sharing in their enthusiasm. What’s so special about his product? It is the rst at-scale robotic insect with su cient thrust to take o —in other words, y— with external power.

Getting ready for takeo

P rofessor Wood’s journey to ight began when he entered

graduate school at the University

Photo by John Mei/THURJ Staff

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Volume 2 Issue 1 | Spring 2009

of California, Berkeley. With a

background in electrical engineer- ing, Wood hoped to nd a research project in his interest as well as

“inherently

interesting of itself.” At that time,

one of the rst

e orts to create

a robotic insect

was starting up, and the project caught Wood’s

attention—yet

what he initially thought he would work on was not what he ended up researching. Wood was geared towards working on controlling the y, but the y didn’t exist yet!

“My adviser said, ‘You have to build the y rst,’” said Wood. “I had to switch gears and become a

di erent sort of engineer.”

A er receiving his PhD, Wood carried over his microrobotics work to Harvard where he was appointed as an Assistant Professor of Electri- cal Engineering and Computer Science. e catalyst behind his

research projects was material design—saying “I want to make this shape, so how do I do that?” at thinking eventually led him down

All insect wings have some degree of compliance due to aerodynamic and inertial loads experienced in ight. Wood hopes to understand why insects have this com- pliance and how

it bene ts them during ight. So robots aren’t like the tin-can creations from

comic books— rather, they are robots that can easily change their shape and size and are made from exible materials. Unlike those working on creating human robots—sensationalized on the big screen in movies like I, Robot, Wood has had to focus on many aspects larger-scale roboti- cists take for granted and that can’t be applied directly on a smaller scale to robotic insects. “Instead of jumping right to questions of control or behavior we have to start from nothing and do everything from scratch,” said Wood.

Fly, Robot, Fly

I n 2007, Wood’s y took ight for

the rst time, xed to guide wires that allowed only vertical motion. e robotic y was integrated from four components:

an actuator (the ight muscles), transmission (thorax), an air frame (exoskeleton), and wings. Weighing in at only 60 mg with a 3 cm wingspan, the tiny mechanical creature could move freely in the

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-20$.$3$2#&'$($0#+&415*1&-',&*-6-(7,&$8&

7$*$3$)$.+&-.9&*',-)./&.,4&3-0,'5-7#&

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two primary paths. “One is microrobotics, creating particular robotic insects, things that y and crawl that are inspired by various aspects of arthropod morphology and control materials,” said Wood. “ e second is so robotics, creating both autonomous robots, which are capable of locomotion, and also creating new materials with inherent compliance like arti cial muscles and embed- ded sensors.” Inherent compliance in wings re- fers to their “degree of oppyness.”

compliance in wings re- fers to their “degree of oppyness.” 18 The Harvard Undergraduate Research Journal

Volume 2 Issue 1 | Spring 2009

FEATURES

vertical direction with a trajec- tory nearly identical to biological counterparts. is robotic y can be put together in under a week – a user- friendly advancement. “In the past the fabrication methods we used took a great deal of skill and time,” said Wood. “ at was ne when it was really just me making them, but when you get new students involved nobody has this very esoteric skill set that they wouldn’t use for anything else.” Now the emphasis is on the empirical portion of the research— building structures and trying to characterize their performance to “ ll in the empty

pieces” of previous models. As Wood noted, once his lab

demonstrated the rst successful ight, “that opened up a dozen

di erent paths—we have an endless

supply of things we need to study.” He hopes to develop robotic insects that can y in multiple dimensions (rather than solely vertically) without an external power source and with the ability to work together in groups. His project is funded by the U.S. Defense Advanced Research Projects Agency, who hopes that at-scale robotic insects can be used as spy technology during

wartime or as a means to locate survivors trapped in hazardous

!"#$%&'()&*+,&

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10)/&)2$$%))32*&

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environments.
But Wood said he encouraged
people to look beyond the face
value.
“Any place you wouldn’t want to
put a human or an animal, there’s
a big class of scenarios for applica-
tion of a mobile robot,” said Wood.
“And in reality, we’re developing
new techniques for fabrication and
actuation at an interesting scale
which individually could be ap-
plied to understand many di erent
phenomena, for example, the uid
mechanics of di erent
wings.”
Photo by John Mei/THURJ Staff

FEATURES

Volume 2 Issue 1 | Spring 2009

hours at the lab each day interact- ing with the students, as well as scheduling weekly lab meetings for

out one of his students, he works to raise money and make sure everyone is happy.

science, bioengineering…every- thing,” said Wood. “So when you’re

stuck, you have a lot of di erent voices from a lot of di erent areas.”

!"#$%&'()%&*$('+&,-./*&,&0.-.1)2&3,-&(2&*$,*&

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%3%)*0(),3&%'+('%%0('+<&).79/*%0&2)(%')%<&

-(.%'+('%%0('+=%5%06*$('+<!"#$%&"'((&)

And by putting all those voices together, Wood and

his students have created a robotic y that is, indeed, ready for take-o and may one day search out soldiers injured in the battle eld or miners trapped underground. As Prof. Wood’s website relates: “Remarked one unimpressed Yale researcher, ‘Leave it to the Harvard fellows to invent new and exciting ways to be irritat- ing.’”

the lab as a whole and for di erent subgroups. When he’s not tinkering with the robotic ies themselves, he says he will o en embark on his own little project that will help

e nice thing about a robotics lab is that it’s very multidisci- plinary—we have students who are studying mechanical engineering, electrical engineering, computer

As an introduction to undergraduates seeking out lab research, Prof Wood sat down with THURJ and described the projects di erent members of his group are currently working on.

Postdoctoral student: Dr. Sangbae Kim

Dr. Kim is working on the integration of so actuators into compliant sheets. To put it simply, he is creating “programmable matter.” “ ere are sheets which fold themselves to create whatever useful devices you might want to have around,” said Wood.

Graduate student: Ben Finio

Finio is working on the thoracic mechanisms, or transmission, of the robotic ies. He is trying to come up with ways to separately include actuators for power and low-power actuators for control. “We want to create a compact mechanical device that can not only ap its wings and crate motion but also crate body torque,” added Wood.

Undergraduates: Elliot Hawkes, Brandon Eum, and Geneva Trotter

Most undergraduates work closely with a graduate student or post-doctoral student. Case in point: Hawkes is working with Kim to integrate novel actuation within self-folding sheets, and Eum creates experiments to quantify the motion of the wings developed by graduate students.

Trotter is working on creating an experimental device that would allow Wood and his group to apply arbitrary pre-loads on a certain class of actuators. She previously worked on characterizing conductive polymers for use in a compliance circuit.

When you put the work of all these students together, what results is a nanorobotic y that we would commonly swat at—but in this case, has widespread applications.

Volume 2 Issue 1 | Spring 2009

Op-Ed

Statistics:

Your chance for happiness (or misery)

By Professor Xiao-Li Meng

Whipple V. N. Jones Professor of Statistics and Department Chair

1. “I keep saying the sexy job in the next ten years will be statisticians.”

