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Origins of the human genome project

JAMES DEWEY WATSON AND ROBERT MULLAN COOK-DEEGAN’
National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892, USA

ABSTRACT The Human Genome Project has become pedigrees (1, 2). Small groups throughout the world worked
a reality. Building on a debate that dates back to 1985, to find chromosome markers for linkage analysis. Two
several genome projects are now in full stride around the groups, under Ray White at the Howard Hughes Medical
world, and more are likely to form in the next several Institute at the University of Utah and under Helen Donis-
years. Italy began its genome program in 1987, and the Keller at Collaborative Research outside Boston, began
United Kingdom and U.S.S.R in 1988. The European large-scale efforts. The Donis-Keller group published a link-
communities mounted several genome projects on yeast, age map of the human genome in 1987 (3).
bacteria, Drosophila, and Arabidospis thaiiana (a rapidly Methods to clone large fragments of DNA developed dur-
growing plant with a small genome) in 1988, and in 1990 ing the 1980s. The discovery of recombinant DNA in the
commenced a new 2-year program on the human genome. middle 1970s enabled the cloning of DNA fragments
In the United States, we have completed the first year of hundreds to several thousands of base pairs in length. Em-
operation of the National Center for Human Genome bellishments of this basic technique, based on constructing
Research at the National Institutes of Health (NIH), now artificial chromosomes replicated in yeast, expanded the size
the largest single funding source for genome research in of DNA inserts to hundreds of thousands of base pairs (4).
the world. There have been dedicated budgets focused on This simplified considerably the daunting task of cloning the
genome-scale research at NIH, the U.S. Department of entire human genome and reconstructing the order of cloned
Energy, and the Howard Hughes Medical Institute for fragments. Work on such large DNA fragments depended on
several years, and results are beginning to accumulate. analytical techniques for handling them. One breakthrough
There were three annual meetings on genome mapping was the discovery that DNA fragments of up to tens of mil-
and sequencing at Cold Spring Harbor, New York, in the lions of base pairs in length could be separated by elec-
spring of 1988, 1989, and 1990; the talks have shifted trophoresis (5). Discovery of the polymerase chain reaction
from a discussion about how to approach problems to allowed rapid amplification of short regions of DNA with
presenting results from experiments already performed. great ease, opening the door to sequencing and other analy-
We have finally begun to work rather than merely talk. sis with extraordinary speed and precision (6).
The purpose of genome projects is to assemble data on the Robert Sinsheimer, then chancellor of the University of
structure of DNA in human chromosomes and those of California at Santa Cruz, convened the first meeting to dis-
other organisms. A second goal is to develop new technol- cuss the technical prospects for sequencing the human ge-
ogles to perform mapping and sequencing. There have nome in June 1985 (7). This meeting did not have the in-
been impressive technical advances in the past 5 years tended result of establishing a research institute on campus,
since the debate about the human genome project began. but it did plant the idea of a large project in the minds of
We are on the verge of beginning pilot projects to test several prominent molecular biologists, most notably Walter
several approaches to sequencing long stretches of DNA, Gilbert, Nobel laureate and professor of biology at Harvard,
using both automation and manual methods. Ordered who became the flag bearer for the genome movement for
sets of yeast artificial chromosome and cosmid clones have several months. He spoke about large-scale sequencing
been assembled to span more than 2 million base pairs of efforts at a Gordon Conference, a meeting on computers and
several human chromosomes, and a region of 10 million molecular biology, and in other places in the late summer
base pairs has been assembled for Caenorhabditis elegans and fall of 1986.
by a collaboration between Washington University and
the Medical Research Council laboratory in Cambridge,
U.K. This project is now turning to sequencing C. elegans ORIGINS OF THE DEPARTMENT OF ENERGY
DNA as a logical extension of this work. These are but the GENOME INITIATIVE
first fruits of the genome project. There is much more to
come.-Watson, J. D., Cook-Deegan, R. M. Origins of On another front, the problem of detecting inherited muta-
the human genome project. FASEBJ. 5: 8-11; 1991. tions in humans had vexed the Department of Energy
(DOE)’ since the Manhattan Project and the United States’

