The Genesis of The Human Genome Project

1 The Genesis of the Human Genome Project Robert Mullan Cook-Deegan Kennedy Institute of Ethics Georgetown University Washington, DC

I. INTRODUCTION The Human Genome Project leapt to center stage in biomédical research policy in 1986 and stayed there for several years. A quick scan of the contents of the front news sections of Science and Nature showed that the genome project was a hot topic for discussion, perhaps second only to acquired immune deficiency syndrome (AIDS). The project became a cover feature for Time (Elmer-Dewitt et al, 1989; Jaroff et al, 1989) and New Republic (Wright, 1990), and was the subject of two books that appeared in 1990 (Bishop and Waldholz, 1990; Wingerson, 1990). It also was the topic of public broadcast documentaries in the United States and Europe, including the "Horizon," "Nova," and "Discover" series. It even earned part of an hour in prime time television as part of ABC's "Perfect Babies" program, followed by a half hour on "Nightline" (19 July 1990). This attention resulted in large part from the energy that went into creating the genome project, the rhetoric expended to promote it, and the inherent public appeal of a road map for human genetics. Interagency rivalry, vigorous debate within science, and concerns about the social implications of human genetic research created controversy and thrust the genome project into public consciousness. Public policy on the genome project was formed in the cruel daylight of productive conflict. The controversies came in waves. Initially, there was concern about whether the genome project, as originally proposed, made any sense technically. This was followed by debates about whether it posed a danger for the style of genetics research involved, what social impact it may have, and whether it was displacing other higher priority science. The genome project became a political

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vehicle for arguments about biotechnology competitiveness and the international regime of scientific data flow. The Department of Energy (DOE) and the National Institutes of Health (NIH) were locked into a competition for control of the project, and factions within both agencies jostled one another in a fight to guide genome research programs. The genome project also captured the imagination of some of the most powerful biomédical researchers, but also aroused the ire of many. The genome story details a high-stakes game played in public theater. This chapter is a brief history of the first five years of the genome debate about the creation of the genome project. The focus is on science policy formation rather than the science of gene mapping. Evolution of the genome project provides a rare view of science policy in progress, and of a new idea implemented in only a few years. This rapid growth and the energy needed to overcome barriers forced major science policy questions of the day to the surface of public discourse. The genome project was buffeted by, but also contributed to debates about, the proper roles of scientists and politicians in setting science policy, the proper role of science in culture and the economy, and scientists* responsibilities to society at large. In short, the genesis of the genome project is a case history of science and the federal government.

II. TECHNICAL AND SCIENTIFIC BACKGROUND The genome project grew from a collision between human genetics and molecular biology. Human genetics is a collection offieldsranging from population studies to clinical diagnosis, but in general these fields have been largely clinical and descriptive, whereas molecular biology has been highly reductionist and focused on mechanism. As these two worlds came together in the 1970s and 1980s, each was fundamentally transformed. A. Origins of gene mapping Human gene mapping began in 1911, when color blindness was deduced to lie on the X chromosome because of its pattern of inheritance: the failure for fathers to transmit it to sons and its rarity among females. For five decades, study of the odd inheritance patterns of X-linked disease remained the only reliable mapping method. The autosomes were largely resistant to mapping. In the late 1960s, two technical developments took place. First, somatic cell hybridization became a mapping strategy. This method mixed chromosomes by fusing together cells from humans and other organisms. The mixed chromosomes fragmented and reorganized into metastable cell lines retaining various amounts of human DNA. It turned out that rodent-human cell lines, after a few generations, generally kept

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mainly rodent and only a small amount of human DNA, and were relatively stable over time. By assembling large numbers of such cell lines, and devising ways to select only those cells containing functional genes of interest, it became possible to map autosomal genes. Also during this period, it became possible to differentiate the 24 distinct human chromosomes under the light microscope by staining them with DNA-binding dyes, yielding a karyotype. Large-scale deletions, rearrangements, and duplications could finally be detected. Somatic cell hybridization and karyotyping dispatched human genetics on its quest for a complete gene map (McKusick, 1988). In the mid-1970s, restriction enzymes, recombinant DNA techniques, and the enormous variety of molecular biological techniques ushered in a new era in gene mapping. Recombinant DNA led to the isolation and cloning of hundreds of human genes, but there was another significant spin-off: mapping by linkage to DNA markers. The idea was to find landmarks along the human chromosomes for study of genetic linkage to diseases or other phenotypic traits. Kan and Dozy (1978) were the first to use linkage to a sequence difference to detect different variants of hemoglobin. This technique used restriction enzymes to cleave DNA at specific sequences, and then probed to detect fragments of varying size, thus revealing hitherto covert sequence diversity. A group of outside scientists were convened at Alta, Utah, in April 1978 to review work being done to map hemochromatosis in the group directed by Mark Skolnick (Bishop and Waldholz, 1990). Skolnick's group argued that statistical linkage to nearby known genes should be sufficient to identify the chromosomal region containing a gene of interest, and methods of statistical linkage and the nature of genetic markers were discussed (R. White, 1988). David Botstein and Ronald Davis were among those in the review group. During the discussion, Botstein suggested that it should be possible to use restriction enzymes in combination with probes to detect sequence variations throughout the genome, thus permitting geneticists to distinguish which parent contributed a particular chromosomal region to a child. One way to do this was to use restriction enzymes to cut DNA and specific probes to detect DNA fragments of varying length, a technique that became known as restriction fragment length polymorphism (RFLP). If one searched for sequence variations using the RFLP technique, then the character under study—perhaps a genetic disease—could be correlated statistically with inheritance of specific chromosomal regions. RFLP markers could thus be used to study families in search of genes, rather than making guesses about what gene might be correlated with a disease and then going to families to confirm or reject the hypothesis. RFLP markers would, for the first time, enable researchers to find genes by knowing only how a disease or trait is inherited, without having to guess what the gene did or produced. The correlation depended only on finding an RFLP

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sequence variation nearby, inherited with the character often enough to establish statistical association. Solomon and Bodmer (1979) made a similar suggestion in the final paragraph of a letter to Lancet. Bodmer later devoted his Allan Award lecture to the organization of the genome, and included a section on RFLP mapping (Bodmer, 1981). Botstein, Davis, Skolnick, and Ray White published a landmark paper in 1980, documenting the insights from the Alta meeting. By elaborating the idea in detail, this paper initiated an explosion of genetic linkage mapping in the 1980s (Botstein, 1980). Mapping by genetic linkage harkened back to mathematical genetics developed late in the nineteenth century and early in this century. The approach was fundamentally classical genetics—the study of the inheritance of observable differences among individuals—supplemented by clinical observation to define the genetic characters under study, and augmented by the modern tools of molecular marking. The process relied on the mathematics of probabilities to make correlations. The communities that studied evolutionary and population genetics immediately understood the significance of genetic linkage mapping. They were joined by a few medical geneticists who were comfortable with the statistical techniques of linkage. When the method yielded success in locating the gene responsible for Huntington^ disease in 1983 (Gusella et al, 1983) and polycystic kidney disease in 1985 (Reeders et al, 1985), clinical genetics quickly adopted it. By the mid-1980s, genetic linkage mapping was in the mainstream of human genetics. Newsweek magazine quipped in August 1987 that there was a disease-a-week being mapped by genetic linkage (Begley et al, 1987). Technical advances further extended the ability to work backward from approximate gene location, determined by linkage to a marker, to find the gene itself and identify its product (in most cases, a protein). The first successful search for a gene starting from its chromosomal location ended in 1987, with the cloning of a gene causing chronic granulomatous disease (Royer et al, 1987). This was soon followed by Duchenne muscular dystrophy (Koenig et al, 1987) and retinoblastoma (Friend et al, 1987; Lee et al, 1987). In each of these cases, however, the gene's approximate location (on the X chromosome for chronic granulomatous disease and Duchenne muscular dystrophy, and on chromosome 13 for retinoblastoma) was already known from patterns of inheritance, human-hamster hybrid cell lines, and the study of patients with small deletions. The process of going from chromosomal location to isolated gene was tedious, unreliable, and often frustrating. Intensive work over eight years failed to produce the Huntington's disease gene, for example. However, many prevalent disease-causing genes were isolated this way, most notably the gene causing cystic fibrosis (Kerem et al, 1989; Riordan et al, 1989; Rommens et al, 1989). Huntington's disease was the first disease mapped by linkage to an RFLP marker, but cystic fibrosis was the first for which a gene was mapped by genetic linkage, and then the regional DNA studied until a gene was found and its product identified.

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B. Molecular biology of human disease Molecular biology is largely a post-World War II phenomenon. Its two seminal events were Avery, MacLeod, and McCarty's late 1943 discovery of DNA as the "transforming principle" that confers heritable traits (Avery et al, 1944), and Watson and Crick's 1953 revelation of the double-helical structure of DNA (Watson and Crick, 1953). The distinctive signature of molecular biology was to understand function through molecular structure. Early work in molecular biology, particularly Delbrück and Luria's "phage" group and its descendants, focused on the simplest of living things: bacterial viruses (Judson, 1979). Beginning in the 1960s, however, molecular biology invaded field after field, applying its increasingly powerful tools to questions of greater complexity. By the mid- to late 1970s, molecular genetics was applied with astonishing success to the study of cancer, as marked by the discovery of oncogenes. The first disease characterized at the molecular level was sickle-cell anemia. In 1949, genetic studies by Neel showed it was a recessive genetic disease (Neel, 1949), and biochemical studies by Pauling revealed structural changes in hemoglobin (Pauling et a/., 1949). In the mid-1950s, Ingram identified the valineglutamine substitution in the ß globin chain by protein fingerprinting (Ingram, 1957). This suggested a mutation in the DNA encoding the ß chain. Molecular biologists studying human disease generally approached genes one at a time, starting with biochemical analysis of a gene product. Application of molecular techniques to chromosome mapping came from pushing molecular biological techniques at both ends: forcing chromosomal mapping to higher resolution, ultimately enabling direct decoding of the DNA base-pair sequence on the one hand, and developing techniques to separate and clone larger and larger fragments of DNA, culminating in techniques to clone megabase stretches of DNA on the other. C. Rapid progress in enabling technologies During the early to mid-1980s, it became possible to handle long strands of DNA without breaking them, by manipulating them in gels rather than in solutions. Pulsed-field gel electrophoresis, a technique first developed by Schwartz and Cantor (1984), enabled separation of DNA molecules several million base pairs in length. Cloning vectors that could consistently contain 30,000-40,000 base-pair DNA inserts became standard fare through incremental improvements made by dozens of laboratories. With these concomitant advances, it became possible to take DNA from chromosomes, clone it, and analyze it to reconstruct the order of cloned DNA fragments, so that eventually a complete map of the original DNA could be assembled. This kind of map had the enormous advantage that the chromosomal DNA would be not only mapped, but also cloned and stored in the freezer for further analysis.

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Two groups began independently to clone DNA from yeast and nematodes, putting the clones in order relative to one another in order to make maps of model organisms. Maynard Olson's laboratory at Washington University began to map the chromosomes of Saccharomyces cerevisiae (baker's yeast). John Sulston and Alan Coulson at the Medical Research Council (MRC) laboratory in Cambridge, England, later joined by Robert Waterston's Washington University laboratory in Saint Louis, worked toward a cloned physical map of the small nematode worm, Caenorhabditis elegans. Work, which began in the early 1980s, began to show promising results by 1986 (Coulson et a/., 1986, Olson et ai., 1986). Both projects centered on organisms central to biological understanding. Yeast was emerging as the core model for eukaryotic genetics. The 12.5megabase genome of S. cerevisiae was a logical early target for physical mapping. Having a set of ordered genomic DNA clones would be an extremely powerful addition to the already formidable armamentarium assembled to attack the genome. Botstein and Gerald Fink, of the Whitehead Institute for Biomédical Research, noted in a 1988 article that the unique power of yeast as a model was "the facility with which the relation between gene structure and protein function can be established." The wealth of data on mutants from classical genetics and the immense power of homologous recombination made it possible to introduce mutations into known genes, or to easily snare genes in the genome, so that "proteins first discovered elsewhere but present in yeast may best be studied first in yeast" (Botstein and Fink, 1988). Additional power came from the yeast research community: "Newcomers find themselves in an atmosphere that encourages cooperation. In keeping with the tradition that began with the phage group founded by Delbrück, Luria, and Hershey, not only are the published strains and mutants generally made available, but many (if not quite all) laboratories in the field routinely exchange strains, protocols, and ideas long before publication." Yeast genetics was ripe for the structural approach, and having stocks of ordered DNA clones representing the genome would be an immensely useful tool. Olson's project was thus enthusiastically greeted. Yeast provided a wonderful experimental model for many aspects of eukaryotic genetics, but single-celled organisms were unsuitable for studying the complex interactions of organismal development, neural function, and cell-to-cell communication. The ideal organism for such work was the nematode, C. elegans. This soil-dwelling 1-mm worm was an unlikely candidate to win a beauty contest, but its short three-day generation time and proclivity to self-fertilize, thus automatically establishing homozygosity, lent itself to genetic inquiry (Kenyon, 1988). The foundation was laid predominantly at the MRC Cambridge laboratory. Sydney Brenner selected C. elegans in the early 1960s as a model to study multicellular phenomena, especially the nervous system (Brenner, 1973,1974). His selection was based on wanting the smallest animal possible with favorable genetics

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in order "to study the effects of mutations in single genes in isogenic animals . . . [as well as] to isolate mutants affecting the behavior of an animal and see what changes have been produced in the nervous system" (Brenner, 1973). This concept followed the logic of molecular neuroscience pioneered by Seymour Benzer in Drosophüa. To carry out Brenner's agenda, it was necessary to find mutant phenotypes, but also to assemble an awesome mass of structural information: the lineages and connections between every cell in the worm's body. Several laboratories at the MRC Cambridge laboratories dedicated themselves to doing just that. Sulston, through a monumental effort, traced the development of the more than 900 somatic cells in the nematode's body, by watching the worms develop under a Nomarski microscope (Brenner, 1973; Kenyon, 1988; Roberts, 1990b; Sulston, 1983; Sulston and Horvitz, 1977; Sulston et al, 1983). John White and his colleagues reconstructed the "wiring diagram" of the nervous system in another tour de force, analyzing 20,000 electron micrographs (Kenyon, 1988; Roberts, 1990b; J. G. White et al, 1986). These two efforts are mind-boggling in their detail. The organism was a reductionist's delight. It was conceivable that with these basic tools it would become possible to understand the entire organism's biology in all its mechanistic detail. The cell lineages and connectivity maps were the starting points for studying what happened when mutations disrupted the normal structure of the organism. Structural genetics was the crucial missing element. Even as the work began on C. elegans, the purpose was to correlate behavior with structure; DNA was the conceptual starting point. Sulston and Brenner estimated the size of the genome early on, to see what they were up against. They estimated the genome size by grinding up nematodes and seeing how much DNA was released, and also by observing the speed of DNA renaturation. These methods suggested that the genome contained 80 million base pairs, giving it "the smallest value of any animal" (Sulston and Brenner, 1974). (This estimate was increased to 100 million base pairs in the late 1980s, as the physical map gave more accurate data.) The genome was segmented into 6 chromosomes that contained 700 genes mapped by 1988 (Kenyon, 1988). A physical map of the worm's genome was the critical next step. Sulston and Coulson took it. Coulson and Sulston labored for several years to make collections of cosmid clones, then "fingerprinted" them by looking for matches in length of restriction fragments (Coulson et al, 1986). Restriction fragment length patterns were stored in a computer, which looked for other cosmids that might exhibit a similar pattern, thus indicating overlap. Coulson and Sulston had over 90% of the genome covered by 16,000 clones in 1986, but the ordered clone collections fell into 700 groups. This was a great boon to the close-knit nematode research community, but the problem remained as to how to close the gaps. Enter David Burke and Maynard Olson, bearing a gift from yeast.

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Burke, a student in Olson's laboratory, became interested in the goingson in chromosomal structure. Burke built on the studies of chromosome segregation in Tetrahymena and other organisms. With support from Andrew Murray and Jack Szostak, Burke constructed cloning vectors that contained selectable markers and a triad of chromosome structural elements: centromeres, telomeres, and autonomous replication sites. With this concoction, he demonstrated that DNA fragments fully an order of magnitude larger than cloned in cosmids could be replicated as yeast artificial chromosomes (YACs) (Burke et al, 1987). This solved several serious problems at once. First, the length of the fragments meant that far fewer clones were needed to span a chromosomal region in ordered clones. Second, the problems in cloning certain kinds of sequences in bacteria might be solved with yeast, a eukaryote, as replication host (Nasmyth and Sulston, 1987). Third, the larger fragment length opened up new fingerprinting methods that improved prospects for detecting overlap between DNA inserts, dramatically expediting progress toward map closure (Lander and Waterman, 1988). Using YACs, the MRC Cambridge and Washington University groups were able to span many gaps, reducing the number of contiguously mapped regions (contigs) from 700 to 346 in seven months (Coulson et al, 1988). By late 1989, the number of gaps was down to 190, with a fourfold increase in length of the average contig (Cook-Deegan et al, 1990). A new refrain was heard in nematode laboratories: "The gaps in maps are filled mainly with the YACs." The physical maps of yeast and nematodes became extremely powerful tools for genetics, and for general understanding. They eliminated the need for each researcher to laboriously develop a clone library and screen it independently. The nematode physical map was put in a computer database available to all laboratories. Those who discovered genes or mutant organisms fed into the system, thus linking physical and genetic maps and strengthening correlations to function. With a useful physical map, the next step was to determine the entire DNA sequence of the C. elegans genome. The MRC and Washington University groups began to do this in 1990. DNA sequencing was developed by groups at the two Cambridges (United Kingdom and Massachusetts), more or less simultaneously but using entirely different approaches. The first DNA sequence was published in 1971, following an immense effort to determine the sequence of the 12-base-pair "sticky ends" of bacteriophage λ (Sanger, 1988; Wu and Taylor, 1971). Sanger's group in Cambridge, United Kingdom, became convinced of the future importance of DNA sequencing, and began working to improve methods. This perpetuated a long tradition of using linear sequence as a structural tool to examine questions in molecular biology. Sänger began with protein sequencing, progressed to the sequencing of ribonucleic acid (RNA), and culminated several decades of work with DNA sequencing (Sänger, 1988), earning two Nobel Prizes along the way. After several years' effort, success was evident. Sänger presented a partial DNA sequence

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to an awe-struck audience in May 1975 (Judson, 1987; Sänger, 1975; Sanger and Coulson, 1975), and published a simpler, modified DNA sequencing method in 1977 (Sanger et al, 1977). Sanger noted in his extraordinary scientific autobiography that "Of the three main activities involved in scientific research, thinking, talking, and doing, I much prefer the last and am probably best at it" (Sänger, 1988). He certainly did a lot of it. In that same article, he gave some insight into why the MRC Cambridge has played such a central role in the development of modern molecular biology: I was in the fortunate position of having a permanent research appointment with the (British) Medical Research Council, and was not under the usual obligation of having to produce a regular output of publishable material, with the result that I could afford to attack problems that were more 'way out' and longer term: in fact, as few others could adopt this approach, I felt under some obligation to do so . . . I like the idea of doing something that nobody else is doing rather than racing to be the first to complete a project. (Sänger, 1988) Sanger confided, however, "I cannot pretend that I was altogether overjoyed by the appearance of a competitive method [for DNA sequencing] " (Sänger, 1988), although the two methods proved to have complementary strengths. The preferred approach varied according to what was sequenced and how the DNA was prepared. The alternative method, developed across the Atlantic, followed persistent effort along an altogether different track. Maxam and Gilbert, working in Cambridge, Massachusetts, developed DNA sequencing from attempting directly to study the binding of the repressor protein that controlled expression of the beta-galactosidase gene. Gilbert's group isolated the first DNA segment from the region, and deduced its DNA sequence between 1972 and 1974. This sequence was 24 base pairs long, and took two years' effort by two superlative investigators (W. Gilbert, Harvard University, personal communication, July 1988). The next step was to use chemical modifications of DNA bases to study the DNA segments that, when bound by proteins, turned gene expression on and off. The insight on how to do this came from a lunch that included Maxam, Gilbert, a graduate student, and Andrei Mirzabekov. Mirzabekov was from Moscow, spending a year in the West. He came to visit Gilbert, fresh from a short stint at the MRC Cambridge laboratory where he had worked on dimethyl sulfate to cleave DNA at guanine and adenine residues. Over lunch, the group decided this might be just the ticket to study which regions of DNA were bound by the repressor protein. Maxam and Gilbert realized that the same approach might, with some further work, permit direct DNA sequencing (Kolata, 1980, also interview, July 1988). Maxam worked to find conditions that would distinguish adenine from guanine. He also found that hydrazine could destabilize

