Biomedical Politics (1991) / Chapter Skim
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The Human Genome Project: The Formation of Federal Policies in the United States, 1986-1990
The Human Genome Project: The Formation of Federal Policies in the United States, 1986-1990
Pages 99-175
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From page 99... ...
. Genome research budgets have grown considerably in 1989 and 1990, and organizational structures have been in flux, but the allocation of funds through lineitem budgets was a pivotal event, in this case signaling the rapid adoption of a science policy initiative.
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From page 100... ...
, Cold Spring Harbor Laboratories, the DOE genome offices in Germantown, Maryland, the Office of the Director, NIH, and the National Center for Human Genome Research at NIH. This study has been an extraordinary opportunity to sift through the history of a science program in its infancy.
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From page 101... ...
There is no disease-oriented constituency supporting the program, and so the genome program is largely a creature of the molecular biologists and human geneticists who conceived it and supported it in its early stages. The human genome project is thus, more than many other areas of biomedical research, under pressure to produce results, and it is likely to be held to greater standards of accountability than other projects for the initial promises made on its behalf.
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From page 102... ...
Historical strands can be traced to evolutionary and population genetics, medical genetics, molecular biology, detection of mutations, advances in instrumentation, and computational biology. The principal factor was a meeting of the fields of human genetics and molecular biology.
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The communities that studied evolutionary and population genetics immediately understood the significance of genetic linkage mapping. They were joined by a few
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From page 104... ...
By the mid-1980s, genetic linkage mapping was part of the mainstream of human genetics. Newsweek magazine quipped in late 1987 that there was a disease a week being mapped by genetic linkage (Begley et al., 19871.
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The first disease characterized at the molecular level was sickle cell anemia. In 1949, genetic studies by Neel showed that it was a recessive genetic disease, and biochemical studies by Pauling and colleagues (1949)
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From page 106... ...
Sanger's group in Cambridge, U.K., developed DNA sequencing after a dedicated and deliberate effort that started with protein sequencing, progressed to the sequencing of ribonucleic acid, and culminated in DNA sequencing. Sanger presented a partial sequence of a virus to an awestruck audience in May 1975 (Judson, 1987J and published a modified, simpler method in 1977 Hanger et al., 19771.
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From page 107... ...
Molecular biology thus generated a cornucopia of technological tricks that allowed scientists to think seriously about constructing physical maps of chromosomes and determining their DNA sequence. Some human geneticists were quick to apply the developing techniques to study diseases, but with a few exceptions, molecular biology was a separate field from human genetics.
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From page 108... ...
ORIGINS OF DEDICATED GENOME RESEARCH PROGRAMS The idea of a systematic gene map of human chromosomes was not new. Human geneticists had talked of it for decades.
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From page 109... ...
and Ray White (HHMI, Utah) , contributed more than half the DNA markers that existed on the human genetic map in 1987 (Doris-Keller et al., 19871.
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From page 110... ...
In some respects, like the journeys to the moon, it is simply a "tour de force;" it is not at all clear that knowledge of the nucleotide sequence of the human genome will, initially, provide deep insights into the physical nature of man. Nevertheless, we are confident that this project will provide an integrating focus for all efforts to use DNA cloning techniques in the study of human genetics.
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From page 111... ...
After the meeting, Sinsheimer summarized its conclusions, which Steven Hall later reported, capturing the modesty of the meeting in "Genesis, the Sequel" (Hall, 19881. The group agreed that it made sense to pursue systematic development of a genetic linkage map, a physical map of ordered clones, and the capacity for large-scale DNA sequencing (Sinsheimer, 19891.
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From page 112... ...
It would have been logical to seek funding from NIH, but such a course presented several problems. The cost estimates from the Santa Cruz meeting $25 to $40 million to build an institute, with an annual budget of roughly $10 million were far too high for a grant or standard research program.
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From page 113... ...
The workshop was in progress just as Schwartz and Cantor were producing the first data using pulsed-field gel electrophoresis for mapping, as George Church was beginning to think of new approaches to DNA sequencing directly from DNA in the native genome of an organism, and as Maynard Olson's physical mapping efforts in yeast were beginning to bear fruit.
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The principal author was physician Mark Bitensky. The memo concerned sequencing the entire human genome and barely mentioned physical or genetic mapping.
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From page 115... ...
The first, physical mapping of the human chromosomes, to last five or six years, took up much of the first phase. The other two components in Phase I were development of high-speed automated DNA sequencing and a research program to improve computer analysis of sequence information.
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From page 116... ...
Bostock confirmed that there had been minor revisions, but essentially the proposal worked out by DOE and OMB in fall 1986 became the basis for a multiyear program agreement. The DOE HERAC endorsed the plan for a DOE genome initiative in a report from its special ad hoc subcommittee.