Key Words: gene mappingS NIH. DOE human genome or-

ganization

‘Abbreviations: YAC, yeast artificial chromosome; DOE,

Department of Energy; NRC, National Research Council; HHMI,
EVENTS LEADING TO SPECIAL GENOME
Howard Hughes Medical Institute; MRC, Medical Research
PROGRAMS Council; ICRF, Imperial Cancer Research Fund; CEPH, Centre
d’Etude du Polymorphisme Humain; HUGO, Human Genome
Advances in several fields made it possible to conceive of a Organization; THUG, The Human Genome organization; Un-
human genome project by 1985. In human genetics, several esco, the United Nations Educational, Scientific, and Culture
groups proposed to use DNA markers interspersed through- Organization; EC, European Communities; NSF, National Science
out the human genome to locate genes studied in human Foundation; OTA, Office of Technology Assessment.

0892-6638/91/0005-00081$O1.50. © FASEB

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 use of atomic bombs against Japan at Hiroshima and centers for collection and distribution of research materials,
Nagasaki in August of 1945. A meeting to assess how direct and recommended a new, dedicated genome research budget
analysis of DNA might be useful in detecting mutations of $200 million per year for 15 years.
among atomic bomb survivors was held in Alta, Utah, in De- Soon after the Cold Spring Harbor meeting in June of
cember, 1984, following recommendations of a scientific 1986 there were several other meetings scheduled to discuss
panel that met earlier that year in Hiroshima (8, 9). In the genome project near Washington, D.C. Two of these were
reviewing the technical approaches to this problem in late large international meetings of invited participants. The first
1985, Charles DeLisi of DOE conceived of a three-pronged was convened in August by the Howard Hughes Medical In-
research program concentrating on advanced DNA sequenc- stitute (HHMI), and was intended to discuss whether and
ing technology, computer analysis, and methods to order how HHMI might contribute to a large international ge-
DNA fragments cloned from the human genome (10). DeLisi nome project. A subsequent meeting was held by NIH in
began a research program focused on these objectives, the October to discuss its role (15-17). NIH plans began to take
DOE Human Genome Initiative, in 1987. This was the first shape.
government program on genome research, and it catalyzed
a vigorous debate in the United States and other nations.
As part of the planning process for the DOE program, Los
GENOME PROGRAMS IN ITALY, THE UNITED
Alamos National Laboratory organized a workshop in Santa
KINGDOM, THE USSR, AND THE EUROPEAN
Fe, New Mexico, in March, 1986. The participants at that
COMMUNITIES
workshop were enthused about the DOE Human Genome
Initiative, endorsing the project already set in motion in
In the wake of the Dulbecco editorial, and soon after DeLisi
Washington, D.C.
reprogramed 1987 funds to commence a DOE genome pro-
gram, the Italian National Research Council began a pilot
NIH REACTION TO THE DOE INITIATIVE project on genome research, involving 15 groups throughout
Italy. Italy saw genome research as a road to world stature
During the same week as the Santa Fe meeting, Renato Dul- in molecular genetics. Dulbecco was appointed the project
becco, President of the Salk Institute, independently pub- coordinator, with Paolo Vezzoni as the deputy (18).
lished a short article in Science arguing that sequencing the Events in the United Kingdom were close on the heels of
human genome would be an efficient way to expedite cancer developments in the United States. Walter Bodmer and Syd-
research (11). As word of the DOE program spread, concerns ney Brenner were present at Cold Spring Harbor and subse-
about its focus and appropriateness were aired. At a Cold quent meetings. They returned to the U.K. Brenner began
Spring Harbor symposium on the Molecular Biology of laying plans to involve the Medical Research Council