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cytosine and thymine, and discovered conditions that would distinguish the two. By August 1976, Maxam was ready to distribute the chemical recipes used in their sequencing reactions at a Gordon Conference. Their method of DNA sequencing was also published during the next year (Maxam and Gilbert, 1977). Molecular biology thus generated a plethora of technological tricks to construct physical maps of chromosomes and to determine DNA sequences. Although some human geneticists were quick to apply the developing techniques to study diseases, with a few exceptions, molecular biology was a separate field from human genetics. Nonetheless, the twofieldswere rapidly converging, as molecular biology tramped into yet another field ripe for the picking. The early to mid-1980s also saw rapid developments in two other highly disparate fields: microcomputers and automation of microchemical manipulation. The computer revolution was imported from other areas, and quickly adapted to the needs of biologists. Personal computers were important because they enabled thousands of laboratories to store and analyze masses of information. They permitted more analysis of raw data, and there was a natural harmony between digital processing and digital analysis of linear DNA sequence information. As information processing became faster and cheaper by orders of magnitude every few years, biologists, including molecular biologists, began to find entirely new uses for computers (T. F. Smith, 1990). Automation of microchemical processes made possible experiments that were too tedious to do by hand. Automation was successfully cultivated at only a few university centers and in companies either already selling analytical instruments to biologists or newly formed to do so. Centrifuges, spectrophotometers, electrophoresis apparatus, and instruments for collecting fluids had long been a part of biochemistry. Molecular biology introduced some new instruments to analyze protein and nucleic acid composition. Reactions to determine the order of amino acids and to synthesize polypeptides were automated. Analysis of DNA was next in line. Serious efforts to synthesize short segments of DNA, essential to developing highly sensitive probes for analyzing genetic experiments, began in the late 1970s, and proved successful by the early 1980s. Automation of DNA sequence determination began around this time in both the United States and Japan. In the United States, the first efforts leading to the current generation of fluorescence-based DNA sequenators began in 1980 at California Institute of Technology (Caltech). Ideas for a DNA sequenator had been intermittently pursued and followed up blind alleys since the mid-1970s in the laboratory of Leroy Hood, whose group had also developed highly successful instruments to sequence peptides, and to synthesize peptides and nucleic acids. The DNA sequenator was the last of a "suite" of four instruments to study proteins and nucleic acids. The fluorescent DNA sequenator was first conceived at Caltech, and subsequently developed there and at the newly founded instrumentation company

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Applied Biosystems, Inc. (ABI), near San Francisco (L. M. Smith et al, 1985; L. M. Smith et al, 1986). A prototype showed promise in 1984, and by late 1986, there was a commercial version ready for market, modified and manufactured by ABI. The ABI machine hit the market in 1987, and was soon joined by a rival fluorescence-based machine manufactured by DuPont (Prober et al, 1987) and another machine based on detecting radioactive phosphorus (Roberts, 1987d; interview at EG&G Biomolecular, Watertown, Massachusetts, August 1987). In Japan, the Science and Technology Agency (STA) began in 1981 to support a project to automate DNA sequencing. This program was the brainchild of Akiyoshi Wada, who had been handed a mantle from STA to improve the analysis of DNA. He chose to focus on instrumentation and to automate wellestablished techniques, rather than simultaneously developing new methods and automation technologies. Wada enticed several corporate sponsors into the project (Fuji Photo, Seiko, and Matsui Knowledge Industries), which became housed at the RIKEN Institute in Tsukuba Science City (Wada, 1984, 1986, 1987a, 1987b, 1988; and interviews 1987, 1988, 1990). An independent automation effort at Hitachi culminated in a DNA sequencer that in 1990 was marketed only in Japan. The automation effort at the European Molecular Biology Laboratory (EMBL) in Heidelberg began in the early 1980s, supported by several European governments. It employed yet a third scheme for fluor-labeled nucleotides, using a different reaction scheme, lane array, and laser detection system (interview with W. Ansorge, EMBL, Genome Sequencing and Mapping Symposium, Cold Spring Harbor, May 1989). This was the prototype for a machine later marketed by LKB-Pharmacia, beginning in 1989. All these technological developments surged forward in the period 1980— 1985. Ideas for a concerted genome project were looming in the background, and several farsighted people brought them forth independently.

III. ORIGINS OF GENOME RESEARCH PROGRAMS A. Recognition of the need for concerted efforts in human genetics Botstein, White, and others floated the idea of systematically assembling an RFLP marker map to NIH and secured an initial grant to begin work. Arlene Wyman and White, working at the University of Massachusetts at Worcester, discovered the first RFLP heterogeneity in late 1979 (Bishop and Waldholz, 1990; Wyman and White, 1980). Botstein had several conversations with NIH staff about scaling up the effort to assemble a complete RFLP map. He got the impression that NIH would have a hard time providing the resources necessary. In the meantime, the Howard Hughes Medical Institute (HHMI) evinced an interest in such a project, and in late 1980 White was recruited to go to the HHMI unit at the University

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of Utah. He did indeed scale up the work considerably, but with private HHMI funds. Systematic RFLP mapping progressed on another front. Botstein and Davis were on the board of a private biotechnology company, Collaborative Research, Inc., from the Boston area. White and, for a short period, Skolnick were outside consultants. Botstein convinced David Baltimore, his Massachusetts Institute of Technology (MIT) colleague and chair of the scientific advisory board, of the promise of RFLP mapping. Collaborative Research hired Helen Donis-Keller from Biogen. Donis-Keller had trained with Walter Gilbert before briefly joining Biogen, another biotechnology company that Gilbert helped establish. Between them, the White and Donis-Keller laboratories laid the foundation for the genetic linkage map of humans, contributing more than half the DNA markers that existed on the human genetic map in 1987 (Donis-Keller et αί., 1987; Roberts, 1987b; R. White, 1988). The world of linkage mapping was transformed by the profusion of markers along the chromosomes. The work had gone dramatically upscale, reaching a feverish pitch, at times exhibiting a sharp, competitive edge (Barinaga, 1987; Bishop and Waldholz, 1990; Roberts, 1987b). James Crow and William Dove compared current events with publication of the first genetic linkage map, Sturtevant's 1913 paper on Drosophila: "These quiet beginnings stand in abrupt contrast to the current hubbub over the human linkage map and the proper definition of a map. With its rival factions and the glare of publicity, the mapping race is almost a genetic Olympics" (Crow and Dove, 1988). As goes sport, so goes science. In retrospect, the systematic search for chromosomal markers and the construction of linkage maps were among the most significant accomplishments of human genetics in the 1980s. Government funding had been sustained for those seeking specific genes or diseases, and thus contributed handfuls of markers from regions of intense interest, but government support had not been the central framework supporting the construction of maps. This was true not only of the laboratories developing new markers, but also of the collaborative network that enabled pooling, comparison, and cross-checking of data. The glue holding the various large genetic linkage efforts was the Centre d'Étude du Polymorphisme Humain (CEPH), a Paris organization founded by Nobelist Jean Dausset with funds from a private French donor (Dausset et ai., 1990; Marx, 1985). Construction of the human genetic linkage marker map thus involved little direct government funding. The idea of focused mapping did get support when it fit into the format of a small scientific project. Maynard Olson's seminal work toward a physical map of S. cerevesiae, for example, was NIH funded. It was unclear, however, how ready NIH would be to support larger efforts. Proposals to apply the physical mapping techniques being used in yeast and nematodes to human chromosomes, in particular the X chromosome, were rejected by scientific

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review groups in 1986 and 1987 (interviews with Theodore Friedmann, January 1987 and October 1988). The review groups noted that the idea was not innovative. Those thinking of the long-term prospects for systematically assembling a physical map of the human genome began to despair, fearing a replay of the RFLP mapping story, with little government support and frustration of those with longterm vision. This time, however, prospects of a rescue from private philanthropy and corporate coffers were remote. The scale of the effort would be substantially larger and the organizational tasks more complex than with genetic linkage mapping. No private corporation or philanthropy could sustain such an effort. Physical mapping alone would consume 10s of millions of dollars, requiring the dedicated effort of several groups for a half decade or more. The final source of concern was DNA sequencing. It was widely practiced, as every molecular biology laboratory did some, but it generally remained the province of thousands of small laboratories focused on small regions. The group under Bart Barrell in Cambridge, United Kingdom, which grew out of the Sänger laboratory, were lonely trailblazers, sequencing the entire genomes of progressively larger organisms (Sänger, 1988). Several private corporations, such as Genentech and DuPont, and some large research groups also scaled up, and began to sequence contiguous regions of the genome known to contain important genes. The largest continuously sequenced stretches in humans, however, were no larger than 50,000-100,000 base pairs. Even regions of intense interest had not been completely sequenced: the HLA complex, the immunoglobulin gene regions, the region containing the Duchenne muscular dystrophy gene, and the terminal tip of the X chromosome known to contain at least 30 disease-related genes. Doing DNA sequencing more efficiently, and focusing it on larger chromosomal regions, would require machines. The initial funding for DNA sequence automation in the United States came as part of a 5-year private grant from the Weingart Institute. Government funds were made available only after three years. When they came, the National Science Foundation (NSF) was the source, not NIH. The work to develop the fluorescent dyes used funds from NSF, the Baxter Foundation, Monsanto, and Upjohn (L. M. Smith et al, 1985; L. M. Smith et al, 1986; interviews with L. Hood, T. Hunkapiller, and M. Hunkapiller, 1987 and 1988). NIH was not entirely a bystander, as a training grant for Lloyd Smith came from the National Institute of General Medical Sciences (NIGMS), but the automation itself was not supported. NIH had no natural home for projects directed toward construction of prototype instruments; it lacked a dedicated technology development program. Government support for a genetic linkage map, physical maps, and DNA sequencing technology was slow to develop. Early attempts to entice NIH to construct a genetic linkage map were rebuffed in part because the logical mechanism was a service contract or other nongrant mechanism. These were held as

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highly suspect, in part because of a highly public disgrace of large contract-based research centered on cancer viruses. Large contracts were used under the Special Cancer Virus Program at the National Cancer Institute (NCI), and consumed $32 million, or 12%, of the NCI budget in 1973. The conduct of this program came under fire, and the National Cancer Board put together an ad hoc committee, chaired by Norton Zinder, to look into it. The Zinder committee painted the portrait of a group of insiders dispensing substantial federal funds with only a sham of peer review and no comprehensive view of their scientific purpose. They did not recommend disbanding the program, and did not find the distinction between grant and contracts helpful in sorting out the management mess. They did recommend much greater involvement of outsiders, reduction of the segment chiefs' power, elimination of practices that produced conflicts of interest, and greater attention to peer review (Zinder et ai., 1974). The experience left a mark on NIH policies for many years. There was, particularly in some institutes, a reluctance to engage in any centrally managed efforts. The reticence that greeted RFLP mapping was feared for physical maps, a full order of magnitude larger in effort required. Development of new automation strategies seemed to fall outside the mainstream of biomédical research. These problems had not been linked, however, and the prevailing wisdom was that small grants could solve the salient problems of genetics much more efficiently than any refocused or planned efforts. In this regard, genetics differed from many other disciplines with closer ties to routine medical practice and a longer history of concerted efforts. Many institutes at NIH faced similar policy issues long before, for example, in deciding how much to spend for clinical trials. Testing new drugs or devices entailed high costs, extensive nationwide collaborations, and systematic NIH staff planning. Most of the NIH budget was devoted to extramural research conducted at universities, independent research centers, and intramural laboratories with a strong tradition of scientific independence. Several institutes, however, also supported a core of targeted efforts. NIGMS was home for biomédical research that had no other home. It had no intramural research base, and prided itself on supporting some of the most basic and undirected research funded by NIH. It was the principal source of funding for basic genetics. The scientific roots of the genome project traced to NIGMS-funded scientists, and NIGMS was their main source of nourishment. It was widely respected as a smoothly running operation dedicated to supporting the best in cutting-edge basic biology. Yet the genome project called for sustained projects directed at collective goods, inimical to the hissez faire values that distinguished NIGMS from other institutes at NIH. The NIGMS style was thus at odds with some important elements of genome research. NIGMS was not the most fertile soil in which to plant the idea for the genome project.

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B. Putting Santa Cruz on the map Several groups began to buck the tide in 1985 and 1986. Norman Anderson and his son Leigh had discussed a large-scale approach to cataloging blood proteins and gene mapping in several national laboratory planning documents (Santa Fe workshop, March 1986, collected unpublished documents). Norman Anderson had been involved in a string of technological advances from high-pressure liquid chromatography to zonal centrifugation to standardization of two-dimensional peptide electrophoresis. Anderson father and son proposed in the fall of 1985 that sequencing the genome and cataloging all known genes should be a concerted national effort, but the idea was recorded in a relatively obscure journal and never caught fire (Anderson and Anderson, 1985). The thread leading to the current genome project became tangled around the Keck Telescope by an odd historical twist. The knot tying them together was Robert Sinsheimer, chancellor of University of California, Santa Cruz (UCSC). The first discussion of a large dedicated genome project came at a workshop convened at UCSC in June 1985. Sinsheimer was a biologist who wanted to leave a mark on his institution. In his own words, he "wanted to put Santa Cruz on the map in biology" (personal communication, July 1988). Mapping is what it was all about. His experience in seeking funds for what became the Keck Telescope catalyzed the Santa Cruz meeting on the human genome. An idea emerged from the Lick Observatory, administered by UCSC, to build the largest optical telescope in the world. One problem was the prohibitive cost of producing the mirror for such a telescope. This problem was solved in principle by an idea from Jerry Nelson of Lawrence Berkeley Laboratory: to pack together 36 small hexagonal mirrors, rather than producing a single large mirror. This lowered the estimated costs from $500 million to $70 million. With this development, UCSC and Lick decided to seek funding from private donors. A story was run in the San Jose Mercury, and Lick administrators got a call from a Mr. Kane, who was familiar with a new foundation, the Hoffman Foundation, created after the death of Max Hoffman, the US importer of Volkswagen and BMW automobiles. Mr. Kane thought Hoffman's wife might be interested in putting up $36 million toward the world's largest telescope. David Gardner, president of the entire University of California, was contacted, and the foundation provided a $36 million check to the University of California, to help build the Hoffman Telescope. It was the largest single contribution to the University of California in its history. Mrs. Hoffman died the next day. UCSC continued to search for funds, but had difficulty securing additional donations, in part because it was a state university largely supported with taxpayer dollars, and in part because the telescope was already named for Max Hoffman. Caltech was approached to see if the telescope could be a joint effort,

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assuming Caltech could help raise the requisite funds. Caltech secured an additional $15 million from its trustees, and then it contacted the W. M. Keck Foundation, established with moneys from Superior Oil. The foundation was willing to help, but wanted to fund the entire effort and name the telescope after Keck. According to this plan, the $36 million from the Hoffman Foundation and other prior donations could be used as operating capital, or to build a smaller sister instrument. This was not the agreement with the Hoffman Foundation, however. UCSC approached the Hoffman trustees with the idea, but overtures were rejected; the $36 million check was returned (Hall, 1988; interview with Sinsheimer, Caltech, 10 July 1988; personal communications 7 September 1988 and 25 July 1990). Big money talked, but bigger money shouted it down. Production of the hexagonal mirrors began early in 1989 with much fanfare. The Keck Telescope now nears completion on the upper slopes of Mauna Kea, joining the cluster of other large telescopes on that Hawaii mountaintop. Sinsheimer's idea for a DNA sequencing center was precipitated by thinking about what he might do to recoup the Hoffman funds. He decided to propose a big attractive biology project. He considered what opportunities might be lost in biology because of an exclusive focus on projects that could be done by small groups without special facilities. He hit upon the idea of sequencing the human genome. He called in several UCSC biologists—Robert Edgar and Harry Noller (and later, Robert Ludwig)—to discuss the idea of setting up an institute at UCSC for this purpose. The others were at first stunned by Sinsheimer's idea, thinking it ludicrously audacious, but after some discussion they decided it was worth further reflection. Edgar and Noller prepared a laudatory position paper on Halloween 1984, which saw the genome sequencing institute as: a noble and inspiring enterprise. 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. The ordered library of cloned DNA that must be produced to allow the genome to be sequenced will itself be of great value to all human genetics researchers. The project will also provide an impetus for improvements in techniques . . . that have already revolutionized the nature of biological research. The UCSC group decided to call a meeting of experts from around the world. Noller wrote to Sänger, who replied, "It seems to me to be the ultimate in sequencing and will probably need to be done eventually, so why not start on it

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now? It's difficult to be certain, but I think the time is ripe" (letter 22 November 1984). The meeting was held on 24-25 May 1985. The group included those pushing the limits of DNA sequencing (Bart Barrell, Lee Hood, and George Church), some originators and practitioners of genetic linkage mapping (David Botstein, Ronald Davis, and Helen Donis-Keller), large-scale physical mappers (John Sulston and Robert Waterston), mavens of large DNA fragment analysis (Leonard Lerman and David Schwartz), and a mathematician concerned with analysis of DNA sequence (Michael Waterman). Science writer Steven Hall later reported on the meeting, capturing its modesty in "Genesis, the Sequel" (Hall, 1988). The group agreed that it made sense systematically to develop a genetic linkage map, a physical map of ordered clones, and the capacity for large-scale DNA sequencing (Sinsheimer, 1989). They decided that the first sequencing efforts should focus on automation and development of faster and cheaper techniques. While the meeting was being organized, Walter Gilbert was off in the Pacific, having resigned as chief executive officer of Biogen, Inc. The Santa Cruz group wanted his blessing, and Edgar finally reached him in late March 1985, in transition back to a faculty position at Harvard (letter, 25 March 1985). Gilbert came to the meeting and developed into the principal torchbearer for the human genome project for a time. Gilbert proved an articulate visionary of science, capable of transmitting excitement to other molecular biologists and to the general public. He translated the ideas at Santa Cruz into specific operating plans in a memo back to Edgar two days after the workshop (letter 27 May 1985), and took the ideas generated there into the power centers of molecular biology. He gave informal presentations on sequencing the genome at a Gordon Conference and at the first international conference on genes and computers in August 1985. Gilbert was extremely well connected, and infected several of his colleagues with enthusiasm, including Paul Berg and James Watson. Gilbert also gave the genome project much greater notice than it would otherwise have achieved, earning features on his role in it from US News and World Report (McAuliffe, 1987), Newsweek (Begley et al, 1987), Boston magazine (del Guercio, 1987), Business Week (Beam and Hamilton, 1987), Insight (Holzman, 1987), and the New York Times Magazine (Kanigel, 1987). He and Lee Hood wrote supporting articles for a special section in Issues in Science and Technology, published by the National Academy of Sciences (Gilbert, 1987; Hood and Smith, 1987), and he and Walter Bodmer each wrote an editorial for The Scientist (Bodmer, 1986b; Gilbert 1986). Gilbert thus kept up the steam in the genome engine, preserving the spirit of Santa Cruz, even as Sinsheimer's local attempts at UCSC were meeting resistance. The Santa Cruz summary statement was sent to several potential funding sources, including HHMI and the Arnold and Mabel Beckman Foundation, but