Hal Varian, Google’s Chief Economist, recently was inter- viewed by e McKinsey Quar- terly, and was quoted (see www. mckinseyquarterly.com/Strategy/ Innovation/):

“I keep saying the sexy job in the next ten years will be statisticians. People think I’m joking, but who would’ve guessed that computer engineers would’ve been the sexy job of the 1990s? e ability to take data—to be able to understand it, to process it, to extract value from it, to visualize it, to communicate it—that’s going to be a hugely important skill in the next decades, not only at the professional level but even at the educational level for elementary school kids, for high school kids, for college kids. Because now we really do have essentially free and ubiquitous data. So the complimentary scarce factor is the ability to understand that data and extract value from it.”

As a professor of statistics, you guessed it, I of course cannot disagree less (just to check if you have had enough co ee!). But as a statistician, I am obligated

Photo by Rose Lincoln/Harvard News Office Professor Meng and his “Happy Team” on the opening
Photo by Rose Lincoln/Harvard News Office
Professor Meng and his “Happy Team” on the opening day of Stat 105
Cassandra Wolos, Kari Lock, Xiao-Li Meng, Yves Chretien, and Paul Edlefsen

to remind you that a professor of any subject can nd quotes – tons of them – to demonstrate the importance of his or her beloved subject. Wait! Does the “reminder” have anything to do with being a statistician? Well, let’s label this question as Puzzle One, and read on. And while we are at it, let me throw in another quote, this time from a recruiter representing Wall Street – yes, they are still hiring – but read this carefully:

“Now more than ever, they are looking for the best and brightest to help get an understanding as to what

caused the housing bubble, and how to properly forecast those prices based on all the variables involved (e.g., interest rates, inventories, short sales, foreclosures, delinquencies, etc.). I am actively seeking those individuals who have the background and desire to apply their Stat/analytical skills speci cally in the Real Estate me- dium. … e trend in these unique economic times is that companies want the more scienti c/mathemati- cal/engineering backgrounds to help them back solve [sic] these very new and volatile markets. My clients these days are actually shying away from MBA-types because today’s equity markets have much more to do with randomness and psychology than business fundamentals.”

Op-Ed

Volume 2 Issue 1 | Spring 2009

Here, the word randomness is what brings statistics and statisti- cians into the picture. Statistics, in a nutshell, is a discipline that studies the best ways of dealing with randomness, or more precisely and broadly, variation. As human beings, we tend to love information but hate uncertainty, especially when we need to make decisions. But information and uncertainty actually are two sides of the same coin. If I ask you to go to the airport to pick up a new student you have never met, my description of her is information only because there are variations - if everyone at the airport looks identical, then my description has no value. On

the other hand, the same variation

causes uncertainty. If all I tell you is to pick up a Chinese female student by the name Xiao-Li (meaning “Little Beauty” ( !" ) in Chinese, not “Plough at Dawn” ( #$ ) ! as in my

Chinese name - an example of uncer- tainty in translation, or lost in transla- tion!), then my description is not informative enough precisely because it still allows too many

“variations” - there may be a substantial number of individuals at the airport

who look like a “Chinese female student.” You then need to do something creative on your own in order to pick up the right one, such as making a name sign.

“Statistics, in a nutshell, is a discipline that studies the best ways of dealing with randomness, or more precisely and broadly, variation

en again, the name sign is use- ful for her to identify that you are the one who is picking her up, only because there is variation among names. Indeed, if it happens that there are two “Xiao-Li” name signs outside the terminal, she will need to do something creative on her own in order to nd the right one. is is of course a trivial fact, and any of us would recognize and deal with the situation when we encounter it. But we may or may not recognize the deeper principle behind it, that is, information is there for the same reason that uncertainty is there. While we are at the airport, let me throw in this almost well- known joke. Mr. Skerry needs to take a ight, but he is terri ed by the possibility, however small, that someone could bring a bomb onto his plane. So he decides to pack a bomb himself, as he reasons that the chance that two individuals bringing bombs onto the same plane is much smaller than that of one individual bringing a bomb. You, of course, are chuckling at this. However, which probabilistic/

Illustration by Evelyn Park/THURJ Staff
Illustration by Evelyn Park/THURJ Staff

Volume 2 Issue 1 | Spring 2009

Op-Ed

statistical principle is he trying to use, or rather violating? Can you easily explain to your fellow students why Mr. Skerry’s argument is ridiculous? If you cannot, then let’s label this as Puzzle Two. Regardless of whether you can or cannot, I hope the discussion above has helped you to see more clearly, and fundamentally, why Google and Wall Street, among many others, are increasingly interested in hiring statisticians. We are now squarely in the information age, with almost everything digitized.

Each of us is trying to see what all the data (which don’t have to be numerical) out there are telling us, on issues from personal health to the global economic crisis. ere is so much variation in almost everything we want to know or study, so what is real information and what is just noise? Mr. Skerry’s reasoning surely is ridiculous, but how many of us have

realized that the many “small prob- abilities” reported in the media and even in scienti c publica- tions, such as prob- abilities of crime

evidence, were based on exactly the same ridiculous reasoning, that is, multiplying probabilities inappropriately?

(i.e., undergraduates) I have spoken with, the number one reason that you did not even consider majoring (or concentrating, to be true to the Harvard spirit!) in statistics is because the AP Statistics you took convinced you that statistics is the most boring subject. We statisticians, of course, are to be blamed for this unfortunate situation. Statistics is an urgently demanded but vastly underap- preciated eld; urgently demanded for reasons discussed above, and vastly underappreciated because too few statisticians, relatively speaking, have e ectively conveyed the excitement of statistics, as a way of scienti c thinking for whatever you do, instead of a collection of tools you may or may not need one day. Tremendous e orts have been made, for example, by the Con- sortium for the Advancement of Undergraduate Statistics Education

anity, and Jesus himself is teaching.” (If you can come up with more impressive praise than this, email me at chair@stat.harvard.edu!). Another colleague, Joe Blitzstein, has single-handedly doubled the enrollment of Stat 110, Introduction to Probability, from 90 students when he took over in 2005-2006, to 188 students this past fall. He is now an international sensation, so to speak – a student was telling her friend in Germany that she was taking this cool stat course with Joe, and her friend responded “Oh, you mean that YouTube stat professor?” (You can satisfy your curiosity by googling “Stat 110 at Harvard.”) Last year, we also launched Stat 105, Real Life Statistics: Your Chance for Happiness (or Misery), and I am teaching it again this semester. is course was designed by my Happy Team, which consisted of 8 Master’s and Ph.D students from the statistics depart-

ment, over a period of two years and many happy dinners (not happy meals!) at the best restaurants Boston can o er. e course aims at

introducing students to the wonderland of statistics, by showcasing how it is used (and mis- used) in real-life situations every student should be able to relate to, either happily or miserably! Unlike many traditional statistical courses, which arrange the material by statistical topics in the approximate order of their complexity, Stat 105 arranges the material by what we call “Real-Life Modules.” For last year’s o ering, the ve modules were (1) Finance (e.g., stock market), (2) Romance (e.g., on-line dating models; not

“Each of us is trying to see what all the data out there are telling us, on issues from personal health to the global economic crisis”

(CAUSE, http://www.causeweb. org/). But clearly more is needed, as surely any successful educational program requires on-going e ort. At Harvard Statistics, we are fortunate to have several rst-class statistical educators who are at the forefront of teaching introductory statistical courses. For example, my colleague, Ken Stanley, who teaches Stat 104, Introduction to Quantita- tive Methods for Economics, has been so e ective that one student wrote in his/her CUE evaluation, “It is like taking a course in Christi-

2. “AP Statistics was the most boring course I took in high school!”