Homo sapiens, Walter Gilbert and Paul Berg cochaired a (MRC), and Bodmer to involve the Imperial Cancer
session on the human genome project. Berg wanted to air Research Fund (ICRF), both of which were already at the
Dulbeccds idea, and Gilbert discussed the mounting en- forefront of genetics. Brenner sent a proposal to the Euro-
thusiasm for a genome project growing out of the Santa Cruz pean community (EC) offices, which was received October 2,
and Santa Fe meetings. A great deal of skepticism was voiced 1986, suggesting an EC genome project. Their efforts yielded
about whether a dedicated research program, particularly results first in the U.K., most notably in the form of a joint
one directed at sequencing, made technical sense, and ICRF-MRC genome program that began in February, 1989
whether DOE was the appropriate agency to direct such an (19). The debate in the EC took longer to produce results,
effort. The fiercest fire was dire.-ted at large-scale sequencing although genome research on nonhuman organisms, includ-
of the genome, which ironically was not part of the DOE ing a sequencing project for yeast, began in the middle of
proposal. The acrimonious east coast debut of the genome 1988. The European Commission approved a 2-year human
project was widely reported in the scientific press, and the genome effort in 1990. In France, there were discussions of
debate echoed in Washington, D.C. While this debate proceeded, a genome project, and several research centers did substan-
DOE’s Health and Environmental Research Advisory Com- tial research, but no government program emerged until
mittee endorsed a Human Genome Initiative, recommend- June 1990. The Ministry of Research asked the biomedical
ing a budget to attain $200 million per year after 3 years (12). research institute, INSERM, to draw up plans for a genome
The National Research Council (NRC) of the National program, which was announced in October 1990. The
Academy of Sciences commenced a study in late September Centre d’Etude du Polymorphisme Humain (CEPH, or
of 1986, in the wake of the Cold Spring Harbor rump session Center for Study of Human Polymorphism) had made Paris
and a July meeting of Academy members and invited guests a center for collaboration of genetic linkage maps (20), which
in Woods Hole, Massachusetts. An NRC committee was ap- were the first and arguably most important maps for human
pointed, composed of eminent molecular biologists and hu- genetics. French stature in molecular biology and CEPH
man geneticists. The NRC committee met several times dur- made France a natural partner in international genome
ing 1987, and issued a report in February 1988 that argued efforts.
strongly for a broader human genome project (13). The com- In the U.S.S.R., Alexander Bayev and Andrei Mirzabekov
mittee included several members who were initially skeptical returned from the 1986 Cold Spring Harbor symposium in-
of genome proposals, such as David Botstein, Shirley Tilgh- fected with enthusiasm for a genome effort. Their timing was
man, and Leon Rosenberg. The chairman, Bruce Alberts, propitious, coinciding with a desire for perestroika in
had written a 1983 editorial highly critical of big science in science, a restructuring of how science is funded in the Soviet
biology (14). The committee was nonetheless convinced of Union. They added a component of project-specific peer
the merits of a systematic approach to genome-scale review mimicking the NIH process to supplement the more
research, and forged a consensus by embracing work on non- traditional institute-by-institute budgeting process. The ge-
human organisms and genetic linkage mapping (i.e., finding nome funding in the U.S.S.R. has since become the mainstay
DNA markers useful in studying pedigrees). The NRC com- of molecular genetics as the largest program supporting
mittee emphasized the importance of databases and stock molecular approaches not only of humans but also of yeast