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there were no takers. Donald Fredrickson, then president of HHMI, was at that time also hearing ideas about the genome project, from somewhat different perspectives, from Charles Scriver, then on the Medical Advisory Board to HHMI, and from George Cahill, an HHMI vice-president. HHMI decided to investigate further, but did not fund the Santa Cruz proposal (papers from the Department of Biology, UCSC). Sinsheimer, meanwhile, was sounding out his colleagues about the idea of a genome sequencing institute. He spoke to James Wyngaarden, director of NIH, at a meeting in Washington, DC, in late February or early March 1985. Sinsheimer's personal note about this conversation stated that Wyngaarden was quite supportive, and urged UCSC to put together a proposal NIGMS. Wyngaarden judged that "it would not be too difficult to get Congressional funding for the project, through NIGMS," according to Sinsheimer. NIH was the logical source for funds, but obtaining them presented problems. The costs estimated at the Santa Cruz meeting, in the range of $25^40 million to build an institute and an annual operating budget of roughly $10 million, were far too high for a grant or standard research program. This would require a special appropriation, which raised the problems of approaching Congress and necessitating the agreement of the president's office for the entire UC system. This would have required agreement among the various campuses that Santa Cruz was the best home, an unlikely point of consensus. Sinsheimer judged that getting university support was contingent on getting a large private donation to start things off. He later lamented, "I thought the extraordinary significance of the project would be more self-evident to some of the prospective donors than proved to be the case" (R. Sinsheimer, personal communication, 7 September 1988). The president's office at UC stalled for several months when Sinsheimer expressed a wish to approach the Hoffman Foundation with his new idea, and the approach was never made. Thus, the initial impetus for the sequencing idea proved a dead end. No other private donor materialized, so the idea of a genome institute at UCSC died a quite death. C. Roots of the DOE program A more successful seed was planted in December 1984, when the Department of Energy sponsored a meeting at Alta, Utah, to discuss how to measure heritable mutations in humans (Cook-Deegan, 1989). This was the same Wasatch Mountain resort where, in 1978, Botstein and Davis had stumbled upon the idea of systematic RFLP mapping. Ray White of the University of Utah organized the 1984 meeting at the behest of Mortimer Mendelsohn of Lawrence Livermore National Laboratory and David Smith of DOE. The specific question was whether new DNA-based methods were sensitive enough to detect any increase in mutations among survivors of the Hiroshima and Nagasaki atomic bomb blasts. A group of

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scientists engaged in developing new DNA analytical techniques were invited to participate. The conclusion of the meeting was that methods could not detect mutations with any reasonably scaled effort, but the workshop had a more lasting effect. It took place just as Cassandra Smith and Charles 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. The congressional Office of Technology Assessment (OTA) was doing a report on technologies to measure heritable mutations in man, because exposure to agent orange, environmental toxins, and radiation were beginning to come before congressional committees (US Congress 1986). Mike Gough, OTA project director, was present at the Alta meeting, and discussed the various technologies in a draft report sent to the DOE for review. Charles DeLisi reviewed the draft as newly appointed head of the Office of Health and Environmental Research (OHER). He recalled looking up from the pages of the draft with the idea for a dedicated project focused on DNA sequencing and computation (DeLisi, 1988). In a scene not atypical of Washington, he reflected on programs under his direction by reading about them in a report prepared by outsiders. DeLisi and David Smith of DOE moved quickly on many fronts during the Christmas lull of 1985. They asked the biology group at Los Alamos National Laboratory for its comments on DeLisi's idea. The Los Alamos group replied with a dense and scattered, but extremely enthusiastic, 5-page memo just before Christmas, penned by physician Mark Bitensky and others. The memo concerned sequencing the entire human genome, and barely mentioned physical or genetic mapping. The Los Alamos memo estimated costs, noted that such a project could become a "DNA-centered mechanism for international cooperation and reduction in tension " and bubbled over the potential technical and human health benefits. Los Alamos even checked with Frank Ruddle of Yale, to ensure that he was willing to testify before Congress in support of such a program. With this initial feedback, Smith and DeLisi began to pull the bureaucratic levers in Washington. In a note to Smith, DeLisi outlined an approach to garner support from the scientific community, from his superiors at DOE, and from Congress. In a return note to DeLisi dated 30 December 1985, Smith mentioned rumors about previous discussions of sequencing the human genome at a Gordon Conference and at a meeting at the University of California the previous summer, but he did not know what had come of these. Smith also anticipated the criticisms that would plague the DOE proposal for some time to come: that it was not science but technical drudgery, that directed research was less efficient than letting small groups decide what is important and do it, and that effort should be concentrated on genes of interest rather than global sequencing. In a reply the next day, DeLisi contended that "regarding the grind, grind, grind argument. . . there will be some

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grind; what we are discussing is whether the grinding should be spread out over 30 years or compressed into 10." He presciently noted that "we are talking about $100-150 million per year spread out over somewhat more than a decade," and asserted that such a project certainly would rate as more important than the lower 1% of grants that funding of this magnitude would displace. He suggested that the political effort should not focus on whether it would displace other work, but instead on how to gain support for new funding. DeLisi discussed the idea with his superior, Alvin Trivelpiece, who supported the idea and charged the DOE life sciences advisory committee (the Health and Environmental Research Advisory Committee, or HERAC) to report back to him about the idea. This followed several discussions with DeLisi about the possibility of doing a genome project in DOE. Trivelpiece and DeLisi had discussed why DOE did not have the same high stature in biology that it had in high-energy physics, and they aspired to change that situation by providing a project that would propel DOE to the forefront of biology. Trivelpiece, as director of the Office of Energy Research, reported directly to the secretary of energy (then John Herrington), who in turn reported directly to the president. As part of the outreach to the scientific community, Los Alamos was asked to convene a workshop (1) to find out if there was consensus that the project was feasible and should be started, (2) to delineate medical and scientific benefits and to outline a scientific strategy, and (3) to discuss international cooperation, especially with the Soviet Union. A workshop was held at Santa Fe on 3-4 March, with "a rare and impassioned esprit" according to the memo that summarized it. Discussion at the Santa Fe workshop had clearly added an emphasis on physical mapping by ordering clone libraries as a crucial first step (Bitensky, 1986; collected papers from Santa Fe Workshop, DOE, 1986). In letters back to Bitensky, there was consensus on the importance of a new project and on what should be done next, but a wide range of opinions about how to organize the effort. Anthony Carrano and Elbert Branscomb from Lawrence Livermore National Laboratory stressed the importance of clone maps and warned that "a program whose announced purpose was simply to 'sequence the human genome* might unnecessarily and incorrectly arouse fears of territorial and financial usurpation in the biomédical research community" (Carrano and (Branscomb, 1986). They certainly got that right. David Comings was further from the mark when he averred that the whole physical mapping component might be funded "without any stirring up of any congressmen or other related creatures" (Comings, 1986). The creatures were not so docile; indeed they proved downright ornery. By May 1986, DeLisi had produced an internal planning memo to carry the request for a line item budget. This went to Trivelpiece and up through the DOE bureaucracy. The project had been broken into two phases by then. Phase I had three components: Physical mapping of the human chromosomes took up

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much of the first phase, to last five or six years. The other two components in Phase I were development of high-speed automated D N A sequencing and a research program to improve computer analysis of sequence information. DeLisi's background in computational biology came to the fore here. Phase II, contingent on success in Phase I, would entail sequencing the banks of D N A clones put together in a physical map of the chromosomes. DeLisi spoke of a project analogous to a space program, except that it would entail the efforts of many agencies and a more distributed work structure, with "one agency playing the lead, managerial role . . . DOE is a natural organization to play the lead" (6 May memo to Trivelpiece). A five-year budget of $5, 10, 19, 22, and 22 million was proposed for fiscal years 1987-1991 (separate 6 May memo to Trivelpiece). Plans survived the internal DOE review, and a series of meetings were scheduled, beginning in the fall of 1986, with Judy Bostock, the DOE life sciences budget officer in the White House Office of Management and Budget (OMB). OMB sits atop the federal bureaucracy, with responsibility to oversee management and prepare the president's budget request to Congress each year. It operates as a black box with enormous power, full of political intrigue. Although OMB sends shivers of fear down the spines of most people in federal service, it is less sinister and more systematic than it often appears; however, individuals do count. DOE's genome meetings with Bostock were focused on planning for fiscal years 1988 and beyond. Bostock was a physicist from MIT, with a strong interest in biology, especially in improving the speed and efficiency of biological research. She believed that better instruments would improve the quality of biology and biologists' lives (interviews, OMB, 23 September 1988 and 4 April 1989). She saw molecular biology as an extremely inefficient process in which postdoctoral and graduate students did mindless manual work that would be better done by robots or automated instruments. DeLisi was proposing a program focused on making the analysis of DNA much more systematic and efficient, a laudatory goal that capitalized on the resources of national laboratories. The budget briefing documents for the O H E R - O M B meetings included a budget projection for fiscal years 1987— 1990 of $5.64, 11.55, 18, and 22 million. The cover sheet for the DOE document to OMB specified a four-year project starting 1 October 1987, extending to 30 September 1991, and costing $95 million. By simple arithmetic, this suggests there was an agreement for a fiscal year 1991 budget of $40-45 million. Decisions about a Phase II budget were to be made in 1990 and 1991. The DOE advisory committee, HERAC, endorsed the plan for a DOE genome initiative in a report from its special ad hoc subcommittee. The subcommittee was a blue-ribbon scientific group chaired by Ignacio Tinoco, a highly respected chemist from the University of California, Berkeley, then on sabbatical for a year at the University of Colorado in Boulder. The report urged a budget of

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$200 million per year, and made a case for DOE leadership of the effort. Budget projections made by the committee were not connected to the multiyear DOEOMB budget agreement. DOE advisors had long thought about budgets for the project, since the first Santa Fe meeting in March 1986. At the second Santa Fe meeting in January 1987, a group from the subcommittee had an informal meeting with David Padwa, formerly of Agrigenetics. Padwa urged that the genome project seek a budget large enough for Congress to get excited about, but not so large that it provoked resistance from within science. The lower threshold seemed to be $50-100 million. The HERAC subcommittee formally considered projections on 5-6 February 1987, at a meeting in the Denver Stouffer's Hotel. The DOE-OMB agreement is dated earlier, 18 December 1986. DeLisi had briefed OMB, on 5 September, getting tentative agreement (Hall, 1988). DeLisi was willing to listen to the subcommittee's advice, but the commitment to go ahead with a project, including its multiyear budget, was made before DeLisi knew what the subcommittee would say. The HERAC committee did not discuss which agency should lead at its final meeting to draft the report. This was pointed out to HERAC when it met to consider its subcommittee's report in March 1987. By April, when the report was released, Tinoco, as subcommittee chair, and Mort Mendelsohn, a member of the subcommittee and chair of HERAC, had canvased members to support language in favor of DOE leadership. Later interviews with members of that subcommittee revealed that at least 7 of the 14 had reservations, but agreed to the suggested language because they perceived inaction on the part of NIH; it was more important to them that the project get done than that their favorite agency do it. Despite the go-ahead from the bureaucracy, the job was not complete. There was the two-step congressional process. For any new action performed by the federal government, Congress must authorize it and appropriate funds for it. These processes are interdependent but distinct. Authorization falls to a pair of committees, one each in the House and Senate. The authorization committee differs for each major science agency, determined by an intricate set of jurisdictional rules negotiated over the years among committees. The authorizing committee structure is not parallel between the House and Senate, because the two houses have different boundaries, drawn in part to accommodate the individual interests of past and current committee chairs. The appropriations process, in contrast, is parallel in the two houses, and follows a relatively stable annual routine. The president's budget proposal is submitted in January, and referred to the appropriations committees. Except in unusual circumstances (as occurred once during the Reagan years, violating the spirit, if not the letter, of the Constitution), the House takes action first, and the Senate works from the House figures. If there are new programs under consideration, appropriations are theoretically, and in most cases actually, contingent on prior passage of an authorization statute. The appropriations committees are not

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to legislate, but rather to fund activities under rules set by other committees. The idea is that the authorization committees create programs and agencies, and set the framework, whereas the appropriations committees fund the actual operations. Agencies take the funds and do the job. The interpretation of these distinctions can be tight or loose, depending on the circumstances. (One of the nation's first large science agencies, the US Geological Survey, for example, was created and operated for years under a rider to an appropriations bill, without an authorization statute [Dupree, 1985; Guston, 1990].) To get the genome program started, DeLisi took $4.5 million in funds from the pre-existing fiscal year 1987 budget and reallocated them to the genome effort. Such limited "reprogramming" is standard fare, permitted by the appropriation and authorization committees within reasonable limits. For 1988 and later budgets, however, DOE needed support from its authorization committees and funding from the appropriations committees. DeLisi noted the need for congressional action in his first December 1985 personal note, and he had indeed held some meetings with congressional staff in 1986. There was little problem in the Senate, as DOE could probably count on strong support from Senator Pete Domenici and tacit approval of Senator Wendell Ford, the key figures on the authorization committee. Domenici also sat on the appropriations and budget committees. The problem was in the House. Staff of the relevant DOE authorization subcommittee in the House were getting mixed signals about the DOE genome initiative. They had read the generally negative response to it in Science magazine, and a few calls to contacts in molecular biology elicited both support and opposition. Eileen Lee was the resident biologist on staff, and was understandably uncertain what tack to take. The problem was further complicated by the politics of DeLisi's other biology programs. The committee staff on the majority party were generally disposed to support initiatives coming from DOE staff, who were after all paid to do just such planning, but DeLisi had problematic relations with at least one staff member on the subcommittee; it was unclear to the other staff whether they should expend the political capital to defend DeLisi on the genome initiative. 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 Biomédical Research to ask James Watson to testify against the DOE genome program. Eileen Lee arranged for Leroy Hood to testify before the committee, after having called O T A and several other contacts for suggestions. Hood agreed, oblivious to the political maelstrom swirling around him. At the 17 March hearing, he passionately projected a glowing vision of the genome project (US House of Representatives, 1987b). Hood strongly supported a new genome initiative and asserted a role for DOE, NIH, and NSF. Hood thus deftly ducked the troublesome question of which agency should hold the reins; Watson's threatened opposition

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never materialized. 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, nuclear plant workers, and least cost energy, but the genome program glided through the hearings unscathed. When the hearing was over, I escorted Hood (who did not know me then) to the elevators, through the maze in the Rayburn House Office Building. He asked, "Is that it?" I asked what he meant, He replied, "Do we get the money?" I remember shuddering and trying to keep from rolling my eyes. I said something about this being a step toward DOE's budget, but only the first of many. Hood dashed into a cab and headed for National Airport. He was a long way from home. The appropriations process was less troublesome than was authorization, and presented no major obstacles once the genome project had OMB approval. The DOE budget process for fiscal years 1988 and 1989 held true to the initial agreement with OMB, seeking $12 million and $18 million, respectively. It exceeded the initial agreement only in 1990, when it sought $28 million instead of the original $22 million. The seeds that Charles DeLisi planted found fertile soil in the Senate, but for very different reasons. Senator Pete Domenici was a staunch supporter of the national laboratories in New Mexico, although he long believed that they produced far less long-term benefit for the local economy of his state than they should. He convened a panel of influential personalities to discuss the future of the national laboratories on Saturday morning, 2 May 1987, in the US Capitol. The meeting featured former Congressman Barber Conable, head of the World Bank; Donald Fredrickson, former director of NIH; Ed Zschau, former California congressman and successful entrepreneur; Jack McConnell, director of advanced technologies for Johnson & Johnson; and the directors of several national laboratories. In the middle of the meeting, Domenici asked, "What happens if peace breaks out?" This was of concern because the vast bulk of work supported at the two laboratories in New Mexico was focused on nuclear weapon production and defense-related research and development. Domenici wanted to know how the immense research resources of the national laboratories could be better integrated into the local economy. He also sought a new mission for national laboratories that did not depend on cold war rhetoric, and that might move them into the growth areas of science, clearly including biology. There was no way that Domenici could have foreseen the events of late 1989, with the transformation of Eastern Europe, but it did seem likely that sooner or later the Reagan defense spending juggernaut would lose steam. Donald Fredrickson, then president of HHMI, suggested that the national laboratories might be encouraged to play a role in the human genome project. Jack McConnell took hold of the ideas discussed at the meeting and helped draft legislation that resulted in Senate bill 1480. By that time, Los Alamos

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was already beginning its genome program. This show of strong support from the Senate secured its future at a time of potential vulnerability. DeLisi and Smith anticipated many of the arguments that would be made for and against the genome project. What was missing from their thoughts, however, proved just as important: competition with NIH and acceptance among molecular biologists and human geneticists. DeLisi remarked later that "moving unilaterally was not my preference, nor did I consider it optimal." He met with great enthusiasm from Vincent De Vita, director of NCI, where DeLisi had worked before. The problem, from DeLisi's perspective, was that NIGMS was the NIH institute supporting the most relevant fields of science. DeLisi saw a hole, put his head down, and ran. He put the genome project on the public agenda, but not without getting tackled. The well-known NIGMS response was that if it were to be done, they should do it, but it should not be done . . . One of my choices was to use the NIH style of cautious consensus building. At times, perhaps most of the time, that is the best procedure; but in my judgment, this was not such a time. I made a deliberate decision to move vigorously forward with the best scientific advice we could muster (HERAC). I am quite willing to take the criticism, rational or not, that such movement provokes . . . I would have been far more timid about subjecting myself to . . . criticisms . . . if I saw my future career path confined to government. (DeLisi, personal communication, March 1990) Several technical elements are remarkable by their absence from early consideration. There was very little discussion of genetic linkage mapping—the first and arguably the most important step to making the project useful to the research community—and scant attention to the study of nonhuman organisms as either pilot projects or even scientifically important subjects to study. One could argue that these were outside the range of biology at DOE, but this strains the argument, because genetic linkage mapping is highly mathematical, requires systematic repetitive searches for DNA markers, and thus presents a great opportunity for exactly the sort of large group effort advocated by DOE. DOE strongly emphasized bacterial genetics immediately after World War II, and continued to support many groups working on nonhuman biology, so the de-emphasis of nonhuman organisms was perplexing. The initial thrust of the DOE program may have reflected the particular interests of the individuals resident in national laboratories, or perhaps it was a political judgment that support would be easier to sustain for an effort focused on human DNA but that avoided turf already well demarcated within NIH's territory. Whatever the justifications, the neglect of genetic linkage mapping and nonhuman genetics drove a wedge between DOE and much of the

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biomédical research community. The enthusiasm driving the DOE human genome proposal proved sufficient to keep it going, but it was a rough ride. D. Origins of the NIH program On 7 March 1986, as many Santa Fe workshop participants were returning to their laboratories, an article by Renato Dulbecco was published in Science magazine (Dulbecco, 1986). Dulbecco, a Nobel laureate and president of the Salk Institute, was highly respected for his quiet demeanor and careful approach to science. The article thus caught the attention of many, and generated a wave of discussions in the laboratories of universities and research centers throughout the world. Dulbecco argued that the early emphasis in cancer had been on exogenous factors: viruses, chemical mutagens, and their mechanisms of action. According to Dulbecco, cancer research was at a turning point so that "if we wish to learn more about cancer, we must now concentrate on the cellular genome." The nature of the connection to research specifically on cancer was a bit imprecise, but Dulbecco was not known as a crusader or self-promoter—quite the opposite—and one had to take note of any proposal coming from him. Like Sinsheimer, Dulbecco came to the idea from deliberately thinking big. He was preparing a review paper on the genetic approach to cancer. Although cancer is only infrequently a genetic disease in the sense of being inherited, the steps leading to uncontrolled cellular growth clearly involve changes in DNA. Dulbecco's argument for sequencing was that important questions in biology ultimately entailed the study of DNA, and extensive sequence information would be a tool of immense utility in the study of cancer. He saw the sequence as a reference standard against which to measure changes taking place in cancer. He argued that some reference standard was needed, because there was not then and never would be another standard available because of human genetic variation. This set humans apart from some other species, such as the mouse, for which there existed 150 well-characterized, genetically homogeneous strains. He saw the sequence information as itself generating new biological hypotheses to be tested by experiment (interview, Salk Institute, January 1987). Dulbecco's view of the central importance of sequence information was based on intuition, more an inchoate sense of what would feed into the most productive research strategies of the future than a concrete step-by-step argument. Indeed, he apologized for "hand-waving," but nonetheless asserted that sequence information would be an intimate part of understanding some of the most fundamental problems of biology: cancer, chronic disease, evolution, and development (interview, January 1987). Dulbecco noted the need for biology to encompass some collective enterprises of use to all, in addition to its extremely successful agenda of mounting small narrowly focused inquiries.