As a professor of statistics, I hear this almost every time I tell some- one that I teach statistics: “Oh, that was really a hard course for me!” or, “I really didn’t like my stat course!” And for nearly every one of you

Op-Ed

Volume 2 Issue 1 | Spring 2009

dating on-line models!), (3) Medical Sciences (e.g., Viagra trial; not trying Viagra!), (4) Law (e.g., OJ Simpson trial), and (5) Wine and Chocolate Tasting (depending on your age!). is semester, we are replacing the Law module by an Election module, given the historic election we all just witnessed (and now that OJ is behind bars). More information about the rst o ering can be found in the Valentine’s Day edition of Harvard Gazette exactly one year ago (http:// www.news.harvard.edu/

gazette/2008/02.14/11-stats.

html). For the current o ering, check the Stat 105 course website (open to anyone with a Harvard ID) and view the video for the rst-day introductory lecture to enjoy a virtual chocolate tasting, with or without wine! All these e orts are aimed to make “statistics not just palatable, but delicious” (the title of the aforementioned Gazette article) to all of you, who, I am 98% sure (that

“Our happiness or misery often literally depends on our understanding of statistics, whether we realize it or not”

Illustration by Evelyn Park/THURJ Staff
Illustration by Evelyn Park/THURJ Staff

research, regardless of the subject, but also in your life. Our happiness or misery o en literally depends on (but of course is not necessarily determined by) our understanding of statistics, whether we realize it

or not. Statistics or, more generally, quantitative evidence is being used everywhere in the media, scienti c publications, etc., to

persuade us to buy a product, an argument, a theory, etc. Some of the claims are statistically and scienti cally sound, and many others are not. A good percentage of them are even deliberate lies, intended to deceive the public in order to make a pro t. If you have been one of those ipping channels

in the wee hours and have given your credit card number over the

phone because of those convincing “infomercial statistics,” chances are that you would have been much more satis ed by trying out the chocolates or wine o ered by our Stat 105 class! (And of course if you have a relative who had been convinced by the dazzling “return statistics” of Mr. “Made-O ,” then no amount of chocolates or wine could compensate!)

3. “Honey, I know you are in excruciating pain, but which treatment do you want?”

Here is another real-life scenario that literally makes your happiness or misery depending on your understanding of statistics, if you,

is the highest assurance any profes- sional statistician would give!), will need statistics not only in your own

Volume 2 Issue 1 | Spring 2009

like me, unfortunately su er from kidney stones. Two treatments for kidney stones were evaluated in a medical study. Treatment A has a success rate of 78% and treatment B, 83%. Which one should you choose? Surely treatment B, right? Well, what if I tell you that when treatment A and treatment B are applied to those who su er small stones, the success rates become,

respectively, 93% and 87%, and when they are applied to those who carry large stones, the success rate for treatment A is 73% and

for treatment B it is 69%?

regardless of the sizes of the stones, treatment A has a higher success rate. Surely you then should choose treatment A, right? Confused? You should be, if you don’t understand Simpson’s Paradox (no relationship with OJ, though there could be a paradox with him too, if he is still looking for himself), one of the most fundamental statistical phenomena, which is responsible for a vast quantity of misinformation in literature and in the public. ere is actually no paradox at all in the mathematical sense. e numbers

at is,

Op-Ed

I reported above are from an actual

study (Charig et. al., British Medical Journal (Clinical Research Ed), March 1986, 292 (6524): 879–882), and you can verify them yourself:

for treatment A, there were 350 patients, 87 carrying small stones, among which

treatment

A was suc-

cessful for 81 patients; for the remaining 263 patients with large

stones, treat- ment A was successful for 192 of

them. For treatment B, there were also 350 patients, with 270 su ering small stones, and among them 234 were successfully treated by treat- ment B; for the remaining 80 with large stones, treatment B was found successful for 55 of them.

are its general implications? Did it actually happen with some studies

you have done or read?

this Puzzle ree and read on, unless you really su er from kidney stones, in which case let me distract you by telling you how I was treated

Let’s label

“Simpson’s Paradox

is

responsible for a vast quantity of misinformation in the literature and in the public

And

by Dr. Coe from e University of Chicago (where I taught from 1991-2001), a world renowned nephrologist, who treats his patients with statistical principles! Once Dr. Coe learned that I was a statistician, he said, as I recall, “Well, you then should understand this well. e kidney stones are ac- tually formed by a Poisson process, with those crystals bumping into each other. So what you need to do is to drink a lot of liquid, any kind of liquid, water, juice, co ee, even beers and wine, anything that helps to reduce the Poisson rate for

Now you do the math!

then think statistically – how could this happen? at is, how could treatment B have a better success rate overall than treatment A, and yet a worse rate in each subgroup

de ned by the stone size? What

caused such a “paradox”? What

Illustration by Evelyn Park/THURJ Staff
Illustration by Evelyn Park/THURJ Staff

Op-Ed

crystals to bond with each other.” He was obviously pleased to nally nd a patient who understood

“Poisson process,” and surely the feeling was mutual as I was pleased that I was treated by a doctor who understood statistics! Of course

I have followed his advice closely, and have not had any episodes of

close to the boundaries, either 1 or 2, suggests something to watch for. Indeed, my physician asked me to schedule an appointment with an endocrinologist for further studies. is of course is a rational suggestion, given the “normal” interpretation of my test result and the fact that I was having various

“I was sad to think how many other people had unnecessarily worried and gone through additional tests, simply because of an elementary statistical mistake in setting the ‘normal limits’”

kidney stones for the past 15 years or so. And I have never had any surgery for kidney stones, nor am I on any other treatment now other than a lot of drinking – so next

time you see me pouring myself a glass of wine, I may be just trying to reduce my Poisson rate for crystals

bonding!