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From page 117... ...
The appropriations process, in contrast, is a parallel process with a relatively stable annual routine. The President's budget proposal is submitted in January each year and then goes to the appropriations committees.
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From page 118... ...
Claudine Schneider, ranking Republican on the committee, was dissatisfied with DOE's record on research into environmental health hazards, and her staff director, Eric Erdheim, was rumored to have called the Delegation for Biomedical Research to ask James Watson to testify against the DOE genome program. (Erdheim did, indeed, speak with Bradie Metheny, lobbyist for the delegation, but nothing came of it; Erdheim was not so much opposed to the genome project as suspicious of any new proposal coming from DeLisi.
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From page 119... ...
Schneider's latent distrust broke the surface in a series of questions about DOE reports on health effects of radiation on submarine workers, Hiroshima and Nagasaki survivors, and nuclear plant workers and reports on least-cost energy, but the genome program glided through the hearings unscathed. The appropriations process was less troublesome than authorization and presented no major obstacles once the genome project had OMB approval.
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From page 120... ...
It was clear from the outset that the DOE initiative would include national laboratory centers for genome research. Taking advantage of national laboratory resources was one of two principal justifications for DOE assuring the lead role in the project (the other being the areas of related research that were part of the DOE mission, particularly mutation detection)
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From page 121... ...
Several technical elements are also remarkable by their absence from early consideration. The DOE proposals for the project contain very little discussion of genetic linkage mapping—the first and arguably the most important step in making the project useful to the research
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From page 122... ...
DOE strongly emphasized bacterial genetics immediately after World War II, and continued to support many groups working on nonhuman biology. Whatever the justifications, the neglect of genetic linkage mapping and nonhuman genetics drove a wedge between DOE and much of the biomedical research community.
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From page 123... ...
. He concluded his talk by urging a commitment to systematic mapping and sequencing, as "a revolutionary step forward." Victor McKusick, dean of human genetics and keeper of Mendelian Inheritance in Man, the gold standard human genetic disease data base, was the next speaker.
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From page 124... ...
The issue came to a head at an evening session not originally on the program. Paul Berg was unaware of the discussions in DOE and Santa Cruz but he had read Dulbecco's article and suggested to Watson that it might be useful to have an informal discussion of a genome sequencing effort at the Cold Spring Harbor meeting (P.
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From page 125... ...
. The first step, however, was to shift the scene of the action from the quiet scientific mecca of Cold Spring Harbor to Washington, D.C.
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From page 126... ...
Scriver was fascinated by the prospect of a human genome project, thinking primarily of the immense impact systematic mapping could have on clinical genetics and the patients he saw each day in his Montreal genetics clinic. Yet he called the decision to fund genetic linkage mapping, for which he became a champion on the Medical Advisory Board, "a close thing" on the part of HHMI.
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From page 127... ...
Before and after the Cold Spring Harbor meeting, James Watson was busy behind the scenes, trying to put together the pieces of a project that would be to his liking. Watson had been a power broker in molecular biology, since soon after he and Francis Crick discovered the double helical structure of DNA, and he had a well-deserved reputation for speaking his mind.
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From page 128... ...
Plans to involve NAS were hatched around the time of the Cold Spring Harbor meeting in June 1986. On July 3, John Burris, executive director of the Academy's Board on Basic Biology, wrote a short proposal to fund a small group meeting to discuss the genome project in August.
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From page 129... ...
A January meeting had three technical sessions: (1) genetic linkage mapping, somatic cell hybrid mapping, and physical mapping; (2)
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From page 130... ...
It was he who noted the importance of having enough genetic linkage markers to assemble a physical map, thus cementing the "marriage" of those twin objectives, and he also clearly articulated the distinctive feature of genome research that would set it apart from other genetic studies: a focus on projects of increasing scale (size of DNA to be handled or mapped, degree of map resolution, speed, cost, accuracy, or other factors)
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When the news from Cold Spring Harbor was reported, it attracted the attention of several Hill staff.
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agencies and research institutions were doing in the field of genome research. Papers on Japan and Europe were commissioned, as was this history of the biology and of analogous periods of development in physics.
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From page 133... ...
The content of the memorandum was immaterial, but the process was important for each agency in facing the reality that they would both have genome programs for the foreseeable future and that Congress would be quite sensitive to interagency bickering. Until the release of the NRC and OTA reports, and, indeed, for a few months afterward, staff from both agencies appeared to believe that Congress would somehow designate their agency the lead organization.
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He was highly respected as a clinician and human geneticist, and he accepted the job with some reluctance, stating this openly. In his confirmation hearings before the Senate, he noted, "I did not actively seek the post .
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From page 135... ...