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By the summer of 1986, the rumor networks of molecular biology were abuzz with talk of the DOE human genome proposal. Dulbecco's proposal helped build the wave. News of the Santa Fe workshop was disseminated by those who attended it; those in the mainstream of molecular biology were beginning to take the idea seriously. As is often the case, Cold Spring Harbor Laboratory became the focal point. A landmark symposium demurely titled "The Molecular Biology of Homo Sapiens" took place at Cold Spring Harbor in June 1986, bringing together the giants of human genetics and molecular biology. There were 123 speakers and an audience of 311 reviewing the astonishing progress in two decades of human genetics (Watson, 1986). The genome project was a hot topic. Walter Bodmer, a British human geneticist of broad view familiar with both molecular methods and mathematical analysis, was the keynote speaker. He emphasized the importance of gene maps and the advantages of having a DNA reference dictionary. He concluded his talk by urging a commitment to systematic mapping and sequencing, as "a revolutionary step forward." Bodmer argued that the project is "enormously worthwhile, has no defense implications, and generates no case for competition between laboratories and nations." Moreover, it was better than big science in physics or space because "It is no good getting a man a third or a quarter of the way to Mars . . . However, a quarter or a third . . . of the total human genome sequence . . . could already provide a most valuable yield of applications" (Bodmer, 1986a). Victor McKusick, dean of human genetics and keeper of the "Mendelian Inheritance in Man" data, the gold standard compendium of human genetic disease, was next at bat. He summarized the status of the gene map and finished his talk by urging a dedicated effort to genomic mapping and sequencing (McKusick, 1986). He argued that "complete mapping of the human genome and complete sequencing are one and the same thing," because of the intricate interdependence of genetic linkage maps, physical maps, and DNA sequence data. He urged the audience to get on with the work, and pointed to the future importance of managing the massive flood of data to come from human genetics. Leroy Hood enthused about successful early experiments with automated DNA sequencing (Lewin, 1986a). Debate on the genome project came to a head at an evening session not originally on the program. Paul Berg, another Nobel laureate, was unaware of discussions at Santa Cruz and Santa Fe. He 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 symposium (P. Berg, personal communication, March 1990). Watson was aware of the Santa Cruz and Santa Fe meetings through his erstwhile laboratory co-worker and fellow Nobel laureate Walter Gilbert. He called Gilbert at Harvard, asking him to co-chair a genome

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project discussion with Berg. (W. Gilbert and J. Watson, personal communications, United Nations Educational, Scientific, and Cultural Organization conference, Moscow, June 1989). Berg arrived at Cold Spring Harbor to find himself co-chair of a session scheduled by Watson (Berg, personal communication, March 1990). The idea was to ventilate the proposals for a genome project. Berg led off by trying to channel discussion into the scientific merits of mapping and sequencing, and the technical approaches that might make the effort feasible. Gilbert briefly described the Santa Cruz and Santa Fe meetings, and then went to the essentials covered in his earlier letter to Edgar after Santa Cruz. He noted that DNA sequence was accumulating at only 2 million base pairs per year. At that rate, there would be no reference sequence for the human genome for a thousand years. He thought that could be reduced to 100 years with no special effort, but that a dedicated effort involving 30,000 person-years, on the scale of the space shuttle project, would produce a dramatic acceleration with enormous benefits. Gilbert began to write down numbers, large numbers that aroused the audience. Gilbert's cost projections provoked an uproar. At $1 per base pair, there could be a reference sequence of the human genome for about $3 billion. The audience was stunned. This was a huge budget. Gilbert seemed to be urging a commitment to a $3 billion project for sequencing alone, plus whatever it would cost to perform the mapping and other steps leading to sequencing. Berg called for discussion about whether it would be worthwhile to have the DNA sequence of the human genome, setting aside the cost issue. That idea did not fly. Botstein rose to the podium when he could no longer contain his volcanic energy. He asked that scientists "not go forward under the flag of Asilomar," taking a swipe at Berg (who played a prominent role in the recombinant DNA debate at Asilomar and elsewhere). Botstein presumably meant that molecular biologists should be aware of the political hazards of their endeavor from the outset. He noted that if Lewis and Clark had followed a similar approach to mapping the American West, a millimeter at a time, they would still be somewhere in North Dakota. Botstein emphasized that scientists were amateur politicians and should be wary of making grandiose political proposals. He voiced concern that researchers would become "indentured" to a mindless sequencing project. He closed by pleading that molecular biologists "maybe accept the goal, but not give away our ability to decide what is important because we have decided on the space shuttle" (D. Botstein, from tape recorded by C. Thomas Caskey). This broke the dam, and applause spread through the audience. Several speakers followed, including Maxine Singer, Leonard Lerman, Peter Pearson, Giorgio Bernardi, and others. Many reiterated Botstein's sentiments; others supported the notion of a sexy proposal that could attract public support but were ambivalent about its impact on science. David Smith from DOE spoke on the focus of the DOE proposal, but he was clearly on the defensive, even ceding in response

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to one question that perhaps DOE should not lead such an effort. His comments were largely swept away by the pent-up waters, although he noted that many people in the audience later came forward privately to indicate their support. Berg struggled intermittently and unsuccessfully to refocus the meeting on the technical and scientific aspects of the proposals. Molecular biologists were not enthused by the DOE Human Genome Initiative, perceiving it as a misguided bureaucratic initiative and, more importantly, as a direct threat to their own research funding. The dispute was covered by Roger Lewin of Science magazine, whose news articles were the first signals of the debate to come for many in science and in government (Lewin, 1986b, 1986c). The debate moved from the scientific Mecca, Cold Spring Harbor, to the political Gomorrah, Washington, DC. E. Seeds of the Howard Hughes Medical Institute program The first Washington genome show was produced by the Howard Hughes Medical Institute. It was a gala event held on the NIH campus, 23 July 1986. Watson, Gilbert, and Holly Smith sat next to one another cribbing notes in the Nobel laureates' corner. Donald Fredrickson, former director of NIH and then president of HHMI, introduced and closed the meeting, which was chaired by Walter Bodmer. The meeting turned into something of a love-fest for a redefined genome project. There were several brief presentations about the technologies and what was going on in US agencies and in other parts of the world, but mainly, it was a show of power, a battleship summit for molecular biology. The HHMI interest can be traced along several paths. HHMI staff credit Ray Gesteland and Charles Scriver as the people principally responsible for getting HHMI interested in gene mapping. Gesteland was a student in the Watson laboratory in the mid-1960s, and later became an HHMI investigator at the University of Utah. Gesteland suggested to George Cahill, HHMI vice-president for scientific training and development, that HHMI might support the ideas for systematic RFLP mapping proposed by the group surrounding Botstein at MIT. Botstein had independently raised the idea of RFLP mapping with HHMI trustee George Thorn. Ray White, then at the University of Massachusetts at Worcester, had by then contacted Botstein about RFLP mapping. White first heard about the RFLP mapping idea from Maurice Fox, under whom he had studied. Fox had been one of those who recruited Botstein to MIT. Fox met Mark Skolnick at a breast cancer meeting, and Skolnick infected him with the RFLP bug. He returned to Boston and called White, a former student, to urge him to call Botstein. White became enthused about a search for genetic linkage markers, and decided to commit his efforts toward finding out if it could work. Cahill recruited White to go to Utah. In the background was a desire among some HHMI trustees to strengthen ties to Salt Lake City, because of Howard Hughes's Mormon connections. White was attracted in part because of the incredibly rich and detailed

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Mormon pedigrees kept by the University of Utah that might be useful for clinical genetic studies. The large and well-documented families were a unique resource. They would be invaluable not only in the search for RFLP variants, but also for disease-gene mapping once the markers were in place. Indeed, the Mormon pedigrees had been a real focus of Skolnick's work. White commenced work to construct a genetic linkage map when he moved to Salt Lake City in November 1980. Charles Scriver, a Canadian, was a human geneticist of international reputation who served on the HHMI Medical Advisory Board from the late 1970s into the mid-1980s, a period during which the Institute's annual funding for biomédical research increased from just over $10 million to more than $200 million, following the death of Howard Hughes in 1976. Scriver was fascinated by the prospect of a human genome project, thinking primarily of the immense impact systematic mapping could have on clinical genetics. He was concerned about science, but also about the patients he saw each day in his Montreal genetics clinic. 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. Scriver became convinced that support of genetics databases was an essential next step, mainly through conversations with Francis Ruddle and later with White. Scriver worked to persuade the other members of the Medical Advisory Board. HHMI began to support the human gene mapping workshops held every two years, the Human Gene Mapping Library at its facility near Yale University, and the computerized version of McKusick's "Mendelian Inheritance in Man" database (Pines, 1986). A special meeting to discuss the HHMI human genetic resources was convened in Coconut Grove, Florida, on 15 February 1986. The focus was on how to manage the massive increase in information about genetic marker maps, locations determined by somatic cell genetics, and new D N A probes. There was also much discussion of the emerging broad outlines of the genome project. The Coconut Grove meeting took place two weeks before the DOE meeting in Santa Fe on sequencing the genome, but the two meetings were in separate orbits. Those involved with DOE planning overlapped only at the distal margin with those consulted by HHMI. They were only later brought together, in a shower of attention, under the umbrella of the Human Genome Project. Watson met with Fredrickson on April 1 to indicate his strong support for an HHMI presence in genome research. The July HHMI meeting at NIH grew out of the Coconut Grove confab. The July meeting was scheduled to gain information for a meeting of the Hughes trustees the following month. The focus on databases converged with dispute about the DOE proposal. In the wake of Cold Spring Harbor, there was a palpable tension surrounding the HHMI forum. The stage was set. Science journalists and others interested in science policy flocked to the show.

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The HHMI forum was a turning point, but the new direction was not entirely clear at the time. Roger Lewin opened his report of the meeting in Science with the observation that "The drive to initiate a Big Science project to sequence the entire human genome is running out of steam" (Lewin, 1986d). Hood asserted that massive sequencing was premature, and that the focus should instead be on improving the technologies. Yet the meeting was far from an outright rejection of the genome project; it proved instead to be a mechanism to rechannel its energies. Those attending the meeting agreed that the time was ripe to mount a special initiative in gene mapping and technology development, to redress deficiencies in the infrastructure undergirding genetics. This agreement was obscured by the more conspicuous disagreements about priorities and the proper style of leadership. Chair Bodmer could not contain himself when David Smith presented an outline of the DOE genome initiative. Bodmer interjected that the DOE proposal did not acknowledge the importance of genetic mapping. While Smith continued, a bit shaken, Sydney Brenner, seated at the meeting table, conspicuously passed a note to Gilbert and Watson that was read by those around them: "This is a retreat." DOE was on hostile turf, in the NIH homeland. Thus began a several-year period during which NIH and DOE jousted over the genome project. Indeed, which agency would prevail became the dominant topic of discussion about the genome project until well into 1988. There was an emerging consensus beneath the currents of tension, however. At the HHMI forum, the question imperceptibly shifted from whether to start a genome project to what it encompassed, how best to do it, and who should lead it. HHMI was presumed to be a neutral party in the dispute, a philanthropy with international reach and a commitment to shared informational resources in human genetics. HHMI was seen as a small partner to the federal agencies, rapidly responding when federal agencies could not, and filling in niches left vacant by the NIH behemoth. The shape of the HHMI program was becoming clear. A special presentation on the genome project was scheduled for the HHMI trustees in August. Maya Pines, a renowned science writer, was commissioned to describe gene mapping and sequencing, as background for deciding on continued support of basic genetics and a multiyear funding initiative for genomic databases. She posed a rhetorical question in the title of her piece, "Shall We Grasp the Opportunity to Map and Sequence all Human Genes and Create a 'Human Gene Dictionary'?" (Pines, 1986; also personal communication, August 1988). The answer was obvious. The proposal was approved, with George Cahill (later, Max Cowan) and Diane Hinton of HHMI having principal administrative responsibility.

F. The National Research Council report James Dewey Watson was busy behind the scenes, trying to put together the pieces for a project to his liking. Soon after he and Francis Crick discovered the doublehelical structure of DNA, Watson had become a power broker in molecular

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biology. He had a well-deserved reputation for speaking his mind, and then some. Within science, many found him obnoxious and his arrogance distasteful, but almost every molecular biologist learned to respect his biological intuition, and his ability to identify the truly important questions and to create an environment in which bright people could contend with the best groups in the world. Those who worked closely with him liked him, and accepted his brashness as impatience with anything not meeting his high standards. First at Harvard and later at Cold Spring Harbor Laboratory, he was an impresario of top-notch molecular biology. He used his status as "father of DNA" to get what he thought was needed to promote the best in molecular biology. Stephen Hall noted in a Smithsonian profile that "It is precisely Watson's candor and integrity, and his willingness to take the heat," that made his colleagues support him (Hall, 1990). Watson thought the nation needed a genome project, but not in the flavor proffered by DOE. He scheduled Berg and Gilbert's Cold Spring Harbor rump session on the genome project, and began to agitate for involvement of the National Academy of Sciences (NAS), arguing that it should mount a study quickly. His position was quite simple, and he stated it publicly at the HHMI meeting: "I am for the project, although everyone I talk to at Cold Spring Harbor is against it." He was following his intuition, again, against the stream. The NAS was a logical place to go. Devising a national strategy for mapping and sequencing clearly involved substantial scientific and technical issues, for which the National Research Council (NRC) at NAS was created around the time of the Civil War. Furthermore, the NRC process ensured a systematic assessment often absent from open-ended debate. A report from the NRC also carried special weight in Congress and in executive agencies. Convening a panel on the genome project was a considerable risk for genome proponents at the time, however, because sentiments were largely against the DOE proposal, which had dominated discussion to that point. An NRC report that equivocated or came out against a genome project would likely kill the idea in any agency, for several years at least. A positive report would not guarantee its success, particularly if it asked for extra funding, but a negative report would be an almost insurmountable obstacle. Plans to involve NAS congealed around the time of the Cold Spring Harbor meeting in June 1986. On 3 July, John Burris, executive director of the Board on Basic Biology at the NAS, wrote a short proposal to fund a small group meeting to discuss the genome project in August. A discussion of the options was placed on the agenda of the NAS's Board on Basic Biology at a meeting in Wood's Hole, Massachusetts, on 5 August. The meeting included DeLisi, Wyngaarden, Kirschstein, Watson, Cantor, Gilbert, Hood, White, Ruddle, Kingsbury, Frank Press (president of NAS), and several NAS staff. The board noted its support for physical mapping and expressly withheld its support from a massive sequencing program. It suggested that NRC form a committee to decide whether a genome project made technical sense, and if so what its goals should be. Burris prepared

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a proposal for approval within the NAS. Watson directed Burris to Michael Witunsky of the James S. McDonnell Foundation for funding of the study. McDonnell had a check to NAS within a week. Bruce Alberts was selected as chair. He had written an editorial the previous year that argued against "Big Science" in biology (Alberts, 1985); he had taken no position on the genome project, but would be seen as neutral or even inclined to oppose the genome project. Furthermore, his experience in writing a major textbook confirmed his talents to ensure that a report was written quickly and well. The original hope was to complete the NRC study in six months, or at least by mid-summer 1987. Several others identified as skeptics were appointed to the panel, notably Botstein and Shirley Tilghman. The committee was peppered with Nobel laureates: Gilbert, Watson, and Daniel Nathans from Johns Hopkins. Sydney Brenner was invited to represent the views of British mappers and sequencers, and John Tooze from the European Molecular Biology Organization to speak for the Europeans as a group. Cantor, Hood, and Ruddle represented different technical backgrounds, and McKusick, Leon Rosenberg (dean of Yale Medical School) and Stuart Orkin (whose laboratory had done seminal work on chronic granulomatous disease and several other diseases) represented human genetics. Alberts and Burris hatched a strategy intended to slowly build consensus, if that proved possible. The first meeting on 5 December 1986 was intended to give the committee a sense of the general lay of the land, with presentations from the US organizations with special genome-related activities (NIH, DOE, NSF, HHMI, and OTA), followed by a survey of activities in Europe. The remainder of the day was devoted to what the report should cover, and what further information needed to be gathered. Burris and Alberts elected to focus early meetings almost exclusively on technical background, and to postpone discussion of policy options and funding until the technical stakes were clear. The committee opted to bring in those with "hands-on" experience in the technologies under discussion, prudently divining that subsequent policy debates would be less acrimonious as the facts themselves settled many points. Early in 1987, the dynamics of the committee took an interesting turn. Walter Gilbert announced plans to form the Genome Corporation, to map and sequence the genome as a private company. He resigned from the NRC committee to avoid a conflict of interest. Gilbert had consistently proselytized for a fast-track genome project, and despaired of the government ever acting decisively to begin one. Several other committee members felt Gilbert was such a strong champion that he impeded consensus; his assertiveness elicited a backlash. His resignation paradoxically made it possible for those skeptical of the project to participate in redefining it. Donis-Keller, Gusella, and White, the giant figures of genetic linkage mapping, opened the next NRC committee meeting. The afternoon was a snapshot of the political landscape, with presentations from O T A and Wyngaarden.

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Maynard Olson had been appointed to replace Gilbert on the committee, a critical addition. Olson's work in physical mapping and large D N A fragment cloning was at the heart of the science under discussion, and he brought quiet but occasionally biting insights to the discussion. His philosophical approach and arid humor were well suited to illuminate conceptual muddles and to forge consensus on a technical base. It was Olson who noted the importance of having sufficient genetic linkage markers to help orient a physical map, thus cementing the union of genetic linkage and physical mapping. Olson also concisely articulated what might distinguish genome research from other genetics, an extension of the Sänger tradition of the MRC Cambridge laboratory, to illuminate function by analyzing structure in projects of increasing scale. The basic idea was to foster projects regarded as impossible, but just barely so, to stretch but not to break. Olson argued that projects should be considered genome research only if they promised to increase scale factors by 3-fold to 10-fold (size of DNA to be handled or mapped, degree of map resolution, speed, cost, accuracy, or other factors). By the end of the March meeting, it was clear that the skeptics had been converted by redefinition of the genome project's goals. The NRC panel was a microcosm of biomédical research, with panel members deliberately selected to be balanced. The panel's deliberation process for the first time systematically assessed the arguments for and against a dedicated genome project. The NRC committee surveyed the various technical components constituent to a genome project, and unified them into a scientific strategy. Alberts called the NRC committee "the most fun of any committee I have worked on" because of the talented people on it, the rapid learning process it entailed, the uncertainty of its outcome, and its direct impact on policy. The NRC report succeeded to a remarkable degree in setting a scientific agenda. This was the critical missing element from 1986 to early 1988. The direct impact of the NRC committee can be seen in the appropriations process for the 1989 budget at NIH, when chair Natcher referred directly to the report, particularly to its budget projections. The NAS report had one critical weakness, however: its recommendations about how the project should be organized. The scientists on the committee made little attempt to survey what the agencies were doing. Their interest and experience were not in science administration, but in science. Yet NIH, DOE, and Congress were percolating ideas about genome projects vigorously. The NRC committee members had informal contacts, principally with NIH, but there was no systematic attempt to gather information essential to credible policy recommendations. The federal bureaucracies are highly complex, and the political process of their interactions with one another and with Congress unpredictable. Having an impact on policy requires extensive knowledge about the workings of large bureaucracies, jurisdictional boundaries in Congress, and the histories of pivotal figures. One reviewer who was sent the penultimate draft of the NRC report was intimately