Here is another example where Dr. Coe saved me much trouble and worry because of his – and my

– understanding of statistics. While

I was at e University of Chicago,

I su ered for a long period from

fatigues and various pains of unknown cause. So my primary- care physician did all sorts of tests on me. One of them was checking my thyroid function. One result came back on the “borderline” – I don’t recall which test and what were the exact values, but for the sake of the story, let’s say my value was 1.1 and the normal range listed was (1.0 – 2.0). Most people would consider this interval (1.0 – 2.0) to imply that values close to 1.5 to be “normal” and a test result

symptoms, which could have been due to a thyroid disorder of some sort. Since the quality of doctors mat- ters (obviously!), and it happened that I had a regular follow-up visit

with Dr. Coe shortly a er that test,

I asked him if he could recommend

a colleague who is an endocrinolo-

gist. He naturally asked me why, and I showed him the test results. He laughed and sighed at the same time: “Well, these doctors really don’t know anything,” (I assume it’s OK for a well-known doctor to say that!). He continued, “For years I have told them that they shouldn’t provide “normal limits” as such when the distribution is highly skewed! You actually have the most typical value in the population! You of course understand that they should have taken a log or something.” As a statistician, I was both happy and sad. I was happy of course that I had no reason to worry about my thyroid (and I still don’t to this date). I was sad to think how many other people had

Volume 2 Issue 1 | Spring 2009

unnecessarily worried and gone through additional tests, simply because of an elementary statistical mistake in setting the “normal limits.” Incidentally, I was told by a medical student that when a pa- tient’s list of test results come back from the lab, abbreviation WNL a er the name of a test indicates that the result was “within normal limits.” e inside joke is that it really stands for “we never looked.” Having incorrectly set normal limits could be even worse than “we never looked”! I hope by now I have distracted you enough from your kidney- stone su ering, and that you understand what Dr. Coe was laughing and sighing about. If not, let’s label this as Puzzle Four, and read on again.

4. “The best thing about being a statistician is that you get to play in every- one’s backyard.”

is quote is attributed to John Tukey, a statistical giant who also coined the terms “so ware” and “bit” (see http://www.princeton.

edu/pr/news/00/q3/0727-tukey.

htm or e New York Times, July 28, 2000). is is literally true, as many statisticians, myself included, can personally testify. Other than teaching the delicious Stat 105 class and other courses (e.g., I also co-teach, with Joe Blitzstein, Stat 303, e Art and Practice of Teaching Statistics, aimed at training more and better future statistical educators), I am currently conducting – together with researchers from the Harvard- Smithsonian Observatory – a workshop on AstroStat for dealing

Volume 2 Issue 1 | Spring 2009

Op-Ed

with astronomical amounts of data from astrophysics; working with a group of geophysicists

from the University of Illinois and the National Weather Service on climate change; writing papers with a team of psychiatrists from the Harvard Medical School and Columbia University on estimating disparities in mental health services;

collaborating with researchers from Harvard’s engineering school on signal processing, particularly for

digital cameras, via wavelets methods; publishing

articles with statistical geneticists at e University of Chicago and deCode Genetics in Iceland on how to measure information in genetic studies; preparing reports with my ex-postdoc at e University of Chicago on AIDS reporting delay to the CDC

(Center of Disease Control).

I of

course also play in statistics’ own backyard, or perhaps I should say front yard, investigating statistical foundational issues, such as to what extent size matters – do more data automatically imply more accurate results? ( is one will take more thinking, so let’s consider it the last Puzzle of the Day.) If you nd the range of my

have provided a snapshot on how practically useful and intellectually

ful lling it is to be a statistician, or at least to be able to reason with good statistical insights. I am certainly having great fun, both professionally and personally, as a statistics professor, and I hope you will be able to share some of the fun by taking at least one statistics course, no matter

“I hope you will be able to share some of the fun by taking at least one statistics course, no matter how much you hated that idea before

“backyard” activities impressive, check out our webpage (stat. harvard.edu), and prepare to be dazzled by a wide range of “front yard” research my colleagues are conducting, such as Sam Kou’s absolutely pioneering work on statistical models for neon- biochemical experiments. I hope the quotes and stories

how much you hated that idea be- fore. You will then, among many other bene ts, easily nd out the answers to all ve puzzles

listed above. If you want to think hard about them now to challenge yourself, of course that is part of the fun! But if you start to lose sleep over any of them and feel miserable, email me (chair@ stat.harvard.edu) – remember, I promised you both happiness and misery!

Photo by Yewenyi/Wikipedia

BOOK REVIEW

Volume 2 Issue 1 | Spring 2009

A Marxist utopia in your backyard?

Book review: The Superorganism

By Fernando Racimo, THURJ Sta

E dward O. Wilson once proclaimed: “Karl Marx was right, socialism works, it is just that he had the wrong species.” e renowned American

biologist has dedicated his life to studying the organ- isms that would have made the German philosopher proud: ants, bees and termites – the stalwarts of social living. Wilson’s new book, e Superorganism– co-au- thored with the biologist Bert Hölldobler – seeks to unravel the mysteries of insect eusociality:

a social system that in many ways surpasses human societies in its complexity and cohe- sion. e book begins by giving an evolutionary survey of the origins of eusociality before transi- tioning into an extensive ecological account of the inner workings of a variety of insect colonies. e last chapters are devoted to analyzing

the most extraordinary displays of eusociality,

like fungi agriculure in leaf-cutter ants and the giant structures built by African termites to house their brood. What exactly is eusociality? As the authors make clear, eusocial colonies generally possess three de n- ing characteristics: cooperative care of the young, overlaps between generations of individuals, and reproductive castes. e last feature implies that some

members of the group (workers and soldiers) forfeit

their individual right to reproduce in order to dedi- cate more amounts of time, e ort, and resources to taking care of the brood and of those individuals who do get to reproduce – either one queen or a group of them, depending on the species under study. But unlike what Marx had in mind, eusociality has no room for centralized planning. Wilson and Hölldobler aim to show that there is no central administrator inside a bee hive or a termite

mound: the queen is too busy producing eggs and the workers are too busy, well, working. erefore, planning comes about as an emergent property of each individual’s percep- tions and actions. But how do thousands of insects with brains smaller than the tip of a needle manage to coordinate and exchange so much information?

e book dedicates an entire chapter to the many forms of eusocial communica- tion, another to the development of simple decision rules associated with di erent inputs of information, and another to the interplay of communication and information in determining castes and allowing for cooperative teamwork to gather resources or attack neighboring colonies. Wilson and Hölldobler have

A complex social system exists within this termite mound
A complex social system exists within this termite
mound

Volume 2 Issue 1 | Spring 2009

an ability to make complex biology seem like a piece of cake, and that ability is at their best in these three chapters. From long-lasting chemical trails to alarm pheromones, the processes that underlie the exchange of information between workers, soldiers and queens are detailed with true mastery. ey emphasize how little science has revealed about eusocial communica- tion and how much more remains to be discovered. eir one aw in this analysis is perhaps their overly narrow focus on ant communication, while saying little to nothing about communication in bees, termites or other eusocial insects, like aphids and thrips. is is, nevertheless, justi able given how much is known about ants (especially because of the authors’ own scienti c contributions) and how little is known about other colonial organisms. ough e cient mechanisms for communication allow the colony to maximize its energy input and reproductive output, eusociality also entails a measure of internal con ict. Chances are that Marx would have been slightly disappointed, even if he had applied his sociopolitical theories to the world of ants and termites. In fact, some female worke`r ants mutilate their brother’s wings to prevent them from mating with other queens; workers may also kill queens who

“Wilson and Hölldobler have an ability to make complex biology seem like a piece of cake.”

recognizably do not possess the gene that causes the killing in the rst place. Con ict indeed permeates what seems like a cohesive system from an outsider’s viewpoint. In fact, there is so much con ict inside certain colo- nies that the word “superorganism” may not exactly be the right way to describe a eusocial colony. All of the cells in an organism’s body carry the same versions of each gene, so it is extremely unlikely that a group of cells will try to harm any of the other cells. ey are all in for the ride, and they all privilege the survival and reproduction of the organism above anything (cancer and autoimmune diseases are rare exceptions). Genes need to cooperate in order to be passed on to future generations.