A straight reading of his text would suggest it had second priority to AIDS. The NIH appropriation for genome research did not require a special authorization, as such research clearly fell within the bounds of NIH's biomedical research mission.
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From page 136... ...
Each year, they merely asked the NIH director what he would do with sums of money in addition to those requested, in $100 million increments. In the House appropriations hearing, Congressman David Obey, who had read an article in the Washington Post about the genome project, tapped into what had become the major issue related to genome research by asking several questions about gene mapping.
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From page 137... ...
Domenici attempted to add the bill as an amendment to the trade bill under active consideration in spring 1987, and his staff began to call other Senate and House committees with jurisdiction. Key to this effort were Senator Chiles, chairman of the NIH appropriations subcommittee and of the entire Budget Committee and generally accepting of NIH initiatives in biotechnology, and Senator Edward Kennedy, chairman of the NIH authorization committee.
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From page 138... ...
Domenici urged his strong support for a DOE role in genome research. Norman Anderson pulled out all the stops in a moment of zeal:
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. to say that here is the possibility at one shot of finding the cause of some 2,3;00 human diseases is Err.
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From page 140... ...
Many scientists, however, saw this contention as failure to appreciate the collective and dedicated efforts needed to finish maps and develop new technologies. NIH's neglect of dedicated genetic linkage mapping and DNA sequencing instrumentation was cited as symptomatic of a deficiency in NIH's resource planning.
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NIH's first dedicated funding for genome research $17.2 millioncame in December 1987, when President Reagan signed the 1988 appropriations law (two months into the fiscal year)
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From page 142... ...
In his replies to the House Appropriations Committee for fiscal year 1988, he asked for $30 million in genome research funds in his fifth increment of $100 million above the administration request, and another $15 million in the eleventh increment (the penultimate of 12 such increments)
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From page 143... ...
NIH appropriations for fiscal year 1989 were more or less routine, with NIGMS requesting $28 million for genome research in this, the final year of the Reagan administration. Congress and the President had agreed on a two-year budget plan the previous fall, in the wake of the October 1987 stock market crash, and the President's budget request held to this agreement.
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From page 144... ...
When the President's budget request came out, it asked for $100 million for genome research at NIH. (The $62 million apparently had been increased to $100 million by dividing up some excess monies left from the removal of other programs during OMB review fJohn Barry, free-lance writer, personal communication, May 19901.)
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From page 145... ...
Only those who actually made the decisions for the appropriations committees could answer such a question, but they simply did not make the decisions on these terms nor should they. The NRC report and the rhetoric supporting the genome initiative leaned heavily on the principle that the new initiative should come from "new" funds, but this kind of money did not exist.
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From page 146... ...
Kirschstein's reputation among appropriations committee staff as a solid administrator of great integrity was a necessary element. Wyngaarden first created the line item in response to a ritual question from Congress and then shepherded the budget request through its labyrinthine appropriations
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From page 147... ...
SOCIAL ISSUES EMERGE The debate about the genome project changed substantially in 1989, moving from the question of which agency should lead it to issues of international scientific cooperation, economic competition, and concern about social implications of the research. These issues had always been in the background, but with successful joint planning by NIH and DOE and little controversy about budget levels, attention turned to them.
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From page 148... ...
Watson foresaw the importance of educating the public through courses, books, and public meetings, and of devising new means to think through the consequences of genome research and anticipate public policy needs. His argument was that, although the genome project was "completely correct" in pursuing gene maps and DNA sequence data as fast as possible, it was essential to be completely candid about how such information could be abused and to suggest laws to prevent such abuse, because, as he said "we certainly don't want to mislead Congress" (Watson, 19881.
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From page 149... ...
Congress, Senate, 19891. Gore's interest in the implications of human genetics dated from the early 1980s, when he held a series of hearings on human gene therapy, in vitro fertilization, and biotechnology.
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From page 150... ...
Second, human genetics offered technological options that were not available before. Before genetic testing was developed, individuals at risk for Huntington's disease or anxious about whether they were carners of sickle cell or Tay-Sachs disease did not have to worry about such tests.
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From page 151... ...
Congress, Senate, 19881. The research was given a big boost at a joint NIH-DOE planning retreat held at the Banbury Center, Cold Spring Harbor Laboratory, in late August 1989.
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From page 152... ...
Secretary of Health and Human Services Louis Sullivan created the National Center for Human Genome Research in October 1989, giving the project administrative authority to spend federal funds, pending approval of an advisory council. Much staff time went into organizing chromosome-specific meetings, workshops on cloning large DNA inserts, DNA sequencing, informatics, and other topics.
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From page 153... ...