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familiar with the organization of science agencies, having directed one and worked with several others. He was appalled by the organizational options and conveyed his dismay to the committee and NRC staff, provoking a rewrite of the section on administration. Other reviewers had similar, although less pointed, concerns about the organizational options. Subsequent interviews with committee members indicated that the committee did not have enough data on which to base a recommendation, but felt it had to do so to execute its responsibility. There had not been a meeting to discuss project organization and administration, and last minute phone calls did not crystallize a solid consensus. The report was released recommending that there be one lead agency, but failing to specify whether it should be NIH or DOE (National Research Council, 1988). The report evaded the question of what would happen if Congress tried to choose between them. Congress would have to decide whether NIH or DOE should lead the genome project. If plans had been drawn from scratch, say in 1985, this lead-agency structure would clearly have been the preferable organization. By 1988, however, both agencies had multimillion dollar budgets, advisory committees, planning documents, and just as important, expectant constituencies and congressional patrons. If the committee intended that one agency should have a formal mandate to complete the genome project, with funding coming from several pots, then it would have been politically feasible, but effectively meaningless. How would NIH as "lead" agency decide how DOE should spend its funds, or vice versa7. If a lead agency controlled all the funding from one pot, then either the NIH or the DOE program had to be dismantled. Creating a program is considerably easier than burying one; the NRC recommendation proposed a politically hopeless task and invited open warfare between NIH and DOE. This is a war that would likely have killed the project NRC intended to promote. The NRC committee was undoubtedly expressing ambivalence about both NIH and DOE leadership, viewing the NIH commitment as feeble and late, and DOE's justification of the genome project under the banner of mutation detection as disingenuous. NIH's ability to mount a concerted effort was suspect, but molecular biology under DOE would likely be treated as a footnote to high-energy physics. DOE's vaunted ability to manage large projects seemed to derive more from the Manhattan project than from recent projects. DOE was getting a bloody nose from radioactive waste handling at its weapons production facilities. Equivocation on the policy options for bureaucratic organization resulted from failure to find a clear winner. G. Securing NIH appropriations James Wyngaarden played the central role in securing NIH's genome budget. President Reagan nominated him, and he became the NIH director in the spring of 1982. Wyngaarden came from Duke University, where he had been chair of its Department of Medicine for 15 years. He was highly respected as a clinician and

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human geneticist. He accepted the job with some reluctance, and stated this openly. In his confirmation hearings before the Senate, he noted, "I did not actively seek the p o s t . . . my acceptance of that honor is out of a sense of obligation based on an awareness of the vital role of NIH in biomédical research" (US Senate, 1982). In a 1988 interview, he said he accepted the position because of considerable worry about what might happen to NIH if a caretaker were nominated, instead of a person thoroughly familiar with biomédical research. The concern was rooted in a case example, that is, the damage wrought on Veterans' Administration health and research programs at the hands of a golf-playing caretaker. Wyngaarden first heard about the DOE genome program in London, at a meeting of the European Medical Research Council, 4-7 June 1986, when someone asked him what he thought about the plan to spend $3.5 billion to sequence the genome. He was shocked; the idea seemed to him "like the National Bureau of Standards proposing to build the B-2 bomber" (interview, NIH, 19 September 1988). At roughly the same time, Ruth Kirschstein, director of NIGMS, began to get feedback from DOE's March workshop in Santa Fe. DeLisi had invited an NIH representative to the Santa Fe meeting, but the invitation got lost in the deluge of mail that pours into the NIH director's office. DeLisi sent materials about the meeting afterward, as preparation for a meeting with Wyngaarden and Norman Anderson, but this got little attention until Wyngaarden returned from London. Wyngaarden then asked Kirschstein to convene a group to decide how NIH should respond to DOE. Kirschstein summarized the 27 June meeting of that group in a 2 July memo to Wyngaarden, noting that "first and foremost, while it is clear that the Department of Energy has taken, and will continue to have, the lead role in this endeavor, the NIH must and should play an important part." The bottom line was profound ambivalence, translated into NIH argot. The NIH group recommended that Wyngaarden focus the upcoming NIH director's Advisory Committee meeting in October on the genome project, in time to make plans for the fiscal year 1988 budget. They also noted the need for increased support of GenBank, the database funded by NIGMS to archive and disseminate DNA sequence information. The 16-17 October 1986 meeting of the Advisory Committee to the NIH director followed on the heels of the HHMI forum, and featured another all-star cast. The aura of Nobel laureates and aspirants suffused conference room 10 in Building 31, the same site as the HHMI forum. The format was more structured and the policy issues were becoming more evident. The main conclusions were that (1) NIH should eschew Big Science or a crash program, (2) the study of nonhuman organisms was important to make map and sequence data useful, (3) it might soon be feasible to sequence the human genome, and (4) information handling was already a problem (Office of Program Planning and Evaluation, 1987). As Joseph Palca noted in Nature, "The initial polarization of opinions has given way to a more

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constructive consensus that some concerted effort can begin without rending the fabric of biological science" (Palca, 1986). An NIH working group was appointed after this meeting. Wyngaarden chaired the working group, which also included the directors of several NIH institutes, centers, and divisions: Kirschstein, Duane Alexander (director of the National Institute of Child Health and Human Development), Betty Pickett (director of the Division of Research Resources), Donald Lindberg (director of the National Library of Medicine), and Jay Moskowitz (Program Planning and Evaluation). George Palade (Nobel laureate from Yale) was the lone outsider. Rachel Levinson became executive secretary of the working group, and the staff person most closely tracking genome activities. The group, which met in November and December, produced recommendations for enhanced support of databases and prepared two new research program announcements to be issued by NIGMS. Wyngaarden's early concern was to make sure that NIH had a major role in any large genome program that went forward, but he did not want to make any long-term commitments yet. He was in favor of the concept of the genome project "from the very start," but did not want to get too far in front of his constituency when there was so much dissension among NIH-supported researchers. He likened his position on the genome project to Lincoln's waiting for success at Antietam before announcing the Emancipation Proclamation, so as not to jeopardize Union support in Europe. His second analogy was to Roosevelt's delay in pushing the Lend-Lease Act until public sentiment supported the course he had already chosen (personal communication, 19 Sept 1988). Wyngaarden did support the genome project where it counted the most, in the appropriations process. In his summary statement to the House and Senate appropriations committees for fiscal year 1988 (in February and March 1987), he cast gene mapping in high profile. The description of the extra dollars requested did not match the scientific strategy being outlined by the NRC committee, hinting only at extensions of ongoing gene hunts, but it was still a new line item in the NIH budget. In his statement, Wyngaarden mentioned NIH's centennial, the urgency of AIDS research, and then the genome project. A straight reading of his text would suggest that gene mapping as a research priority was second only to AIDS. The NIH appropriation for genome research did not require a special authorization, as it clearly fell within the bounds of NIH's biomédical research mission. Unless someone in Congress objected, much could be done through appropriations alone. Fiscal year 1988 was one of the years when the NIH budget dance ignored the beat of the administration request, as Congressman Obey made explicit in his comments. Because the NIH director is part of the administration, however, Wyngaarden had to tow the administration line, defending the official administration requests before Congress. Testimony before legislative or appropriations committees is reviewed by officials in the Department of Health and Human Services (DHHS) and in the Office of Management and Budget. The ponderous

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bureaucracies have notoriously thin skins and brook little deviation from settled policy; in the absence of an explicit policy, new initiatives are viewed askance. However, the bureaucracy cannot interfere with Congress's authority to ask whatever questions it likes, and interfering with honest answers is a violation of federal whistle-blowing laws. Over the years, appropriations committees had devised a simple way to differentiate NIH's true priorities from the administration malarkey. Each year, they asked the NIH director what he would do with sums of money in addition to those requested, in $100 million increments. In his replies to the House Appropriations Committee forfiscalyear 1988, Wyngaarden asked for $30 million in genome research funds as part of the fifth $100 million increment, and another $15 million in the eleventh increment (of 12). Michael Stephens, staff on the House Appropriations Committee, recalled making some minor modifications, adding a few special projects, and stopping somewhere between increments 5 and 10 in NIH budget additions that year (interview, May 1989, US Capitol). The starting point, however, was guidance provided by Wyngaarden's blueprint (US House of Representatives, 1987a). After Wyngaarden testified in early spring 1987, Nobelists David Baltimore and James Watson briefed members and staff of the House and Senate appropriations committees. They were invited to speak informally as part of a series of meetings occasionally put together by Bradie Metheny of the Delegation for Basic Biomédical Research (affectionately known around NIH as the Nobel Delegation) . Baltimore and Watson met briefly before the session on 1 May to go over their remarks. The meeting included Congressmen Natcher and Conte, chair and ranking Republican of the NIH appropriations subcommittee, and also Representative Early, a subcommittee member and staunch NIH supporter of many years. Senator Weicker, who had been chair of the Senate appropriations subcommittee for NIH until late 1986, was also present (Metheny, personal communications, 17 and 31 May 1988). The principal aim of the meeting was to promote funding for AIDS research. Watson also supported adding $30 million to NIH's budget for genome research (Watson, 1990). The House responded to Wyngaarden by appropriating $30 million for genome research, the amount in the fifth increment. The Senate was less enthusiastic. Maureen Byrnes, staff to Senator Weicker, recalled that he was not as enthusiastic about the genome project as the House delegation. Other Senators, such as Harkin, were more enthusiastic but less senior; they did not get to set the mark (interview, June 1990). Michael Hall, staff director for the new chair, Lawton Chiles, got no clear signal of strong support, and put in a $6 million mark. The House and Senate bills went to conference committee for resolution of differences. The usual response in such cases was to split the difference unless one house or the other could convince the other side. In this case, the arithmetic mean of $18 million emerged from the House-Senate conference. The bill passed and became

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law. Because this was a year that Gramm-Rudman-Hollings recissions were effected, NIH had a final appropriation of $17.2 million for genome research at NIGMS that year. In private conversations, NIGMS staff estimated that $5 million of this was diverted from existing funds, and the rest was "new" money. An additional $3.85 million funded a new National Center for Biotechnology Information. The Regents of the National Library of Medicine (NLM) identified molecular biology as an important area in which the NLM's emerging expertise in electronic databasing would become increasingly important. An outside support organization, the Friends of the National Library of Medicine, took up the cause, and drafted a bill for Congressman Claude Pepper, an old friend of Fran Howard. Howard was a long-time NLM supporter with strong Democratic credentials, as sister of the late senator, vice-president, and democratic candidate for president, Hubert H. Humphrey. Howard had interests in medicine and was the widow of a prominent physician. The NLM bill was to establish an information management center to support the biomédical research and biotechnology efforts in the United States. It added a new NLM budget authorization rising to $10 million annually. Pepper held a moving hearing on the bill on 6 March 1987, at which the victims of genetic diseases testified. Pepper held a hearing before his own subcommittee of the Select Committee on Aging, which had no legislative authority. NIH, unlike many other agencies, is authorized through bills for three-year intervals as a rule, and 1987 was not one of the years when such a bill was in Congress. There was thus no logical vehicle to which the NLM bill could be attached, and so it stood alone. The NLM provisions werefinallyfolded into the NIH authorization bill that passed more than a year later. The appropriations committee acted before then, and appropriated $3.85 million for fiscal year 1988, with the understanding that it was to be spent toward the purposes specified in the languishing Pepper bill. NIH appropriations forfiscalyear 1989 were more or less routine. NIGMS requested $28 million for genome research. This was 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 17 October 1987 stock market crash, and the president's budget request held to this agreement. This was the one year under Reagan when the NIH request was taken seriously by the appropriations committees, and the requested amount was granted. There was one sidelight in the 1989 appropriations hearings, in that the NRC report was available (National Research Council, 1988). Representative Natcher led off a series of human genome questions by asking Wyngaarden how the $28 million genome budget request from NIH fit with the $200 million recommended by the NRC committee (US House of Representatives, 1988). This gave Wyngaarden an opening to explain that there would be higher budget requests in future years. The question, of course, was prepared by NIH staff and forwarded to the committee.

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NIH's appropriations for 1990 involved several complications. NIH forwarded a budget request to the DHHS and then to OMB, with a final request of $62 million. When the president's budget request came out of OMB, it sought $100 million for genome research at NIH. The $62 million was apparently increased to $100 million by divvying up some excess moneys left from removal of other programs during OMB review (John Barry, personal communication, May 1990). The increase surprised NIH, and signaled support for the NIH genome project high in OMB or elsewhere in the White House. Confusion surrounded the process, as this was a time of transition from the Reagan to the Bush administration, and it was not clear whether the support for genome research came from a carried-over Reagan appointee or from a new Bush player. In the end, it did not matter, as staff used the initial request level, known from NIH documents sent to the House Appropriations Committee, as the basis for deliberations. The final 1990 appropriation was $59.5 million after some minor cuts. During negotiations on the 1990 budget, Wyngaarden discussed the need to create a separate administrative center for the genome project, as the genome budget had become sufficiently large. He got agreement from the House to allocate the 1990 budget request to a new center that the DHHS would create by administrative fiat. The Senate agreed thoroughly the same budget figure, but left the funds in NIGMS. In conference, the report followed the House, creating a new budget center. This created a budget for the National Center for Human Genome Research. The 1990 NIH genome budget was subject to last-minute negotiations in a Senate looking for ways to fund new initiatives elsewhere in DHHS. One eleventh-hour proposal had a genome budget reduction from $62 million to $50 million, with the $12 million added to funds taken from elsewhere in NIH to fund programs for the homeless. This illustrated the twofold vulnerability of new programs at NIH. Activities that showed a rapid growth were highlighted by their percentage budget increases, tracked closely by appropriations staff, and NIH took up an increasingly high fraction of the discretionary funding in DHHS. DHHS disbursed over $300 billion in funds each year, but the vast bulk went to entitlement programs (Social Security, Medicare, and Medicaid) and were not subject to congressional appropriations or direct agency control. This made NIH's $8 billion budget a plump fruit to be squeezed for new initiatives in health and social services. The budget history highlights the illusory dichotomy between "new" and "existing" moneys. One of the most divisive debates within the biomédical research community was miscast in these terms, with supporters of investigator-initiated small grants contending that the genome project was carved from their province, while defenders of the genome project argued that the political attractiveness of the project increased the size of the pie without in any way cutting into other

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efforts. There was scant evidence for either view. Would the $87 million 1990 genome budgets at NIH and DOE have been appropriated elsewhere for biomedical research if there had been no genome proposal? Only those who actually made the decisions for the appropriations committees could answer such questions, but neither did they make the decisions on these terms, nor should they. It seemed highly unlikely that all these funds would have gone for biomédical research, given the drive to fund outside initiatives, so the pie for biomédical research was in all likelihood made larger. Critics did not bother to trace these details of NIH genome appropriations, but they might well have been concerned even if they did. Although it was clear that the project was started with "new" funding, could they be certain that congressional excitement about the genome project would not later dissipate, leaving behind a large tank to be filled with cash each year? Arguing in favor of the genome project on the basis of new money left it open to attacks on the same point. The potential of a scientific effort to outlive its justification, and to hungrily consume funds without accounting to collateral fields was hardly unique to the genome project. Indeed, it was far more likely with well-entrenched programs. But the genome project was more vulnerable to criticism because of the arguments made to garner support for the project initially. The NRC report used "new money" arguments (National Research Council, 1988). Its support of the genome initiative was explicitly contingent on new incremental funds. Taken literally, every dollar devoted to genome research would have to come from moneys that otherwise would not have been allocated to NIH. The genome budget was not given a great deal of attention in the appropriations process, and it was merely one of thousands of such decisions; in interviews with appropriations committee staff, it became clear that this was not a highly contentious part of the budget deliberations. It did not generate enough controversy to leave strong memory traces. They did not think of the genome budget as new or old, but simply as part of the budget suggested by the NIH director. The demand that each dollar for genome research come from a pot that would not otherwise have existed was meaningless in this context. Wyngaarden's priorities were in close harmony with the NRC committee and OTA, which had advisory committees that spent two years considering the wisdom of the investment. Genome funds were dispersed by the same mechanisms used throughout NIH, although toward more specific ends. The decision was analogous to deciding when a new territory was crowded enough to build roads and make rules about land and water use. The genome was largely virgin territory, but molecular biologists had begun to stake claims. When was the time to plan resources for the common good? The rhetoric of "new" funding distracted from the central question of how much of the NIH budget should go to collective efforts to establish an infra-

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structure for future genetics versus expansions of undirected research and other worthy ends. Initial funding in 1988 was just under 2% of a budget request increment (or 0.2% of the overall budget). Was Wyngaarden right in his decision to dedicate the funds to genome research? The answer hinged on whether the genome project filled an unmet need. The NRC committee and leaders of the biomédical research community identified weaknesses in the pattern of NIH funding: a neglect of genome-scale mapping efforts, inattention to development of new technologies, and insufficient funding of databases and shared resources. How much was it worth to fix those problems? If the genome project was worth doing, it should not have been made contingent on finding "new" moneys. The unfortunate semantics of new money failed to acknowledge that the genome project was a response to policy failure at NIH; that argument belittled the central importance of mapping, sequencing, and technology development, which merited a high priority on their own account. Appropriations for the DOE and NIH genome projects were the most significant policy actions. With NIH and DOE in separate governmental departments vying for position, there were only two places to forge a global strategy, in the White House or in Congress. Science policy in the Reagan administration was dictated largely by the budget process. The ritual until the final year of the administration was to propose unrealistically low NIH budgets, leaving room for increased funding in other areas. NIH was one of the most popular executive agencies in Congress, because of its medical research mission and a reputation for being well run and "clean," despite being thought of stodgy, overly cautious, and somewhat paranoid. For the first seven years under Reagan, Congress increased the NIH budget far above the requested amount. This effectively gave power over the NIH budget, especially new budget items, to the appropriations committees in the House and Senate. This contrasted starkly with the DOE budget, where the president's request was much more likely to be cut than augmented. For DOE, the "inside game" that DeLisi played, going through formal budget review in DOE and OMB, was much more important than for NIH. NIH's budget was an "outside game," played in the public arena of congressional politics—hearings, press reports, Capitol Hill meetings—in the hurly-burly centered in the Capitol. Article 1 of the Constitution gave Congress sole federal authority to tax and spend, and this was the principal source of congressional power, a power not wielded so forcefully by any other legislative body in the world. H. Congressional mediation between NIH and DOE Congress, through its Byzantine budget process, made the most important policy decisions by appropriating funds for both NIH and DOE genome programs. How the twin programs would coordinate their work, what direction they would take,

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how to integrate them into industrial policy, and whether and how to organize international collaboration remained unresolved. DeLisi and Wyngaarden promoted funding their respective agencies' genome programs, and the NRC set a scientific strategy and endorsed the need for a budget increment. Sorting through options to address the other policy questions fell to the congressional Office of Technology Assessment (OTA). Victor McKusick, invited by Gary Ellis and Kathi Hanna, presented the arguments for mapping the human genome at a summer 1986 biotechnology meeting at O T A . When news from the Cold Spring Harbor donnybrook was reported in the science press, it attracted the attention of several congressional staff. Lesley Russell, science staff to chair Dingell of the Energy and Commerce Committee, and I (then working at OTA) instigated an O T A assessment of the genome project. By pure happenstance, the O T A and NRC projects were approved within an hour of one another on 23 September 1986. O T A reports were distinct from NRC, in that they were written primarily by staff. A panel of experts helped with each project, but its role was advisory. I directed a team of exceptionally capable staff for the O T A project. Patricia Hoben, trained in molecular biology at Yale and fresh from a postdoctoral stint at the University of California, San Francisco, kept abreast of technical developments and wrote a clear and well-illustrated introduction to the technologies. Jacqueline Courteau had obtained her bachelor's degree in the history of science at Radcliffe and was in the final stages of securing her master's degree from the science writing program at Johns Hopkins. She gathered information about databases and repositories, and took primary responsibility for finding information about foreign genome plans (US Congress, 1988). O T A had little impact on the scientific agenda. It was not positioned to render a scientific judgment, whereas the NRC report clearly laid out a scientific strategy. Consensus on the strategy was a necessary precondition for the political decision about whether and to what degree a program should be funded. The NRC and O T A reports thus complemented one another. NRC performed the most important function by articulating a scientific program that captured the need for collective resources and focused efforts. O T A more systematically gathered information about bureaucratic moves and political choices, and acted as a wellinformed but neutral observer, expert in science policy but not science itself. When the NRC committee recommended organization under a lead agency, but neglected to say which, the mess was left for O T A to clean up. There was no avoiding the issue, since the interagency rivalries were well publicized and had long been known in Congress. In the House appropriations hearing for the 1988 budget, Congressman Obey asked several questions about genome research, stimulated by a Larry Thompson article in the Washington Post. Obey wanted to know why the DOE was