BOOK REVIEW

Yet this is not exactly the case in the eusocial kingdom: parents, siblings and o spring are not exact copies of one another and the levels of relatedness between each other – though uncommonly high – are

“But unlike what Marx had in mind, eusociality has no room for centralized planning.”

not exactly as high as those between the cells in our body. e authors show many examples of the chaos that sometimes ensues when a queen dies and the foundations of colonial hierarchy begin to shake. Usually, communication and agonistic rituals prevent widespread violence. Grabbing a subordinate’s antennae and shaking them, for example, constitutes a display of superiority in contests for power and prevents subordinates from continuing their attempts at climbing the social ladder (biology shows that bul- lying is by no means limited to high school corridors). But con ict may go much farther than bullying. In ponerine ants, as the queen gets old and weak, some workers (called gamergates) acquire the ability to reproduce. Once they are recognized by other workers as reproductives, they are also able to mark other potential gamergates with a chemical. e signal ef- fectively activates policing behavior in workers, which proceed to spread-eagle and o en kill the potential gamergates who dare defy the reproductive right of the already established gamergates. Given such high degrees of cooperation, con ict and communication, there is one central issue that the book addresses poorly: how did it all come to be that way? Wilson and Hölldobler make use of multilevel selection theory to explain the origins of eusociality. Multi-level selection theory is the idea that altruistic traits are naturally selected in the course of evolution because they bene t a group of individuals as opposed to the individual members of the group. So long as the group has low intra-group genetic variance (members are more related to themselves than to outsiders), the trait will be selected and become widespread. us, certain behaviors and communication mechanisms in ants must – according to Wilson and Hölldobler – have

BOOK REVIEW

evolved because they were advantageous to the group. eir argument seems to run opposed to inclusive t- ness theory: the idea that traits can be selected not just because they bene t an individual’s o spring but also because they bene t close genetic relatives who have a high probability of carrying the same genes as the individual with the traits. For Wilson and Hölldobler inclusive tness theory is not a su cient explanation for eusocial behavior. It is thus necessary to use

Volume 2 Issue 1 | Spring 2009

separate processes, creating confusion as to what exactly they mean when they refer to the evolution of eusociality. Despite the sloppiness of the book when describing evolutionary phenomena, its elegance and clarity when it comes to physiological, organizational and ecological processes are unmatched. Not only do the authors succeed at making the reader understand how dynastic succession a ects the overarching dynamics of the

“[The Superorganism] is a telling account of a social world that is highly distinct from human societies and yet has managed to thrive during millions of years of evolutionary struggle.”

multilevel selection theory to explain some aspects of eusociality. And they stress this point in repeated instances throughout the book from the division of labor to self-imposed restrictions to reproduction. e problem with this approach is that, as many scientists are now realizing, multilevel selection is just another side of the coin of inclusive tness theory. Both theories are accurate because, in reality, both are just two equivalent methods of explaining the same mechanism. Stating that altruistic group traits are selected when group members are closely related to each other is just another way of saying that altruistic individual traits will be selected when they are directed towards close kin. Even Wilson and Hölldobler admit to this point at the very beginning of their book: “It is important to keep in mind that mathematical gene- selectionist (inclusive tness models) can be translated into multilevel selection models and vice-versa.” And yet they don’t seem to apply their own realization to the rest of the book: the authors repeatedly make the distinction between the two theories as if they were

eusocial kingdom or how recruitment to new nest sites occurs over time, they also make sure the reader ‘sees’ these and many other behaviors in vivid photographs and illustrations. An example is the image of a group of weaver ants forming a “living bridge” with their own bodies to pull leaves together, which truly enlivens Wilson and Hölldobler’s narrative of nest construction. Overall, e Superorganism constitutes a compre- hensive analysis of a complex biological system by two masters in the eld. But more than that, it is also a telling account of a social world that is highly distinct from human societies and yet has managed to thrive during millions of years of evolutionary struggle. Both of its authors have studied these creatures for decades and, through this book, they make a compelling case for the value of this knowledge and the many questions that still remain unanswered. Ants, bees and wasps do not live in communist utopias. Nevertheless, their extraordinary ability to cooperate with one another and carry out coordinated enterprises by the millions is something Marx would have de nitely envied.

Research

Biomechanics

RESEARCH

Volume 2 Issue 1 | Spring 2009

Elasticity in ionically cross-linked neuro lament networks

Norman Y. Yao §* , Yi-Chia Lin * , Chase P. Broedersz , Karen E. Kasza , Frederick C. MacKintosh , and David A. Weitz *

§ Harvard College 2008; * Department of Physics, Harvard University, Cambridge, MA 02138, USA; Department of Physics and Astronomy, Vrije Universiteit, 1081HV Amsterdam, The Netherlands; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.

Neuro laments are found in abundance in the cytoskeleton of neurons, where they act as an intracellular framework protecting the neuron from external stresses. To elucidate the nature of the mechanical properties that provide this protection, we measure the linear and nonlinear viscoelastic properties of networks of neuro laments. ese networks are so solids that exhibit dramatic strain sti ening above critical strains of 30–70%. Surprisingly, divalent ions, such as Mg 2+ , Ca 2+ , and Zn 2+ act as e ective cross-linkers for neuro lament networks, controlling their solid-like elastic response. is behavior is comparable to that of actin-binding proteins in reconstituted lamentous actin. We show that the elasticity of neuro lament networks is entropic in origin and is consistent with a model for cross-linked semi exible networks, which we use to quantify the cross-linking by divalent ions.

Introduction

e mechanical and functional properties of cells depend largely on their cytoskeleton, which is comprised of networks of biopolymers; these include microtubules, actin, and intermediate laments. A complex interplay of the mechanics of these networks provides cytoskeletal structure with the relative importance of the individual networks depending strongly on the type of cell [1]. e complexity of the intermingled structure and the mechanical behavior of these networks in vivo has led to extensive in vitro studies of networks of individual biopolymers. Many of these studies have focused on reconstituted networks of lamentous actin (F-actin) which dominates the mechanics of the cytoskeleton of many cells [2-7]. However, intermediate laments also form an important network in the cytoskeleton of many cells; moreover, in some cells they form the most important network. For example, in mature axons, neuro laments, a type IV intermediate lament, are the most abundant cytoskeletal element overwhelming the amount of actin and outnumbering microtubules by more than an order of magnitude [8]. Neuro laments (NF) are assembled from three polypeptide sub- units NF-Light (NF-L), NF-Medium (NF-M), and NF-Heavy (NF-H), with molecular masses of 68 kDa, 150 kDa and 200 kDa, respectively [8]. ey have a diameter d ~ 10 nm, a persistence length believed to be of order l p ~ 0.2 µm and an in vitro contour length L ~ 5 µm. ey share a conserved sequence with all other intermediate laments, which is responsible for the formation of coiled dimers that eventually assemble into tetramers and nally into laments. Unlike other intermediate laments such as vimentin and desmin, neuro laments have long carboxy terminal extensions that protrude