Probably, there would have been considerable discussion about sequencing, about data bases, about genetic linkage maps, about physical mapping, and about computational biology, but these "abouts" could conceivably have remained segregated in their scientific communities of origin. The human genome project need not have emerged so quickly from the collision of human genetics and molecular biology, and it need not have been projected as a major new initiative meriting serious high-level political attention.
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From page 154... ...
Most of the policy statements made by scientists had little impact because those in Congress who were making decisions were insulated from them. Most members of Congress had a few regular sources of scientific information on which they relied, and they also listened to committee staff, the NRC, and OTA.
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From page 155... ...
whether it successfully confronts the broader social implications that emerge as human genetics advances. APPENDIX A Where Was OSTP?
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From page 156... ...
This perception was true, in fact, but an opportunity was missed to leverage the Japanese government into much greater support for genome research, which might have avoided at least some of the controversy that later ensued over data sharing by U.S. and Japanese genome investigators.
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From page 157... ...
Noting that genome research will help in the study of disease does not answer the question about the optimal balance between the collective, concerted effort to map and sequence the genome and more decentralized, undirected research, or that done in pursuit of particular
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From page 158... ...
The relationship of the genome project to biotechnology is murky and confused. Genome research will clearly push the limits of DNA-based methods, and these advances will have broad applicability, not only in research but also in medical diagnosis and treatment, agriculture, pharmaceutical development, and other industrial sectors.
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From page 159... ...
There were many attempts to formulate budgets for the human genome project. The earliest were performed in conjunction with the Santa Cruz meeting, at the first Santa Fe meeting, and at meetings held thereafter.
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From page 161... ...
A subgroup was tasked to produce cost options. Botstein spearheaded this effort and came up with three options that would enable various amounts of genetic linkage mapping, physical mapping, sequencing, and other activities.
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From page 162... ...
First, there was really only one way to project coststo estimate how many people could be productively engaged in the various component tasks. With genetic linkage mapping, the wobble came from disagreement about how high the resolution needed to be.
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From page 163... ...
It is not clear what was meant by this statement, but this and similar language cropped up in dozens of letters, articles, meetings, and private discussions. It is not technically feasible to sequence the human genome in 1990, despite a half decade of impressive gains in power, speed, and simplicity of component steps (e.g., cloning larger DNA fragments, ordering clone libraries, DNA sequencing, and analyzing map and sequence data)
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From page 164... ...
, there will be a great deal of useful sequence data even if only 5 percent or so of the genome is sequenced, because investigators will attack the most clearly interesting regions first. Genetic and physical maps will be useful no matter how incomplete, but the value of the genome project depends on their completeness.
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From page 165... ...
51. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory.
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From page 166... ...
51. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory.
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From page 167... ...
1977. DNA sequencing with chain-terminating inhibitors.
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From page 168... ...
51. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory.
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From page 169... ...
By almost anyone's criteria, mapping and solving the human genome's sequence was viewed as a bold and exceedingly ambitious scientific and technical challenge, but one thatwould very likely be expensive in terms of resources, personnel, and funding. Aside from its initial influential groupofproponents Sinsheimer, DeLisi, Gilbert, Dulbecco, Hood, and Cantor the plan to sequence the entire human genome, when it Paul Berg is the Willson Professor of Biochemistry and Director of the Stanford University Medical School's Beckman Center for Molecular and Genetic Medicine.
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From page 170... ...
One aspect of the scientific debate is worth noting. As initially conceived, the human genome project's goal was to obtain the sequence of the 3 billion base pairs comprising the haploid genetic complement.
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From page 171... ...
Cook-Deegan points up several innovations in government-supported science. Besides the somewhat novel joint and coordinated sponsorship of genome research by N I H and DOE, there is the acknowledgment that eth ical and cultural values need to be reconciled with the program's objectives and applications.
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From page 172... ...
Alternatively, funding for the genome project could be stretched out, as was done in the space program. The case study does not indicate the extent to which the scientist activists, various advisory panels, or government agencies seriously considered the consequences of a fiscal crisis on Congress's ability or willingness to support the genome initiative.
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From page 173... ...
More or less at once, a number of geneticists and molecular biologists saw the possibility of mapping and sequencing the entire human genome. A few developed visions of an immense and expensive project, making an analogy with the space program.
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From page 174... ...
DOE/Office of Energy Research and OMB defined objectives, mechanisms, and tentative funding levels at a time when, according to the case, a poll of attendees at the Cold Spring Harbor conference would have voted against any early undertaking. Of course, the policy choices defined in mid-1986 were later to change, but the later effort would have been slower and different without this spadework.
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From page 175... ...
COMMENTARY · 175 and could take advantage of, New Mexicans' concern about the future of Los Alamos. Watson clearly pushed a hurcile out of his way by manifesting awareness of fears that the genome project might awaken.
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