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proposing to lead such a project, to which Wyngaarden replied that DOE had legitimate interests in detecting mutations, but NIH was outspending DOE by a hundred to one in the relevant fields, and so NIH should . . . He was about to finish his policy recommendation when Obey interrupted, asking for further clarification of DOE's interest. Wyngaarden said to Nature magazine several weeks later that he thought it was presumptuous of DOE to claim leadership when it was spending less than $10 million a year in the area (Palca, 1987), but he was not pressed on what NIH should do about it. Leslie Roberts of Science magazine opened the "Research News" section of the magazine with a depiction of interagency squabbling (Roberts, 1987a), and captured the confused positions of scientists and administrators during this formative period. David Kingsbury of NSF emerged as a mediator, attempting to channel the conflict, first through the Biotechnology Science Coordinating Committee (formed principally to deal with interagency disagreements over the release of genetically altered organisms into the environment) and then through the Domestic Policy Council (a cabinet-level group) (Ackerman, 1988; Crawford, 1987b; Roberts, 1987a). Kingsbury's role meant that NSF had to stay out of the competition. NSF's policy position was quite clear for several years—it had no genome program per se, although NSF support for instrumentation and nonhuman biology was directly relevant. This was a position crafted in the bureaucratic netherworld where truth wears gray. Kingsbury's political base eroded quickly when he was implicated in a conflict of interest. The Department of Justice began an investigation related to his financial connections with Porton (Crawford, 1987a), a company with aspirations in biotechnology that grew out of the famed chemical warfare establishment in England. NSF was thus taken out of the ring for several years, and reentered only in 1989 with its instrumentation centers and plans for a plant genome research focused on Arabidopsis thaliana, a plant with conveniently small genome and short generation time. NSF thus entered the game late, at least as a declared contestant, but on a strong base in plant science and instrumentation. Interagency disagreements at the strategic policy level had little daily impact on those administering grants and sponsoring activities in NIH and DOE, or on those obtaining grants from the agencies. If anything, there were special efforts to cooperate because of the intense scrutiny by Science, Nature, and science writers in the major daily newspapers. Indeed, the degree of disruptive battling between NIH and DOE was less than other high-stakes turf disputes within the Public Health Service or DOE. Squabbling over the genome in the upper reaches of the bureaucracy, however, reached directly into Congress in the form of legislation. Senator Pete Domenici introduced S. 1480 early in 1987, the bill crafted by Jack McConnell and Domenici's staff to promote technology transfer from DOE-funded national laboratories. In the section covering thé genome project, Domenici's bill gave the

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secretary of energy a mandate to map the human genome. The energy secretary was to direct a research consortium dedicated to this purpose by chairing a national policy board on the human genome that included the NIH director, NSF director, the secretary of agriculture, and other officials. Domenici attempted to add the bill as an amendment to the trade bill under active consideration in the spring of 1987. His staff began to call other Senate and House committees with jurisdiction. Senator Chiles, chair of the NIH appropriations subcommittee and of the full budget committee, and Senator Kennedy, chair of the NIH authorization committee, were keys to the bill's prospects (interviews and discussions with Andrew Bush, Jack McConnell, Denise Greenleaf, Paul Gilman, Martha Buddecke, Rand Snell, Mona Sarfaty, Stephen Keith, 1987-1990). Chiles was generally accepting of NIH initiatives in biotechnology. By an irony typical of congressional politics, the genome project was linked to orange groves in Florida. Chiles's interest in biotechnology stemmed from a 1982 or 1983 meeting with his constituent, Francis Aloysius Wood, dean of the School of Agriculture at the University of Florida (interview with Chiles, 8 August 1988). Wood caught the senator's attention by describing how gene manipulation could move the frost belt 60 miles north. This meant more land could be devoted to cultivating a large crop plant of immense importance to Florida. Wood explained graphically how deletion of some genes that cause ice crystals to form on fruit, by creation of so-called ice-minus bacteria, might lower the temperature necessary to cause fruit damage. Changing the temperature at which fruit becomes damaged would reduce the annual worries of Florida's orange growers and would expand the territory acceptable for planting. When the Senate majority became Democratic in the 1986 election, Chiles became chair of the appropriations subcommittee for NIH. His main interest at NIH was biotechnology policy. The genome project became linked to biotechnology through Domenici's bill. The language used by scientists to justify the project also linked genome research to advances in biotechnology. When Domenici's bill first came to his attention, Chiles spoke with his legislative aide Rand Snell in a brief conversation en route from the Senate floor after a vote. The DOE dominance did not seem quite right; it did not seem fair to NIH that the DOE had the mandate and the energy secretary chaired the consortium steering committee. Patricia Hoben from OTA happened to meet with Snell on another matter, the competitiveness of US biotechnology. When she heard about the proposal, Hoben asked whether there had been outside consultation with university researchers. Hoben suggested that Snell call Bruce Alberts in particular, as chair of the NRC committee. Alberts was noncommittal, but did indicate that there was indeed ambivalence about DOE leadership and a strong feeling among some of the NRC committee that NIH should be the lead agency (discussions with Rand Snell, 1988, 1989, and 1990). Chiles refused to bite on Domenici's bill, and thus began a long process of negotiation that led

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to a Chiles-Kennedy-Domenici bill, S. 1966, that included a genome project provision modified from Domenici's, and that gave NIH and DOE joint leadership. Kennedy's staff also called their extensive contacts. Kennedy's position on the issue was critical as chair of the NIH authorization committee. Kennedy was an opinion leader in the Senate on health and biomédical research, matters far less partisan than most others in the same committee (which also had jurisdiction over labor-related issues). Committee staff Mona Sarfaty and Stephen Keith discovered the same ambivalence about genome research, and hostility to DOE leadership, among their contacts as had Snell. Lisa Raines, who worked closely with staff for Kennedy and Chiles, worked for the Industrial Biotechnology Association (IBA), a trade association for the larger biotechnology companies. To determine an IBA position, Raines surveyed her membership on the Domenici bill. The survey showed a strong consensus in favor of funding a genome project, but only under the aegis of NIH (Industrial Biotechnology Association, 1987). During the week, a storm of protest calls came into the offices of Domenici, Chiles, and Kennedy. The Domenici bill was dropped as an amendment to the trade bill. Domenici did not give up. He held a genome workshop in Santa Fe on 31 August 1987. It was Charles DeLisi's last day on the job at DOE, before he left to head a department of mathematical biology at Mt. Sinai Medical Center in New York City. Domenici pronounced his strong support for a DOE role in genome research in stentorian tones. Norman Anderson pulled out all the stops in a moment of zeal: I think so far as the man in the street is concerned . . . to say that here is the possibility at one shot of finding the cause of some 2,500 human diseases is really stunning . . . A century from now, as history books are written, the big projects that were important in this century are the genome project, and after it possibly space and then the atomic bomb (the order of those, I don't know). But the man who first proposes to do the genome project in the United States Congress is in history." (US Senate, 1987b) It was a good way to get attention. Domenici and Wyngaarden came to loggerheads. At hearings on Domenici's bill on 17 September 1987, Wyngaarden articulated his desire for what might be paraphrased as "the mission and the money, but not the management." This came during an interchange with Domenici in the question-and-answer session following Wyngaarden's testimony: Domenici: If you were assured that it was not the intention of the legislation to in any way denigrate or detract from your ongoing activities,

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would you recommend that the United States of America have a policy of mapping the human genome as expeditiously as possible? Wyngaarden: Yes, sir. Unequivocally, yes. Domenici (several exchanges later) : If Congress wants to do it, how do we do it? Just give the NIH more money under their existing program and give DOE some more money . . . Wyngaarden: I think that is a very good way to do it. Domenici: And would it get done? Wyngaarden: Yes. Domenici: Without any changes in the law? Wyngaarden: I think so. [James Decker, representing DOE, concurred with Wyngaarden.] Domenici went on: I love you both and I think you are great. But I absolutely do not believe you. I believe it would get done. But I am quite sure that it would not get done in the most expeditious manner, because I do not think you would be charged with doing that. I do not think you would send up any requests of a priority nature with reference to it, because you do not have enough money to do what you are doing. And if you tried to send up the request, it would be thrown in the waste basket at OMB . . . (US Senate, 1987a) Wyngaarden and Domenici locked horns for several minutes more, over definitions of what the other had meant, but it was clear that the basic issue was, at base, one of mutual distrust between the legislative and executive branches of government. Congress, in the person of Domenici, did not trust the agencies to act quickly, and the agencies, principally in the person of Wyngaarden as supported by Deckers, did not want to have Congress "crossing the i's and dotting the t's [sic]," and tying internal priority setting and budgeting processes in knots. Neither side could win decisively, and the policy process unfolded over many months of thrusts and parries. Within NIH, and among the power brokers in molecular biology, there was a division of opinion about NIITs role. NIGMS director Kirschstein articulated one position strongly. Kirschstein was particularly concerned that the genome project not become a political juggernaut that could endanger small group pursuit of basic genetic knowledge, for which NIGMS was the largest source of funding in the world. On 29 May 1987, NIGMS issued two new announcements for grants in mapping and computation to demonstrate a special willingness to support such work, but did not formally set aside funds for this purpose. Kirschstein had earlier canvassed all the NIH institutes to find out how much was being spent on grants that involved gene mapping or DNA sequencing, producing a figure of $313 million in fiscal year 1987, of which $90 million was for work on humans. In her own institute, the grant officers spent days poring over

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their grant portfolios to come up with the figures, revealing the energy with which Kirschstein worked to support her position that NIH was already acting aggressively. Kirschstein argued that the NIGMS announcements were "not exactly business as usual, but not highly targeted either." Rachel Levinson, staff to Wyngaarden working on the genome policies, corroborated this, arguing there was no need "for a concerted effort because it is not new. Every institute has work related to mapping and sequencing" (Roberts, 1987a). This was likely intended to assuage fears of a major shift in policy that could threaten investigator-initiated research, but it backfired. The message heard by opinion leaders in molecular biology, including many Kirschstein supporters, was that NIH thought it was doing all it needed to do. Many scientists saw this as failure to appreciate the need for collective and deliberately orchestrated efforts to construct 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. In interviews with dozens of molecular biologists, including Berg, Baltimore, Botstein, Watson, Gilbert, Hood, and others, NIH's official position was cited as missing the point of the genome project: to fill a need for concerted and focused efforts to create common resources. Kirschstein took this position because she saw it as essential to placate those worried about the genome project's impact on other basic genetic research and to defend NIH against incursions from DOE, but it set the genome project on a course away from NIGMS. NIH's first dedicated funding for genome research came in December 1987, when President Reagan signed the 1988 appropriations law (two months into the fiscal year). The law gave $17.2 million to NIH. Wyngaarden convened an ad hoc advisory committee, which met 29 February-1 March 1988 in Reston, Virginia. The meeting took place only a few weeks after release of the NRC report. The ad hoc committee was chaired by David Baltimore, who had written against the Big Science genome approach (Baltimore, 1987). The ad hoc committee made recommendations closely following the NRC blueprint. Watson urged that an esteemed scientist be appointed director of the NIH genome efforts. He stated later that "I did not realize that I could be perceived as arguing for my own subsequent appointment" (Watson, 1990). One pointed exchange took place between Kirschstein and Watson at an OTA workshop on costs of the genome project in August 1987. The meeting was chaired by Berg, and was intended to ferret out the strategies for genome mapping and sequencing by forcing a discussion of budget items that would be of concern to Congress. At one point, the discussion digressed to discussion of management issues. Kirschstein and Watson clashed over the need for assertive planning by NIH. Watson wanted powerful direction; Kirschstein argued for the wisdom of the investigator-initiated grant mechanism. Watson, interviewed after the OTA meeting and asked if he were willing to be the "tsar" that he thought necessary, said "I

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can't think of a job I'd like less" (Roberts, 1987c). He later called many others to find someone willing to take the job, but none able was willing (and needless to say, none willing was able). Wyngaarden was beset by disagreement about the proper style for promoting genome research, with Kirschstein and Watson articulating incompatible options, exemplifying a rift within the biomédical research community. Wyngaarden had to choose. As preparations for the Reston meeting were under way, Watson and Baltimore met with Wyngaarden on 17 December 1987 to discuss AIDS research and the human genome. Watson expressed his views that NIH had missed the boat on the genome project, and clearly stated his opposition to Kirschstein's stay-the-course approach. With the backing of an NRC report presenting a coherent scientific plan and with congressional signals auguring well for substantial appropriations, Wyngaarden chose the high road. The OTA report was used mainly in two hearings on the NIH and DOE programs, held in April and June 1988. Both hearings centered on the remaining policy question: Which agency should lead the effort? The Chiles-KennedyDomenici bill, S. 1966, came out of Kennedy's committee and was passed 88 to 1 in the Senate. It was referred to two committees in the House. In its final form, it created an interagency task force to tackle the genome. NIH and DOE were faced with two options: conspicuous cooperation or a strong likelihood of legislation that embodied Congress's preferred framework. The agencies opted to sign a memorandum of understanding in hopes of staving off House action on the bill, having reached a tacit agreement with staff from the Energy and Commerce Committee. The content of the memorandum was less important than agreement on a process for joint planning, forcing NIH and DOE to face the political reality that the other would also have a genome program. Congress would be on the watch for interagency bickering. Until the release of the NRC and OTA reports, and indeed for months after, both NIH staff and DOE staff appeared to believe that Congress would somehow designate their agency the genome leader. It is not clear, however, how they thought this might happen. In conversations with congressional staff, DOE and NIH representatives voiced disappointment that NRC and OTA ducked a tough call, yet there was no call to make. The existence of twin genome programs was set as soon as DOE got its first authorization and appropriation through Congress and as long as NIH wanted a role. The only events to prevent the birth of two programs would have been the death of both agencies' efforts in a bout of internecine warfare, a preemptive strike by NIH in the spring or summer of 1987 when the DOE authorization was vulnerable, or NIH's abdication to DOE leadership. Given that both agencies had assembled the political support requisite for a genome program, and were unwilling to accede to the other's research planning apparatus, Congress could only muck up the works by trying to pick which should have control. If it came to outright battle, blood would have flowed onto the field.

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Each agency might have attempted to launch its own program, while urging destruction of the rival agency's aimed at the same target. This was an extremely dangerous course; the only out was a truce. Remarkably, what developed was a true joint effort. I. Maturation of a joint five-year plan Wyngaarden designated Watson an associate director of NIH in October 1988, heading up the new Office of Human Genome Research. Watson hired Elke Jordan, former associate director under Kirschstein and erstwhile molecular biologist from Matthew Meselson's laboratory, when it was down the hall from Watson's in the 1960s. Watson also hired Mark Guyer, a bacterial geneticist who worked at Genex Corporation and then joined NIGMS staff. Jordan and Guyer were the first full-time genome staff at NIH. Congress remained concerned about the interagency politics of genome research. In questions about funding an NIH genome program for the 1989 budget, appropriations subcommmittee chair Natcher also asked what agency should take the lead. Wyngaarden was unequivocal and direct in his answer, saying, "I think NIH is the appropriate agency" (US House of Representatives, 1988). The hearing took place within weeks of the NIH ad hoc advisory committee meeting in Reston, Virginia. Wyngaarden's strong support for NIH leadership on the human genome project in Reston and before the appropriations committee were the clear statements of purpose that had been eagerly awaited by opinion leaders in molecular biology. The NIH program began to pick up steam. NIH and DOE signed the Memorandum of Understanding in the fall of 1988, to avoid the structure imposed by the Chiles-Kennedy-Domenici bill. This ratified an existing informal arrangement, but grew into substantially more, as bona fide joint planning began to seem advantageous to both agencies. Throughout 1988 and 1989, staff at NIH and DOE met to discuss how to carry out the terms of the memorandum. They finally settled on appointing a joint NIH-DOE advisory group, comprised of members taken from the advisory panels for each agency's outside advisory group. Rand Snell, from Chiles's personal staff, and Michael Hall, staff director of the NIH appropriations subcommittee, inserted language into the appropriations conference report, a document that accompanied the bill to explain congressional intent. The conference report expressed concern about interagency coordination, and stipulated that NIH and DOE report back to Congress "the optimal strategy for mapping and sequencing the human genome" in time for the 1991 budget cycle (US Senate, 1988). Watson was insistent on responding with a "serious" planning document. The impetus was given a further boost at a joint NIH-DOE planning retreat at the Banbury Center, Cold Spring Harbor Laboratories, 28-30 August 1989.

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For many months, an informal coordinating committee met monthly to make the logistical arrangements among the various agencies and organizations. Diane Hinton of HHMI, Mark Guyer of the genome office, Irene Eckstrand of NIGMS, John Wooley of NSF, and Ben Barnhart of DOE formed the core, and others attended occasionally. The loosely coordinated plans formed by this informal group began to gel when combined in a retreat setting with the powerhouses of genome research. The advisory committees for both DOE and NIH were convened with agency staff at the first Banbury retreat. A few experts in genome research also were invited. Norton Zinder, chair of the NIH's genome advisory committee, organized the discussion into task areas, asking work groups to specify goals and means of achieving them. Much of the meeting focused on how to construct physical maps. Maynard Olson and others concentrated on the idea of using short stretches of DNA sequence as unique "tags" that would serve as landmarks on the chromosomes. Laboratories using different methods could thus compare results directly. Earlier that year at the Cold Spring Harbor symposium, Cassandra Smith had raised the idea of using sequence information as an index. Olson and Botstein again raised it at Banbury, as a common reporting language for both physical and genetic linkage mapping, acting as a bridge between them and also as a link to DNA sequencing. It was seized upon quickly, given the name Sequence-Tagged Sites (STS), and a group agreed to prepare a paper for Science (Olson et al, 1989; Roberts, 1989a). NIH and DOE staff expected to prepare a five-year plan going into the meeting. Barnhart and Zinder thought that no specific planning draft would emerge from the retreat (Palca, 1989), but proved themselves wrong. The shape of the plan became considerably clearer after the retreat, and staff decided to focus the report by adopting the goal-oriented format (US Department of Health and Human Services and US Department of Energy, 1990). The human genome project began to consolidate in late 1989. DOE plans remained on course, with little change in the administrative structure (despite an increasingly felt need for more staff). Secretary of Health and Human Services Louis Sullivan created the National Center for Human Genome Research (NCHGR) in October 1989, moving it out of the NIH director's office and giving the project administrative authority to spend federal funds (under direction of a council to be appointed for the center). Staff efforts focused on peer review of grants and the first genome centers at NIH, and into organizing genome efforts: chromosome-specific meetings; workshops on cloning large DNA inserts; and working groups on DNA sequencing, informatics, and social issues. Upper management, particularly Elke Jordan and Mark Guyer at NIH and Ben Barnhart at DOE, focused on preparing the joint five-year plan for Congress. The two oversight hearings in October and November 1989 gave way to appropriations hearings in both houses of Congress in the spring of 1990, and another oversight hearing in July.