from the lament backbone [9]. ese highly charged “side-arms” lead to signi cant interactions among individual laments as well as between laments and ions [10]. Although the interaction of divalent ions and rigid polymers has been previously examined, little is known about the electrostatic cross-linking mechanism [11]. Networks of neuro laments are weakly elastic; however, these networks are able to withstand large strains and exhibit pronounced sti ening with increasing strain [12, 13]. An understanding of the underlying origin of this elastic behavior remains elusive; in particular, even the nature of the cross-linkers, which must be present in such a network, is not known. Further, recent ndings have shown that NF aggregation and increased network sti ness are common in patients with amyotrophic lateral sclerosis (ALS) and Parkinson’s. us, an understanding of the fundamental mechanical properties of these networks of neuro laments is an essential rst step in elucidating the role of neuro laments in a multitude of diseases [14]. However, the elastic behavior of these networks has not as yet been systematically studied. Here, we report the linear and nonlinear viscoelastic properties of networks of neuro laments. We show that these networks form cross-linked gels; the cross-linking is governed by divalent ions such as Mg 2+ at millimolar concentrations. To explain the origins of the network’s elasticity, we apply a semi exible polymer model, which ascribes the network elasticity to the stretching of thermal uctua- tions; this quantitatively accounts for the linear and nonlinear elas- ticity of neuro lament networks, and ultimately, even allows us to extract microstructural network parameters such as the persistence length and the average distance between cross-links directly from bulk rheology.

Author to whom correspondence should be addressed: Department of Physics and School of Engineering and Applied Sciences, Harvard University, Pierce 231, 29 Oxford Street, Cambridge, MA 02138, USA. E-mail: weitz@seas.harvard.edu.

Biomechanics

Volume 2 Issue 1 | Spring 2009

Materials and Methods

Materials Neuro laments are puri ed from bovine spinal cords using a standard procedure [9, 15, 16]. e fresh tissue is homogenized in the presence of bu er A (Mes 0.1 M, MgCl 2 1 mM, EGTA 1 mM, pH 6.8) and then centrifuged at a K-factor of 298.8 (Beckman 70 Ti). e crude neuro lament pellet is puri ed overnight on a discontinuous sucrose g radient with 0.8 M sucrose (5.9 ml), 1.5 M sucrose (1.3 ml) and 2.0 M sucrose (1.0 ml). A er overnight sedimentation, the concentration of the puri ed neuro lament is determined with a B radford Assay using bovine serum albumen (BSA) as a standard. e puri ed neuro lament is dialyzed against bu er A containing 0.8 M sucrose for 76 hours and then 120 μl aliquots are ash frozen in liquid nitrogen and stored at -80 °C.

RESEARCH

σ, resulting in a total stress of the form σ(t) = σ + |δσ| sin(ωt). e resultant strain is γ(t) = γ + |δγ| sin(ωt + φ), yielding a di erential elastic modulus and a di erential viscous modulus

[2].

Scaling Parameters To compare the experiments with theory, we collapse the di eren- tial measurements onto a single master curve by scaling the sti ness K' and stress σ by two free parameters for each data set. According to theory, the sti ness versus stress should have a single, universal form apart from these two scale factors. We determine the scale factors by cubic-spline tting the data sets to piecewise polynomials; these polynomials are then scaled onto the predicted sti ening curve using a least squares regression.

Results and Discussion

Bulk Rheology e mechanical response of the cross-linked neuro lament networks is measured with a
Bulk Rheology
e mechanical response of the cross-linked neuro lament
networks is measured with a stress-controlled rheometer (HR Nano,
Bohlin Instruments) using a 20 mm diameter 2 degree stainless
steel cone plate geometry and a gap size of 50 μm. Before rheological
testing, the neuro lament samples are thawed on ice, a er which they
are quickly pipetted onto the stainless steel bottom plate of the rhe-
ometer in the presence of varying concentrations of Mg 2+ . We utilize
a solvent trap to prevent our networks from drying. To measure the
linear viscoelastic moduli, we apply an oscillatory stress of the form
σ(t) = A sin(ωt), where A is the amplitude of the stress and ω is the
frequency. e resulting strain is of the form γ(t) = B sin(ωt + φ)
and yields the storage modulus
and the loss modulus
. To determine the frequency dependence of the
linear moduli, G'(ω) and G''(ω) are sampled over a range of frequen-
cies from 0.006–25 rad/s. In addition, we probe the stress dependence
of the network response by measuring G'(ω) and G''(ω) at a single
frequency varying the amplitude of the oscillatory stress. To probe
nonlinear behavior, we utilize a di erential measurement, an e ec-
tive probe of the tangent elastic modulus, which for a viscoelastic
solid such as neuro laments provides consistent nonlinear measure-
ments of elasticity in comparison to other nonlinear methods [17-19].
To quantify the mechanical properties of neuro laments, we
probe the linear viscoelastic moduli of the network during gelation,
which takes approximately one hour; we characterize this by continu-
ously measuring the linear viscoelastic moduli at a single frequency,
ω = 0.6 rad/s. Gelation of these networks is initiated by the addition of
millimolar amounts of Mg 2+ and during this process we nd that the
linear viscoelastic moduli increase rapidly before reaching a plateau
value. We measure the frequency dependence of the linear viscoelas-
tic moduli over a range of neuro lament and Mg 2+ concentrations.
To ensure that we are probing the linear response, we maintain a
maximum applied stress amplitude below 0.01Pa, corresponding to
strains less than approximately 5%; we nd that the linear moduli
are frequency independent for all tested frequencies, 0.006–25rad/s.
Additionally, neuro lament networks behave as a viscoelastic solid
for all ranges of Mg 2+ concentrations tested and the linear storage
modulus is always at least an order of magnitude greater than the
linear loss modulus, as shown in Fig. 1. is is indicative of a cross-
linked gel and allows us to de ne a plateau elastic modulus G 0 [20].
e elasticity of neuro lament networks is highly nonlinear;
10 2
A small oscillatory stress is superimposed on a steady pre-stress,
, 1mg/ml (5mM)
, 2mg/ml (5mM)
, 2mg/ml (3mM)
A
B
10 1
1
10
10 0
0
10
0.5
mg/ml
2mM Mg 2+
1.5
mg/ml
5mM Mg 2+
2.0
mg/ml
8mM Mg 2+
10 -1
-1
10
10 -3
10 -2
10 -1
10 0
10 -3
10 -2
10 -1
10 0
10 -3
10 -2
10 -1
10 0
f (Hz)
f (Hz)
γ
Fi
2
G',G''(Pa)
G',G''(Pa)

Figure 1. The frequency dependence of the linear viscoelastic moduli of cross-linked networks for a variety of neuro lament

and Mg 2+ concentrations. a. Variations of the moduli at constant Mg 2+ concentration (5 mM) and changing lament concentration; b. Variations of the moduli at constant neuro lament concentration (1.5 mg/ml) and changing Mg 2+ concentration.