ORIGINS OF THE HUMAN GENOME PROJECT 9

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 and other organisms. Bayev and Mirzabekov devised a genetics for many years. HHMI has supported several hu-
research program that was approved by the Politburo for the man genetic databases as well as some of the best human
1989 budget year, and was expanded in 1990. genetics investigators in the United States. NSF has a long
record of support for informatics, mathematical biology, and
INTERVENTION BY CONGRESS instrumentation, and coordinates a project on Arabidopsis
thaliona.
Back in the United States, Congress independently observed The proliferation of research programs in different nations
the debate about a human genome project as it unfolded and agencies is a healthy sign of enthusiasm for genome
during 1986 and 1987. The House Committee on Energy research, laying the informational and technological founda-
and Commerce commissioned a report by the Office of Tech- tions for a new approach to biology. Rapid growth and
nology Assessment (OTA). The OTA report was released in pluralistic sources of support, however, bring their own
April 1988, noting that the debate was not about whether the problems. Coordination of effort is preeminent among these.
research should go forward or not, but about how it should The central thrust of genome projects is to provide methods
be managed and who should coordinate it (21). The march to accelerate biomedical research and to pool information
of human genetics would go on with or without a genome about chromosomal structure. New methods must become
project, but resolution of management issues - especially rapidly dispersed and the information widely disseminated,
those related to databases, sharing of research materials, and or there will be no point in special genome efforts.
cultivation of new technologies-would be more efficient in
the long run if there were an administrative center or centers
accountable to Congress. OTA made no budget recommen- FORMATION OF THE HUMAN GENOME
dations, but noted that projected annual costs of the compo- ORGANIZATION AND UNESCO INVOLVEMENT
nent projects would rise from $47 to $228 million over the
first 5 years; OTA suggested periodic reassessment of budget The HUman Genome Organization (HUGO) was formed at
needs, with a rolling 5-year budget. the first Cold Spring Harbor meeting on genome sequencing
While the NRC and OTA reports were being written, and mapping on April 29, 1988. Victor McKusick provided
Congress appropriated funds to NIH ($17.3 million) and the initial push, with strong support from Sydney Brenner,
DOE ($11.8 million) in 1988 for genome research. For DOE, Leroy Hood, and James Watson. Brenner suggested the
this was a response to internal planning and an agreement name, although he expressed a personal preference for
between DOE and the White House Office of Management THUG (The HUman Genome organization) as the acro-
and Budget. The NIH budget resulted directly from James nym. McKusick was elected founding President, and
Wyngaarden’s testimony and responses to questions from the HUGO began the arduous task of growing into an interna-
House Appropriations Committee (22). These budgets were tional scientific organization. In 1990, HUGO obtained
increased to $28 (NIH) and $18 million (DOE) in 1989, commitments for several years’ funding from the Wellcome
$58.5 and $26 million in 1990, and $87.5 and $47.7 million Trust in the United Kingdom and the Howard Hughes Med-
in 1991. ical Institute in the United States. There were bright
prospects for obtaining funds directly from various national
scientific agencies for specified projects as the organization
EMERGENCE OF A CONCERTED GENOME develops the infrastructure to support international work-
PROJECT shops, fellowships, and other activities.
While HUGO was forming to mediate international
Debate about the respective roles of the NIH and DOE scientific collaboration, the United Nations Educational,
dominated the policy concerns in 1988, with several congres- Scientific, and Cultural Organization (Unesco) evinced an
sional hearings devoted to that topic. A remarkable degree interest in helping coordinate other aspects of international
of joint planning began taking shape in 1989. Early in 1990, genome research. The center of Unesco’s interest evolved
NIH and DOE submitted a 5-year joint research plan to toward ensuring continued input of third world nations in
Congress (23), an unprecedented accomplishment. The genome activities, and support for international conferences
agencies established joint working groups on mapping, infor- and scientist exchanges. The first major genome program
matics (dealing with databases and computational analysis), under Unesco was a fellowship program, cosponsored by the
and social, ethical, and legal implications of genome Third World Academy of Sciences, to provide limited funds
research. for third world scientists to seek training in genome research
Many conferences and workshops are jointly sponsored, centers throughout the world (V. Zharov, Unesco Science
and the agencies are working toward a process to cross-refer Office, personal communication, July 16, 1990).
certain kinds of grant applications, such as pilot sequencing It has taken 5 years for the genome project to be translated
projects and database management. NIH and DOE have from an idea to the beginnings of an international scientific
agreed to notify one another about funding decisions regard- project. It is realistic to assume that it will continue to grow
ing grant proposals reviewed by both agencies. for the next several years. It is essential that the work con-
Much of the public debate during 1987 and 1988 centered tinue, that the results be widely shared, and that govern-
on genome research programs at NIH and DOE. As pro- ments of all developed nations contribute appropriately to
grams at both agencies were successfully launched, the de- the effort.
bate expanded. Other U.S. groups were also involved from
early on: the Howard Hughes Medical Institute; the Na-
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ORIGINS OF THE HUMAN GENOME PROJECT 11

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