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The process for reviewing grants became more routine for genome proposals, although grant reviewers continued to disagree about the specific goals and scope of the project. NIH established standing review panels for genome grants in mid-1990, the mark of a permanent NIH entity, and the advisory council charter was approved. Watson declared that the genome project should officially begin with fiscal year 1991, since the first few years had been dedicated to getting organized. J. A counter-revolution fueled by grant competition Strong crosscurrents hit the genome project as it lifted off the runway. The battle over the 1991 budget was a severe test of support for the project. The early stages looked promising. NCHGR asked for $108 million (upfrom$59.5 million), and the genome office at DOE asked for $46 million (up from $26 million), getting within close range of the aggregate $200 million plateau projected in the NRC plan. If both agencies got their requested budgets, the budget target would likely be reached in 1992. At that point, the high-growth phase would stop, leaving the programs on firm footing and less salient as targets for budget cuts. The first stages went smoothly. The budget requests survived DHHS and OMB review, in fact drawing strong support; however, a storm was brewing outside. The first inkling of trouble was the House appropriations hearing in February. Congressman Obey took Watson strongly to task for failing to account for how genetic information might be abused by insurance companies and employers. The tone of other questioning was less pointed, but the general impression was that the committee was looking for loose change, and would carefully scrutinize programs with either large budget increases or heavy reliance on research centers. The 1990 budget was the first at NIH that included funds for genome centers. There were sufficient funds for three or four and the 1991 budget request anticipated nine such centers. Rumors that the budget was in trouble reached NCHGR a week before the House subcommittee was to consider the final budget marks. Watson and Jordan went to Capitol Hill to meet with Michael Stephens, chair Natcher's aide responsible for the NIH budget. Extremely discouraged, Watson threatened to resign in a stormy meeting. Stephens and Natcher were unimpressed. The genome growth phase coincided with a drop in the proportion of grants funded during each review cycle. The drop stemmed from several policy decisions taken by NIH years before. In the 1980s, NIH began to implement a policy to extend the length of the average research grant, in response to criticisms that investigators were spending far too much time applying for grants. In the standard three-year cycle, an investigator would work for a year, then begin to write grants during the second year so that there would be funding when the third year ended. New proposals thus benefited from only a year's new data, investigators

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spent an inordinate amount of their time as supplicants for money, and the system encouraged a proliferation of proposals to hedge bets against uncertainty. If the grant period were extended to five years, investigators should be able to work relatively worry-free for three years, and would have to apply only 60% as often. This would, in theory, increase productivity and reduce uncertainty and anxiety. Lengthening the grant period actually meant, however, that the amount of new funding available each year would be diminished. Commitments for future years would increase as a fraction of the budget, leaving a smaller pot available for new grants. In the long run, fewer applications would be expected, as the stability of thefive-yearcycle caught hold. To an investigator applying during the transition period, however, the odds were noticeably worse. The effect of longer grant commitments was exacerbated by an increase in the average yearly award, due to inflation of research costs. From 1982 to 1990, the average length of award increased 23%, from 3.3 to 4.3 years, and the average commitment for each grant increased from $107,000 to $208,000, a 94% increase. This reflected both the greater length and higher annual costs. The number of grants actually funded dropped from one-third to one-fourth of the total applications. This decrease was felt directly by the research community, where it was transmuted into immense frustration. Although new scientific vistas were opening in almost every field, they confronted worse funding prospects. Some investigators went hunting for a scapegoat. There was some sniping at AIDS, which accounted for roughly 10% of the NIH budget, but invective was also directed at the genome project. The genome project was vulnerable, as it lacked a disease constituency and its bureaucratic base was as yet small and feeble. Centers of all varieties were under attack throughout NIH, as those supported by small independent grants felt squeezed. The House appropriations committee responded by setting a cap for all centers at NIH, and called for review of the proposed genome centers. They gave NCHGR $66 million for fiscal year 1991, enough to carry forward its previous commitments, but with few funds for new grants or centers. They also left an additional $18 million available for genome research, but gave authority to spend it only to a permanent NIH director. There was no permanent NIH director, however. Wyngaarden had resigned to join the Office of Science and Technology Policy (OSTP) in July 1989, and his position remained vacant until April 1991. The House action was a slap both at the administration for failing to appoint an NIH director and at Watson, with one-fourth of his budget held hostage to a political process well beyond the control of the NCHGR office. Opposition began to organize into letters and letter-writing campaigns directed at Congress and the higher reaches of biomédical research administration. They centered on the NIH role in particular. Leslie Kozak, a disgruntled researcher at the Jackson Laboratory, sent a letter to Senator William Cohen of Maine date 9 January 1990, stating that the genome project "threatened the quality and

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conduct of our nation's health-related research effort." On 26 February, Martin Rechsteiner of the University of Utah wrote letters to acting NIH director Raub, Presidential Science Advisor Bromley, and Senators Gore and Kennedy, which opened, "The human genome project is mediocre science and terrible science policy." Rechsteiner's letter questioned the origins of the project in DOE, warned of sequencing drudgery, challenged the value of sequencing the human genome, and urged that the project be curtailed to reduce divisiveness within biology. These same offices began receiving a string of letters, some of which included copies of the Rechsteiner letter, indicating that it was being used as the basis for a letterwriting campaign against the genome project. Ironically, Rechsteiner cited Alberts's editorial in Cell, which warned of the dangers of Big Science in biology, apparently oblivious to Alberts's role on the NRC panel that crafted the genome strategy. A series of other letters began to pass through the electronic mail networks in biology. One such letter by Michael Syvanen and others urged that scientists write to their own congressional representatives to kill the genome project. In mid-July 1990, an informal survey of the target offices indicated that they had received about 30 or 40 letters on the genome project, running 4 or 5 to 1 against it. (By comparison, the Super-Conducting Supercollider generated about 10 times more mail, in more or less the same ratio.) When genome supporters got wind of this, they began to send letters of their own in support, so by mid-August the odds were evening up. The controversy became most public with the publication of a letter from Bernard Davis and his colleagues in the microbiology department at Harvard Medical School, in the 27 July 1990 issue of Science (Davis et al, 1990). This letter made clear that the competition for research funds drove opposition to the genome project. Davis saluted the redefinition of the genome project by the NRC, but averred "it is doubtful that [genome projects] could generate the strong political appeal of the original proposal." The letter urged that such sequencing as was done be targeted at "units within the chromosomes that have functions." Finally, it hit the center of contention, by asserting that work on model organisms lacked "obvious justification for insulation from competition with other kinds of research," signaling that the real basis for suspicion was that genome research was protected from peer review, or escaped comparison to other research priorities. Given that genome grants were being channeled through standard NIH procedures, contention actually centered on whether genome research deserved a special program and special funding. The Davis letter agreed that some elements needed centralized management, but thought the genome office was getting too big a slice of the pie. The letter asked for a réévaluation of the project, and questioned whether the project merited funding "at a level equivalent to over 20 percent of all other biomédical research," although the origin of that estimate was not specified. If the source of concern was the 1991 budget, between $60 and 70 million of the $108 million

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request was uncommitted, amounting to 4 or 5% of the funds slated for new and competing grants at NIH that year. Five percent was the figure Davis himself used later in congressional testimony. The Davis letter made clear that 20% (or 5%) was too high, but also noted that 0 was too low. How much was the right amount, and how long should NIH take to construct the genetic infrastructure? Reaction against the genome project was precipitated by scarcity of dollars for new and competing grants. The House appropriations subcommittee was indeed attempting to preserve all it could for investigator-initiated grants, but this was not due to the letter-writing campaigns. Subcommittee staff learned of the campaigns only when Watson told them about them, and when Leslie Roberts of Science called to ask if the Rechsteiner and Syvanen campaigns were the reasons for NIH genome budget cuts (Roberts, 1990a). The campaigns failed to target members of the appropriations subcommittees in either the House or the Senate, thus violating the first principles of interest group politics. The Zeitgeist of resistance to funding other than small grants was the motivating force behind the budget cuts, and did the work that those hoping to lobby failed to do. The issue blossomed to full flower at an 11 July 1990 hearing before Senators Ford and Domenici. The Subcommittee on Energy Research of the Senate Energy and Natural Resources Committee held its second set of hearings on the genome. Matthew Murray, a former student in the Hood laboratory than working at the Lawrence Berkeley Laboratory, was doing a short internship in Domenici's office. The idea for a hearing began as a survey of the DOE program. The hearing provided DOE an opportunity to announce that Lawrence Livermore would become the third designated center, joining Lawrence Berkeley and Los Alamos in the DOE genome constellation. As hearing plans progressed, however, Ben Cooper, staff director for the subcommittee, wanted to let genome critics have a voice. He believed their opposition was largely due to misunderstanding of the budget dynamics, and he wanted to give them a chance to speak and be questioned. Martin Rechsteiner and Bernard Davis agreed to testify. Domenici was a chief Senate figure in the budget summit meetings to hammer out a strategy to reduce the federal deficit in conjunction with President Bush, OMB Director Darman, and other congressional leaders. A budget summit meeting was scheduled in conflict with the original hearing time, and the hearing was rescheduled for an earlier time. Staff called all the witnesses, but could only leave a message for Rechsteiner, who had already left Utah. Rechsteiner entered the hearing room at noon, two hours before the time he thought the hearing would start, only to find that it had adjourned minutes before. I greeted him and ushered him to the front, where Domenici was giving posthearing press interviews. The hearing began as a showcase for the DOE program, but ended with Davis summarizing the Science letter questioning the urgency of the genome project, and asking for a réévaluation of its funding levels. Domenici responded with a passionate defense of the genome project: "As someone who is supposed to

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know all about the federal budget, I am rarely in a position where I can look at a program and say that it is exciting enough to keep somebody like myself energized while we are trying to reduce the deficit, but I have found one here" (Mervis, 1990). Domenici had strong praise for Leroy Hood, who focused his remarks on the commercial spin-off of genome research, although using some inaccurate financial figures about Applied Biosystems, Inc. (Mervis, 1990). The fiscal year 1991 budget was eventually passed only after a bitter partisan debate. In the end, the critics were heard, but NIH's budget was cut not because of genome critics as much as because of Congressman Obey's concern about how genetic information would be used. The budget passed by the House had $66 million for the genome center at NIH, with an additional $18 million to be freed from a special fund in the NIH director's reserve only if a permanent NIH director were appointed. The Senate appropriated the full $108 million requested in the president's budget. The final budget for NIH was the arithmetic mean of the House and Senate figures (without the set-aside amount in the House version), less some funds taken out in budget adjustments for all of NIH. The final figure was estimated to be $87.5 million for NIH. DOE's budget had smooth sailing, despite an unusually nasty year in the budget process. Its program was appropriated at the level requested, less only minor adjustments, with $46 million plus an additional $1.8 million in construction funds. K. Origins of the program on ethical, social, and legal issues The tone of the debate broadened from scientific issues to social implications late in 1989. A 9 November hearing before Albert Gore's Senate Subcommittee on Science, Technology and Space touched on international data sharing, but concentrated even more on the social impact of the genome project (US Senate, 1989). Congressional concern about social implications of genetics, and Gore's interest in particular, was long-standing, having been raised in a series of hearings on human gene therapy and reproductive technologies in the early and mid-1980s. Gore had chaired the House subcommittee that convened those hearings. He found that genetics was especially worrisome to the general public, and shared some concerns. It was not an antiscience stance, but an inchoate discomfiture with the prospects of meddling in something so fundamental as a person's genes. Gore's interests continued unabated when he moved from the House to the Senate in 1985. His first opening to air those concerns came when he became chair of the Science, Technology, and Space Subcommittee four years later. Hence the hearing on the genome project. A highly public debate about the genome project combined with conspicuous successes in finding the cystic fibrosis gene to arouse the issues from dormancy. The genome project would clearly result in much greater knowledge

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about human genes and would produce technologies to make genetic tests faster, cheaper, more accurate, and applicable to many more diseases. The issues of genetic discrimination in employment or insurance, and the prospects of backdoor racism through genetic screening and testing were more urgent because of the genome project. The genome project was formulated just as a run of books came out on public policy related to genetic screening, genetic testing, and genetic counseling (Holtzman, 1989; Nelkin and Tancredi, 1989; Rothstein, 1989; US Congress and Office of Technology Assessment, 1988). There had been a rancorous debate about the proper use of AIDS testing during this same period. These factors generated a renewed public concern about how genetic tests would be used. Watson quickly saw the need to confront these issues directly. He announced plans to dedicate some funds to investigate the ethical implications of genome research at his inaugural press conference, upon appointment as associate director of the Office of Human Genome Research in October 1988. He further elaborated these ideas in a speech at the University of California, Los Angeles, in December 1988. He foresaw a need to educate the public through courses, books, and public meetings, and to devise new means to think through the consequences of genome research and anticipate public policy needs. His argument was that although what the genome project was doing was "completely correct" to go after 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 "we certainly don't want to mislead Congress" (Watson, 1988a). Watson's commitment was clarified at several subsequent meetings, and the NIH advisory committee agreed to devote 3 % of the NIH genome budget to fund the activities of a working group chaired by Nancy Wexler and to support a research program (US Department of Health and Human Services and US Department of Energy, 1990). The unprecedented program on ethical, legal, and social implications of genome research was prominently featured in Watson's opening statement before Gore's science subcommittee. Robert Wood, acting director of OHER, spoke after Watson. As Wood was reading his prepared statement into the microphone, Gore turned to his staff and asked if DOE had made a similar commitment of funds to the study of ethical and social implications of the genome project. They were not sure, but could not remember seeing any budget commitment in the DOE statement. Gore interrupted Wood to ask. Wood began a reply to the effect that he believed NIH would address the necessary issues, although DOE was quite concerned about them. Gore came back, asking specifically whether DOE had made a commitment similar to NIH's. Wood said no, and Gore stepped up to the plate. He suggested quite strongly that DOE do so, and noted that there would be future hearings on the genome project at which this issue would come up. Gore's position

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was endorsed by Senator Kerry. It was a s clear a signal as Congress could send (US Senate, 1989). NIH's National Center for Human Genome Research, along with the National Center for Nursing Research, became pioneers by offering sustained NIH support for bioethics research. Bioethics had been supported intermittently by NIH in the past, but without any ongoing program or dedicated budget. The commitment to fund such work was a dramatic departure, an innovation in NIH policy likely to have deep and long-lasting impacts on NIH well beyond the genome center. Congress forced DOE to adopt the same stance. The combined NIH and DOE funding promised to triple federal funding for bioethics over the span of two or three years. Gore was not the only concerned senator. Edwin Froelich, a physician staff member for Senator Hatch, ranking Republican, called DeLisi to his office late in 1986, soon after having learned of the DOE plans for a genome project. Hatch's committee had direct authorization jurisdiction only over NIH, but Forelich nonetheless expressed grave concern to DOE that its genome research should be scrutinized for its broader impact, particularly whether it would lead to more prenatal diagnosis and abortion. Froelich likewise called Ruth Kirschstein when he heard of NIH genome plans in 1987. Kirschstein and W. French Anderson then visited with Froelich to assure him that NIH was indeed concerned about these matters. Froelich wanted some assurance that there would be explicit attention to ethical issues, or the human genetics program would be in jeopardy. Senator Hatch's concern was relayed to University of Utah's President Chase Peterson, via OTA. Peterson met with Hatch's staff to clarify the importance of genome research in Utah, Hatch's home state. Barbara Mikulski, the brusque senator from Maryland, expressed concern to OTA staffin late 1988. Mikulski was concerned that "go-go" science would race far in advance of policies to contain its adverse impacts on individuals and society. It needed to be tempered by a public policy process to anticipate its social impacts. From the opposite, conservative end of the spectrum, Senator Humphrey of New Hampshire, a strong prolife advocate, threatened to block the 1989 NIH authorization bill unless the Biomédical Ethics Advisory Committee (BEAC) was reauthorized. One of BEAC's topics for consideration was the implications of human genetic engineering, a mandate tracing back to 1982 hearings held by Gore in the House. BEAC had placed monitoring the genome project onto its agenda before it quietly disappeared in a morass of controversy surrounding abortion (transcript of 17 February 1989 BEAC meeting). If the point had not already been made, it was brought home where it really counted, in appropriations hearings. In NCHGR's first appropriations hearings (it had come into existence after the prior budget cycle), Congressman Obey pointedly raised questions about how insurers and employers might use genetic information to discriminate unfairly. The House appropriations report for the 1991

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NIH budget stipulated that NIH come up with a systematic plan to deal with such ethical issues and to develop specific policy options to address those issues (US House of Representatives, 1990). Congressional concern about the implications of genome research reflected ambivalence among the general public. Indeed, public reactions to the genome project were principally channeled through discussions of how increased genetic knowledge would change individual choices. Journalists concerned with reaching a wide audience believed the average reader (or viewer, in the case of video documentaries) was inherently interested in the ethical and social changes wrought by genetics, and used this interest as a "hook" into the science. The Time cover feature in 1989 dedicated two of its five pages to description of the ethical and social impacts (Elmer-DeWitt et al, 1989), and social impact was the centerpiece of Robert Wrights (1990) article on Watson. Wright's article was strongly ambivalent about Watson. It suggested that Watson's venture into ethical issues was a political preemptive strike, an insincere attempt to shield his scientific agenda from criticism by having an ethics program he could point to publicly. The implication was that the ethical program was no more than a Machiavellian attempt to curry favor with genome critics in academe by seducing them with grants. New Republic's front cover bore a photograph of Watson framed by the rhetorical question "Mad Scientist?" in bold letters. Wright branded biotechnology critic Jeremy Rifkin a Luddite, but then parroted the arguments from his books Algeny and Who Should Ρ/α^ God? The very real and difficult issues were buried in innuendo and sarcasm. In a scurrilous aside, Wright suggested that David Botstein's switch from genome critic to supporter was based on his seeing the potential for a big NIH grant. Never mind that Botstein had been one of the architects of the genome project's redefinition. Watson fans were deeply offended; genome critics were confirmed in their skepticism. The piece was thinly researched and flippant, but nonetheless signaled trouble ahead for the genome project. Human genetics drew out social concern for several reasons. First, it studied the very stuff of life. Genes did not determine moral status or many valuable human attributes, but they did influence these characters. The genome was, after all, the recipe book that made each person possible. Studying it was threatening, and might lead to further meddling. Second, human genetics offered technological options not available before. Those at risk of Huntington's disease or worried about carrying the genes for sickle-cell or Tay Sachs diseases, did not have to worry about taking a genetic test before gene mapping provided the technology. Technology brought choice, sometimes agonizing choice. This was not different in principle from other medical advances, but it seemed to hit especially hard in the case of genetic disease. There were special concerns about diseases caused by genes, factors beyond control of the person carrying them. Although behavior might change how genes were expressed, it could not change which genes

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were inherited. Third, genetics had been used as a tool for political abuse in the past. Human genetics labored in the shadow of eugenics and racial hygiene. A spate of books noted that scientists and physicians promoted a racist agenda in the first half of this century (Kevles, 1985; Lifton, 1986; Muller-Hill, 19888; Proctor, 1988; Reilly, 1977). The medical model of nondirective genetic counseling explicitly rejected the tenets of eugenics and racial hygiene, but the magnitude of the abuses left a legacy of distrust. Nonscientists were not going to give their trust automatically; scientists would have to earn it. L. Proliferation of international genome research programs The genome debate began in the United States, but quickly spread abroad. The robust international ethos of science did not respect national borders. Italy's genome program began as a pilot in 1987, under the Italian National Research Council, only months after the first DOE reprogramming began in the United States. Consensus rallied around Dulbecco's Science editorial, and Italy saw genome research as a road to world stature in molecular genetics. Dulbecco was appointed the project coordinator, with Paolo Vezzoni as the deputy, and the project grew from 15 participating groups initially to 29 by 1989 (Dulbecco, 1990). The United Kingdom was intimately woven into the fabric of molecular genetics. The MRC Cambridge laboratory was involved in pioneering the DNA sequencing and physical mapping technologies. Representatives from MRC Cambridge attended the major genome meetings, including the first on at Santa Cruz. Their views were solicited for their nonpareil experience in audacious projects pushing the limits of structural biology. Two figures loomed especially large in the United Kingdom. Walter Bodmer and Sydney Brenner were immediately in the fray as the genome debate began. Bodmer keynoted the Cold Spring Harbor meeting in June 1986, and chaired the HHMI meeting in Bethesda two months later. Sydney Brenner attended several early meetings and was later invited onto the NRC panel. Brenner and Bodmer were positioned close to the centers of power in UK science. Brenner was highly positioned in MRC, holding several different posts while the genome debate was under way, and Bodmer was director of research at the Imperial Cancer Research Fund (ICRF), a large privately funded institute in London. MRC and ICRF put together a genome budget with dispatch. The UK genome debate began in 1986, when Brenner approached the MRC's Molecular Genetics Unit with the idea of a genome project. MRC established a scientific advisory board, and approved moving ahead. ICRF was soon brought into the program. MRC and ICRF were expected to contribute roughly equal funding, and coordination was via a joint scientific advisory committee with Sir James Cowan (secretary of MRC) and Bodmer as co-chairs. The UK genome program began in February 1989 as a three-year project, to attain a stable budget