Figure 2. The strain-sti ening behavior of neuro lament net- works at various Mg 2+ and neuro lament concentrations. Close

squares represent G', the elastic modulus and open squares represent G'', the viscous modulus. Dramatic nonlinearities are seen at critical strains ranging from 30–70%.

RESEARCH

14 10 6 2 8 6 4 c (mg/ml) 0.4 0.8 1.2 2 NF 1.6
14
10
6
2
8
6
4
c
(mg/ml)
0.4 0.8 1.2
2
NF
1.6 2.0
0
c
(mM)
Mg
Biomechanics
G
)aP(
0

Figure 3. e linear elastic modulus can be nely tuned by varying the concentration of the cross-linker Mg 2+ and the neuro lament concentra- tion.

above critical strains γ c of 30–70%, the networks show sti ening up to strains of 300% [21], as shown in Fig. 2. is marked strain-sti ening occurs for a wide variety of Mg 2+ and neuro lament concentrations. In addition, by varying the neuro lament concentration c NF and the Mg 2+ concentration c Mg , we can nely tune the linear storage modulus G 0 over a wide range of values, as seen in Fig. 3. e strong dependence of G 0 on Mg 2+ concentration is reminiscent of actin networks cross-linked with the incompliant cross-linkers such as scruin [2, 22, 23]; this suggests that in the case of neuro laments, Mg 2+ is e ectively acting as a cross-linker leading to the formation of a viscoelastic network. us, the neuro laments are cross-linked ionically on length scales comparable to their persistence length; hence, they should behave as semi exible biopolymer networks. We

4 10 3 10 2mM Mg 2+ & 1.5 mg/ml 8mM Mg 2+ & 1.5
4
10
3
10
2mM Mg 2+ & 1.5 mg/ml
8mM Mg 2+ & 1.5 mg/ml
5mM Mg 2+ & 0.5 mg/ml
5mM Mg 2+ & 2.0 mg/ml
2
10
3/2
1
10
0
10
10 -2
10 -1
10 0
10 1
10 2
K' (Pa)

σ

(Pa)

Figure 4. The dependence of K'(σ) on σ for a variety of neuro- lament and Mg 2+ concentrations. All data show an exponent of ap-

proximately 3/2 in agreement with the a ne thermal model.

Volume 2 Issue 1 | Spring 2009

therefore hypothesize that the network elasticity is due to the stretch- ing out of thermal uctuations. ese thermally driven transverse uctuations reduce neuro lament extension resulting in an entropic spring. To consider the entropic e ects we can model the Mg 2+ -cross- linked network as a collection of thermally uctuating semi exible segments of length l c , where l c is the average distance between Mg 2+ cross-links. A convincing test of the hypothesis of entropic elasticity is the nonlinear behavior of the network. When the thermal uctua- tions are pulled out by increasing strain, the elastic modulus of the network exhibits a pronounced increase. To probe this nonlinear elasticity of neuro lament networks, we measure the di erential or tangent elastic modulus K'(σ) at a con-

stant frequency ω = 0.6 rad/s for a variety of neuro lament and Mg 2+

concentrations. If the network elasticity is indeed entropic in origin,

this can provide a natural explanation for the nonlinear behavior in terms of the nonlinear elastic force-extension response of individual laments that deform a nely. Here, the force required to extend a

single lament diverges as the length approaches the full extension

l c , since

[24-26]. Provided the network deformation is

a ne, its macroscopic shear stress is primarily due to the stretch- ing and compression of the individual elements of the network. e

expected divergence of the single- lament tension leads to a scaling

of

; we therefore expect a scaling of network sti ness

with stress of the form K'(σ) ~ σ 3/2 in the highly nonlinear regime [2]. Indeed, ionically cross-linked neuro lament networks show remark- able consistency with this a ne thermal model for a wide range of neuro lament and cross-link concentrations, as shown in Fig. 4. is consistency provides convincing evidence for the entropic nature of the network’s nonlinear elasticity [2, 25]. e a ne thermal model also suggests that the functional form of the data should be identical for all values of c Mg and c NF . To test this, we scale all the data sets for K'(σ) onto a single master curve. is is accomplished by scaling the modulus by a factor G' and the stress by a factor σ'. Consistent with the theoretical prediction, all the data from various neuro lament and Mg 2+ concentrations can indeed be scaled onto a universal curve, as shown in Fig. 5. e scale factor for the modulus is the linear shear modulus G' = G 0 , while the scale factor

3 10 2 10 3/2 1 10 0 10 10 -3 10 -2 10 -1
3
10
2
10
3/2
1
10
0
10
10 -3
10 -2
10 -1
10 0
10 1
K' / G 0

σ//σ

c

Figure 5. Collapse of all data sets of the σ dependence of K' onto

a single universal curve. e solid line represents the theoretical pre- diction of [2]. e scaling parameters are G 0 , the linear elastic modulus and σ c , the critical stress. ese parameters are calculated using a least squares regression.

Volume 2 Issue 1 | Spring 2009

RESEARCH

1 10 2.5 0 1 10 10 -1 10 10 0 c NF (mg/ml) 1.54
1
10
2.5
0
1
10
10
-1
10
10 0
c NF (mg/ml)
1.54
0
10
c NF 1/2 *G 0
G 0 (Pa)

10 0

σ

C c (Pa)

Figure 6. The dependence of c NF 1/2 G 0 on σ c . e solid line is the result

of a regression t to the data and depicts an exponent of 1.54. is is in agreement with the a ne thermal model which predicts an exponent of 3/2. Closed squares are data obtained with Mg 2+ , open squares are data obtained with Ca 2+ , and crossed squares are data obtained with Zn 2+ . e inset shows the dependence of G 0 on c NF and depicts an exponent of 2.5 obtained from regression. is is also consistent with the a ne thermal model which predicts an exponent of 2.2.