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beginning in 1991 (Alwen, 1990). The scientific strategy was a two-pronged approach, one to coordinate ongoing work, including databases and material exchange centers, and the other to impart a new impetus to basic genome research. Brenner noted that once "we have established a center in the UK which has already been of value to our research community, then we will be well placed to play an active role in international efforts" (Dickson, 1989). The Union of Soviet Socialist Republics (USSR) also quickly mounted a genome program, championed by academician Alexander A. Bayev and Andrei Mirzabekov. Bayev had missed the early years of the molecular biology revolution, sidelined to a Siberian prison camp when his research adviser fell afoul of the powers-that-be in the time of Stalin. While Watson and Crick published their structure of DNA, Bayev was spending one of his 18 years in prison as a camp doctor in the Gulag. Bayev was brought back to Moscow after Kruschev briefly gained power in the early 1960s, and he quickly worked up to an international reputation in the molecular biology of bacteriophage. Mirzabekov became one of the star molecular biologists permitted to travel abroad under Brezhnev. Mirzabekov succeeded Bayev as director of the Englehardt Institute when Bayev retired. Bayev became one of the most powerful figures in life sciences in the USSR. In 1987, he drafted a letter circulated to each director in the Academy of Science Institutes. He and Mirzabekov later prepared a proposal for government approval, and Bayev wrote the formal report (Mirzabekov, interview, Bethesda, December 1989). The USSR Council of Ministers approved a genome project in 1988, as one of 14 priority areas in science and technology (Bayev, 1990). Indeed, the genome project became the main support for all of molecular biology in the USSR. As a severely stressed economy left few funds available for scientific research, the genome project proved unusual in its ability to garner political support. The genome project came on the scene just as Gorbachev was gaining power, and perestroïka began. The genome program became an example of perestrol· ka in life sciences. Funds were distributed not only through the traditional channels—to Academy of Science Institutes and thence to program and laboratory directors—but also through individual grants approved by an unprecedented peerreview process. Mirzabekov, who had been at the meeting that spawned the idea for Maxam-Gilbert sequencing, became the director of the genome project, adding to his duties as director of the Englehardt Institute. In Japan, genome planning exhibited the complexity of the highly decentralized process involving scientists, government, and a generally higher dose of corporate interests than in the United States or Europe. The Japanese genome policy process also highlighted the parsimony of Japanese basic research and the lesser power of academic scientists. The Science and Technology Agency (STA) kicked off the genome effort in Japan, with its 1981 project to develop automated DNA sequencing machines. This project started entirely outside the scope of genome debate, but as Akiyoshi Wada, the project's director, began planning for

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expansion of the effort in 1986 and 1987, he visited the United States and found that the genome debate dominated discussions. The STA program eventually was funded again, although not with the substantial budget increases Wada had hoped for. Linkage to an international genome project, however, offered new opportunities. A scientific panel reported in favor of an STA genome program to the minister in a 1989 document (Council for Aeronautics, Electronics, and Other Advanced Technologies, 1988). The project had found a home at the RIKEN Institute (the Institute of Physical and Chemical Research), and came under the direction of Yoji Ikawa, with the specific DNA sequencing effort under Eichi Soeda. The goals for automated sequencing were reduced from 1 megabase per day of raw sequence data to 100 kilobases. A sister project focused on automating other common molecular biology procedures was also begun under Asao Endo at RIKEN. STA also partially funded Nobuyoshi Shimizu's genetic and physical mapping efforts on chromosomes 21 and 22, at Keio University. Under separate auspices, but scientifically related to genome research, STA began a genosphere project under its ERATO program (System for Exploratory Research for Advanced Technology), part of which would include the study of chromosomal structure. Meanwhile, the Ministry of Education (Monbusho), which funds the vast bulk of academic science in Japan, was forming plans of its own. A fact-finding mission visited the United States in 1987, to prepare a report for the ministry. Ken-ichi Matsubara emerged as the scientific leader of the Monbusho initiative. A scientific advisory committee he chaired forwarded a report favorable to the minister of education (Ministry of Education, 1989), and secured a two-year budget for 1989 and 1990. Matsubara worked to broaden and enlarge the program into computational biology and instrumentation, in hopes of a substantial budget increase for 1991 and beyond (interview, 31 July 1990, Osaka University). As Monbusho and STA carried forward their plans, other ministries were planning new genome programs (interviews with staff of Japan Bioindustry Association, STA, and scientists, Tokyo, 2-3 August 1990). The Ministry of Health and Welfare began planning a program that would focus on human genetic diseases, also under the genome umbrella, and announced it would seek a budget to begin in 1991. The Ministry of Agriculture, Forestry, and Fisheries announced a program to map the rice genome to begin in 1991. The Ministry of International Trade and Industry (MITI) began planning a suite of projects focused on robotics, automation, and advanced computation. The MITI plans called for a joint academic-industrial consortium, and was in the works to commence in 1992 or 1993. Japan thus had five executive agencies mounting genome efforts, with different but overlapping objectives and diverse industrial, political, and academic roots. Coordination was assigned to the Science Council of Japan, whose chair was the prime minister and which represented science agencies, although it did not include Monbusho.

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Sydney Brenner alerted officers at the European Commission of the European Communities to the emerging importance of genome research in a short proposal received 2 October 1986. Further discussions elicited support for projects on S. cerevesiae, B. subtilis, Drosophila, and A. thaliana, and multinational efforts commenced in 1988. Human biology provoked more controversy, which delayed approval of a human genome project. Peter Pearson chaired a committee charged with formulating plans, until he moved to Johns Hopkins University, and Malcolm Ferguson-Smith took over. The proposal to support a program in human genetics had its name changed from "Predictive Medicine" to "Human Genome Analysis" (Commission of the European Communities, 1988, 1989), signaling a recognition of social concerns. Inclusion of a program to consider the ethical, social, and legal aspects of genome research cleared the way for approval (Economic and Social Committee, 1988). When such a program was allocated 7% of the budget, and with the understanding that the program would implement confidentiality protections and would explicitly exclude germ line genetic manipulations, the program was approved by council on 29 June 1990 (Council of the European Communities, 1990). The Ministry of Research in France announced its intention to mount a genome research program in June 1990 (Bertrand Jordan, personal communication, 22 August 1990), and officially announced a genome program in November (Holden, 1990). The program was to receive $10 million ($50 million francs) in 1991 and $20 million ($100 million francs) in 1992 (Holden, 1990), to be directed by a groupement d'intérêt public responsible for maintaining high scientific quality and linkage to industrial interests. The French program grew out of several years of discussion, involving the National Institute for Health and Medical Research (INSERM), the National Center for Scientific Research (CNRS), scientists at the Pasteur Institute, the private Center for the Study of Human Polymorphism (CEPH), and several genetics research centers throughout France. Several other countries considered mounting genome efforts, including Australia and Canada, and had scientific groups tasked with formulating plans. M. Formation of the Human Genome Organization The need for international coordination was apparent even as the debate about which agency would run the US effort was going at full throttle. At the first Cold Spring Harbor symposium on genome mapping and sequencing, Victor McKusick circulated the idea of forming a new organization. An impromptu session was scheduled at 5 P.M. 29 April 1988. McKusick spoke of forming an organization modeled on the European Molecular Biology Organization (EMBO). He presented this to the 40 or so scientists present. Watson rose and talked about the early years of EMBO, which had been modeled on the European Center for Nuclear Research (CERN) following conversations with Victor Weisskopf and Leo Szilard.

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Lee Hood endorsed the idea, and argued for an open membership structure. Sydney Brenner suggested the name HUGO, for Human Genome Organization, although he personally had a mild preference for THUG. Brenner nominated McKusick for president of the new organization, and McKusick was elected. HUGO's founding council met for the first time in Montreux, Switzerland, on September 7 (McKusick, 1989). It drafted a four-point list of functions and a brief organizational plan. Vice-presidents were elected from Europe (Bodmer, Jean Dausset) and Japan (Ken-ichi Matsubara). Much of HUGO's early efforts were directed at securing a financial base and deciding who was to be a member. The Montreux meeting had been occupied in part with deciding who was to be a member. The Montreux meeting had been occupied in part with deciding between open and elected membership options. Those advocating selective membership won the day, although HUGO progressively diminished restrictions and eased the process of election. In December 1989, Bodmer was elected president of HUGO. McKusick was named founding president, and the vice-presidential posts were designated by region. Matsubara, of Osaka University, stayed as vice-president from Japan, Charles Cantor donned the mantle for the United States, and Mirzabekov for Eastern Europe. Funding was sparse until 1990, when the Wellcome Trust in the United Kingdom and HHMI in the United States both announced substantial multiyear grants to HUGO. In July 1990, Wyngaarden was appointed executive director of HUGO, becoming the first official permanent staff member. As 1990 drew to a close, HUGO struggled to consolidate a base, focusing its efforts to organize workshops, to track international developments, and to broker agreements on sharing data and materials. N. Third-world interests and UNESCO Scientists from developing nations became concerned that genome research might leave them in the dust. Genetic diseases were a serious public health problem in many regions. Sickle-cell disease and thalassemia were pervasive in the Mediterranean basin, the Middle East, and some parts of Asia. Consanguinity rates of over 20% were not unusual in some regions, particularly where traditional patterns of marriage prevail under Islam, making recessive genetic diseases more common (Wertz and Fletcher, 1989). In other areas, genetic diseases were highly prevalent among select populations. Diagnostic methods derived from genome research might well prove useful in the developing world, and there was concern that the special steps needed to make technologies inexpensive and simple enough would be neglected. The United Nations Educational, Scientific, and Cultural Organization (UNESCO) held meetings in 1989 and 1990 to discuss its role under Director Federico Mayor. UNESCO than appointed an international Scientific Coordinating Council. UNESCO cosponsored several international meetings and a regional

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genome training program in Chile in 1990. Its first program initiative was a fellowship program to promote training of scientists from the developing world, permitting exchange with laboratories in developed nations.

0. Conflicts between science as knowledge and science as investment In the United States, Ralph Hall's House Subcommittee on International Seientifrc Cooperation held a hearing on 19 October 1989. Hall summarized his concern about equitable sharing of the research burden: "If you want to ride on the train, you've got to buy a ticket" (US House of Representatives, 1989). Watson, testifying before him, concurred. George Cahill, representing the Human Genome Organization, acknowledged the problem but pointed to the destructive impact of unilateral restrictions on scientific data. This issue grew from the two heads of science, one the pursuit of pure knowledge for its own sake, conforming to moral values that transcend national borders, and the other an investment in the future of national economies, expected to produce technological capacities to yield new products, new markets, new wealth, and new jobs. The twin objectives of seeking new knowledge and commercially exploiting new technologies generally worked synergistically in domestic politics, tending to generate support for research spending. In the international context, however, these objectives came into conflict. The international ethos of scientific coopération flew in the face of forces promoting economic nationalism. As the rate of growth of the US national economy lagged far behind that of Japan and Germany in the late 1970s and through the 1980s, the US's future economic health became a political theme. The genome project was caught in a policy dilemma. Relations between the United States and Japan became the focus of concern. Members of Congress were concerned that Japan was commercially exploiting basic research results produced at the expense of US taxpayers. The Japanese project to automate DNA sequencing was viewed nervously in the United States. Despite Wada's intention to make the Japanese DNA sequencing effort part of an international scientific bridge, the focus on instrumentation aroused fears that Japan would use its genome project to leapfrog the United States in this high technology market, just as it had in chip production and consumer electronics (Fox, 1987; Sun, 1989). The Japanese government took some steps to assuage this concern, for example, by encouraging universities to buy Applied Biosystems DNA sequenators and providing a budget to do so. Several research groups were quite open in acknowledging that they had purchased the machines "to reduce trade frictions" (interview with Susan Clymer, Fulbright fellow, Tokyo, 3 August 1990). The fires could not be so easily smothered. Japan's robust drive for technology was oddly matched to anemic support for basic science. The trend was evident in publication reviews (Narin and Frame, 1989), although it was clear that pockets of world-class science were emerging in

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Japan. The genome program was no exception. In 1990, aggregate funding for the genome effort in Japan was estimated between $6 and $8 million, depending on how costs were counted, which was more than tenfold lower than the US government contribution through NIH and DOE in absolute terms, or fivefold lower relative to the Gross National Product. (By these same criteria, Italy's proportionate contribution was 29%, the UK's 66%, the USSR's 5% [at official exchange rates, or 78% at unofficial ones]. Those without specific genome programs could not be calculated.)I Watson raised this potentially divisive issue at a June 1989 meeting on the genome project cosponsored by UNESCO and the USSR Academy of Sciences in Moscow. He spoke privately to Yoji Ikawa, the lone Japanese scientist present (at the last minute, Matsubara had been forced to remain in Japan due to the death of a close colleague). Watson urged him to tell his government to substantially increase funding for genome research, or there would be international tensions. Watson followed up with a letter to Matsubara in July, and several public statements, noting that Japan should be grateful to the United States for its post-War benevolence (an extremely sensitive point in Japan). Watson, casting about for a policy tool to induce proportionate contributions from all governments, suggested the United States might limit access to genome research data, at least for a time. At the American Society for Human Genetics meeting in Baltimore, he was quoted as saying, "I'm all for peace, but if there is going to be war, I will fight it" (Roberts, 1989b). The Matsubara letter became the subject of reports in Science and Nature. The issue caused a minor storm in North America and Europe, but a veritable tsunami in Asia (Swinbanks, 1989). In Asia Technology, the story ran as "The Human Gene War" (Johnstone, 1990). Within Japan, scientists agreed that Watson was correct in saying there was insufficient funding for basic research, but deeply resented the public humiliation. They noticeably bristled at the paternalistic tone of his letter. Many believed Watson's remarks were motivated by racism or "Japan-bashing," not knowing that Watson had expressed admiration for, and urged that the United States imitate, Japan's macroeconomic policies at a Harvard University talk a year earlier (Watson, 1988b). Privately, several Japanese scientists hoped the publicity would put pressure on the Japanese government to increase research funding. As Watson's threat to use data as a foreign policy tool suggested, the conflict between norms of science and international trade intruded on the genome project. The problem was not only an imbalance in basic research funding, but also retention of intellectual property. At the first international meeting specifically ^ N P figures for these calculations are taken from the 1990 World Almanac (New York: Pharos Books) and the Statesman s Yearbook, 1989-1990 (New York: St Martin's). Genome budgets are taken from various sources: Italy (Dulbecco, 1990), UK (Alwen, 1990), USSR (Bayev, 1990), Japan (Swinbanks, 1989; Sun, 1989; and interviews with Ken-ichi Matsubara [Osaka University], Masato Chijiya [STA], and others, 31 July-3 August 1990). Unofficial conversion rates for rubles taken from black market rate, Leningrad and Moscow, June 1989.

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devoted to discussion of international cooperation on the genome project, in Valencia, Spain, Bayev clearly articulated the principle of scientific sharing. At the October 1988 meeting, he avowed that "the data should not be the property or privilege of one nation, social group, or private company" (Roberts, 1988). A debate about patent rights, particularly remarks by Beverly Berger of the US Office of Science and Technology Policy, provoked angry comments from the floor about how the genome project could become just another opportunity for big companies in developed nations to exploit the rest of the world. In threatening the free exchange of scientific data, Watson seized one of the few policy options available. He thus declared his understanding that congressional patrons of the genome project saw it as much an investment in the national economy as a cultural endowment. Staff in Congress discussed adding riders to forbid purchase of Japanese instruments under federal grants, or restrictions on funding foreign postdoctoral and graduate students with federal moneys, but few wanted to disrupt the tradition of open science and international collégial exchanges. Watson underestimated the ire his suggestions would arouse in biomedical research circles, especially outside the United States. Having made a noisy foray into this jungle, he let the issue die down in intensity over the next few months, and privately expressed regret that he had written the Matsubara letter. But the issue remained a smoldering problem, caused by the absence of any powerful international coordinating mechanisms. It threatened to burst into flames with the federal deficit crisis and a weakening US economy. Congress, as arbiter of public opinion, would return to the issue. Although Congress would certainly make its presence known, it was less clear whether Congress would play the role of fireman or arsonist.

IV. CONCLUSIONS Scientists created the genome project. They were also the sources to whom policy makers turned for advice along the way. The NRC committee was particularly influential, but there were many independent mechanisms as well. Hundreds of scientists attended the meetings that erected the genome framework. There were no disease constituencies who rose to champion the project, in contrast to cancer, heart disease, Alzheimer's disease, or AIDS. There was strong support from the Alliance for Aging Research and the American Medical Association, but no wellspring of broad public support. Indeed, aside from intermittent press reports, the public remained largely ignorant of the project even after it was under way for three years. Articles in the lay press often focused on the social impacts, expressing legitimate concerns about the implications of all human genetics research. Yet the mechanisms to deal with these concerns were only being put into place. It is impossible to judge now whether the genome project would have happened without the efforts of Charles DeLisi, but it certainly would not have

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happened as fast. Without a strong impetus from DOE, NIH almost certainly would not have reacted as strongly, as quickly, or as systematically. Without interagency rivalry, neither NIH nor DOE would have fought so hard to assess its options, to secure its budget, or to influence the opinions of the scientific community. Vying for genome supremacy also improved the level and degree of analysis, provoking careful scrutiny of scientific strategy by NRC, and examination of other policy issues by OTA. The support of Wyngaarden, Watson, Berg, Botstein, and others within science was contingent on a redefinition of the project's goals. DNA sequencing, databases, genetic linkage maps, physical maps, and computational biology were all areas demanding greater resources and concerted planning, but discussion of these could well have remained disconnected. The extraordinary number of meetings on the genome project testify to the fact that once the idea of a genome project was aired, it was immediately perceived as exciting and important. Norton Zinder noted the consistency with which the genome project was first greeted with skepticism and then accepted as important, indeed inevitable, as it was broadened to include mapping and databases (Zinder, 1990). Sinsheimer, Dulbecco, and DeLisi were merely first to sense the importance of a new push for human genetics. In science policy, as in science, however, being first can matter as much as being absolutely right. Fulfilling scientists' aspirations for the redefined genome project was dependent on the political objectives of members of Congress: Domenici, Chiles, Kennedy, Gore, Natcher, Obey, Scheuer, Dingell, Hall, and others. Congressional concerns centered on improving the health of citizens, laying a foundation for the economic future of the Untied States in biotechnology, and addressing the social implications of genome research. DeLisi put the genome project on the public agenda. Once it was there, scientists vigorously debated its merits, and eventually ratified it. DOE's foray into NIH territory elicited a competitive response, particularly from Wyngaarden, and forced the issue into the uncomfortable glare of public scrutiny. Wyngaarden rose to the challenge. Congress then filled the science policy vacuum at the top of American government by making the critical decisions about budgets and agency leadership. A few pivotal scientific figures clearly had enormous influence. These were the scientists who took the trouble to learn about the policy process. Watson was preeminent among these, but Alberts, Baltimore, Berg, Bodmer, Brenner, Cantor, Dulbecco, Gilbert, Hood, Olson, and others exerted their influence at critical junctures. Many scientists from the national laboratories had decisive voices in steering DOE policies. In the first three years, most scientists talked only to one another. Few took the time to visit with policymakers or to write for an audience outside science journals and science news publications. As the genome budget expanded at the same time as a funding squeeze was felt by many researchers, a countermovement gathered force. Critics began to use the tools of interest group politics, in the form of letter-writing campaigns and targeting of

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Congress and science policymakers high in government. The efforts were unsophisticated at first, but promised to become better targeted. Debate about the genome project rendered in stark outline the weakness of analytical means to deal with some central policy questions. How can rational decisions be made between research infrastructure and undirected investigations? Was federal support of research the scientist's public entitlement, or a means to the end of public welfare as incorporated into the missions of science agencies? How could government balance the needs of science as public knowledge against science as an investment in national economic development? Above all, the creation of the genome project displayed the dependency of modern science on the largesse of the federal government. The purpose of the genome project was to ferret out the fundamental information and methods for future human genetics, and put it where it might be useful, the genetic equivalent of highways and bridges. Dependency on public funding dictated the cast of arguments used to cultivate political support for a project that was as its core a public good. Acknowledgments This article is condensed and substantially rewritten from a paper prepared for the Committee to Study Decisionmaking, Institute of Medicine (IOM), National Academy of Sciences (Cook-Deegan, in press). I am indebted to IOM staff and committee members for encouraging me to get down to writing. This work was supported by grants from the Alfred P. Sloan Foundation and the National Science Foundation. While gathering the relevant material, I was employed by the Office of Technology Assessment, the Biomédical Ethics Advisory Committee, the National Center for Human Genome Research, and Georgetown University. I thank the dozens of individuals who consented to interviews, and many others who contributed background documents and made comments on earlier drafts of the IOM paper.

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