3 0.41 3 0.21 Biomechanics 5 c Mg (mM) 1 1 2 -0.21 G 0
3
0.41
3
0.21
Biomechanics
5
c Mg (mM)
1
1
2
-0.21
G 0 / c * c Mg
σ
c
-2/5
G 0 / c * c NF
σ
c

c NF (mg/ml)

Figure 7. The dependence of G 0 / σ c × c NF -1/5 on c NF . e solid line is

the result of a regression t and exhibits an exponent of 0.41. is is in agreement with the a ne thermal model which predicts an exponent of 2/5. e inset shows the dependence of G 0 /σ c ×c NF -2/5 on c Mg and depicts an exponent of 0.21 obtained by a regression t; this empirical power law was used to collapse the data and to obtain the 0.41 exponent for the c NF dependence.

for the stress is a measure of the critical stress σ c at which the network begins to sti en. is provides additional evidence that the nonlinear elasticity of the Mg 2+ -cross-linked neuro lament networks is due to the entropy associated with single lament stretching. To explore the generality of this ionic cross-linking behavior, we use other divalent ions including Ca 2+ and Zn 2+ . We nd that the e ects of both of these ions are nearly identical to those of Mg 2+ ; they also cross-link neuro lament networks into weak elastic gels. is lack of dependence on the speci c ionic cross-link lends evidence that the interaction between laments and ions is electrostatic in nature. is electrostatic interaction would imply that the various ions are acting as salt-bridges, thereby cross-linking laments into low energy conformations. e ability to scale all data sets of K'(σ) onto a single universal curve also provides a means to convincingly con rm that the linear elasticity is entropic in origin. To accomplish this, we derive an expression that relates the two scaling parameters to each other. For small extensions δl of the entropic spring, the force required can be derived from the wormlike chain model giving

Assuming an a ne deformation, whereby the macroscopic sample strain can be translated into local microscopic deformations, and ac- counting for an isotropic distribution of laments, the full expression for the linear elastic modulus of the network is given by

(2)

[2, 22, 25]. us, if the network’s linear elasticity is dominated by entropy, we expect the scaling c NF 1/2 G 0 ~ σ c 3/2 , where the pre-factor should depend only on k B T and l p ; although the pre-factor will di er for di erent types of laments it should be the same for di erent networks composed of the same lament type and at the same temperature, such as ours. us, plotting c NF 1/2 G 0 as a function of σ for di erent neuro lament networks at the same temperature should result in collapse of the data onto a single curve characterized a 3/2 power law; this even includes systems with di erent divalent ions or di erent ionic concentrations. For a variety of divalent ions, we nd that c NF 1/2 G 0 ~ σ c z , where z = 1.54 ± 0.14 in excellent agreement with this model, as shown in Fig. 6. It is essential to note that the 3/2 exponent found here is not a direct consequence of the 3/2 exponent obtained in Fig. 5, which characterizes the highly nonlinear regime. Instead, the plot of c NF 1/2 G 0 as a function of σ c probes the underlying mechanism and extent of the linear elastic regime.

c

.

For a xed ratio of cross-links R = c Mg /c NF , we expect cross-linking to occur on the scale of the entanglement length, yielding l c ~ c NF [25, 27, 30]. us, we expect the linear storage modulus to scale with neuro lament concentration as G 0 ~ c NF 11/5 [25]. For R = 1000, we nd an approximate scaling of G 0 ~ c NF 25 , consistent with the predicted power law, as shown in the inset of Fig. 6. Interestingly, the stronger concentration dependence of G 0 may be a consequence of the dense cross-linking that we observe. Speci cally, for densely cross-linked networks, corresponding to a minimum l c on the order of the typical spacing between laments as we observe here, the model in Eq. (1) predicts G 0 ~ c NF 25 [25]. e agreement with the a ne thermal model in both the linear and nonlinear regimes con rms the existence of an

-2/5

(1)

where κ = k B Tl p is the bending rigidity of neuro laments, k B T is the thermal energy, and ρ is the lament-length density [2, 25, 27, 28]. e density ρ is also proportional to the mass density c NF , and is related

[29]. Furthermore, the

to the mesh size ζ of the network by

model predicts a characteristic lament tension proportional to and a characteristic stress

, ionically cross-linked neuro lament gel whose elasticity is due to the pulling out of thermal uctuations. e ability of the a ne thermal model to explain the elasticity of

Biomechanics

RESEARCH

the neuro lament network also suggests that we should be able to quantitatively extract network parameters from the bulk rheology. e model predicts that

(3)

and

(4)

where ρ ≈ 2.1!10 13 m -2 for neuro lament networks at a concentra-

tion of 1 mg/mL. is yields a persistence length l p 0.2 µm which is

in excellent agreement with previous measurements [31]. In addition, we nd that l c 0.3 µm which is close to the theoretical mesh size

0.26 μm; surprisingly, this is far below the mesh size of 4µm

inferred from tracer particle motion [1]. Such particle tracking only provides an indirect measure: in weakly cross-linked networks, for

instance, even particles that are larger than the average inter- lament spacing will tend to di use slowly. To further elucidate the cross-linking behavior of Mg 2+ , we explore

and c NF , based on Eq. (3-4). Based on

the dependence of l

. Assuming that Mg 2+ l c is also the typical distance

between binary collisions of lament chains we would expect that

, where l e is the entanglement length. us, for a given

concentration of neuro laments

c

on both c

Mg

the form of G 0 and σ c , we expect that is acting as the cross-linker and that

[25]. is yields

(5)

(6)

where X is the exponent of the Mg2+ concentration. Naively, we would expect that X 1 which would imply that doubling the concentration of Mg2+ would halve the average distance between cross-links. Empirically we nd a much weaker dependence on

. is weaker dependence suggests that

mM concentrations of Mg2+ actually saturate our networks. is is

consistent with a calculation of the percentage of Mg2+ ions, which

actually act as cross-links. e number of cross-linking ions per

; the number density of ions, N in

cMg, where

cubic meter is

a

standard 5 mM Mg2+ concentration is N 30 × 1023. us, there

is

an excess of Mg2+ ions available to act as cross-linkers; this may

account for the weak cross-link dependence. A similarly weak depen- dence has been seen previously with actin networks in the presence of the molecular motor heavy meromysin where X was found to be 0.4

and thus,

, where cA is the actin concentration

and cHMM is the heavy meromysin concentration [32]. Utilizing our empirical power law for cMg, we are able to collapse the curves such

which is in excellent agreement with the

that

predicted exponent 2/5, as shown in Fig. 7. e fact that the cross-

linking distance lc scales directly with cMg further con rms the

role of Mg2+ as the e ective ionic cross-linker of the neuro lament

networks. us, our ndings demonstrate both the entropic origin of neuro lament network’s elasticity as well as the role of Mg 2+ as an e ective ionic cross-linker.

Volume 2 Issue 1 | Spring 2009

Conclusion

We measure the linear and nonlinear viscoelastic properties of cross-linked neuro lament solutions over a wide range Mg 2+ and neuro lament concentrations. Neuro laments are interesting intermediate lament networks whose nonlinear elasticity has not been studied systematically. We show that the neuro lament net- works form densely cross-linked gels, whose elasticity can be well understood within an a ne entropic framework. We provide direct quantitative calculations of l p and l c from bulk rheology using this model. Furthermore, our data provides evidence that Mg 2+ acts as the e ective ionic cross-linker in the neuro lament networks. e weaker than expected dependence that we observe suggests that Mg 2+ may be near saturation in our networks. Future experimental work with other multivalent ions is required to better understand the electrostatic interaction between laments and cross-links; this would lead to a better microscopic understanding of the e ects of electrostatic interactions in the cross-linking of neuro lament net- works. Moreover, the e ect of divalent ions on the cross-linking of networks of other intermediate laments would also be very interest-

ing to explore.

Acknowledgments

is work was supported in part by the NSF (DMR-0602684 and CTS-0505929), the Harvard MRSEC (DMR-0213805), and the Sticht- ing voor Fundamenteel Onderzoek der Materie (FOM/NWO).

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