The Human Genome Project: The Formation of Federal Policies in the United States, 1986-1990

Robert Mullan Cook-Deegan

The human genome project began to take shape in 1985 and 1986 at various meetings and in the rumor mills of science. By the beginning of the federal government's fiscal year 1988, there were formal line items for genome research in the budgets of both the National Institutes of Health (NIH) and the Department of Energy (DOE). Genome research budgets have grown considerably in 1989 and 1990, and organizational structures have been in flux, but the allocation of funds through line-item budgets was a pivotal event, in this case signaling the rapid adoption of a science policy initiative. This paper focuses on how those dedicated budgets were created.

This case is not about the genome project itself, because that is still a nascent enterprise, but rather about the process by which it was conceived, formulated, and ratified at several levels in various federal science agencies. Describing this process is an exercise in contemporary history, retaining the advantages of direct access to the principal decision makers but necessarily suffering from a lack of perspective that only decades can bring. There are three main sources of information.

Robert M. Cook-Deegan is a physician, formerly with the congressional Office of Technology Assessment and the Biomedical Ethics Advisory Committee. In 1991 he joined the Institute of Medicine as Director of the Division of Biobehavioral Medicine and Mental Disorders.



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BIOMEDICAL POLITICS The Human Genome Project: The Formation of Federal Policies in the United States, 1986-1990 Robert Mullan Cook-Deegan The human genome project began to take shape in 1985 and 1986 at various meetings and in the rumor mills of science. By the beginning of the federal government's fiscal year 1988, there were formal line items for genome research in the budgets of both the National Institutes of Health (NIH) and the Department of Energy (DOE). Genome research budgets have grown considerably in 1989 and 1990, and organizational structures have been in flux, but the allocation of funds through line-item budgets was a pivotal event, in this case signaling the rapid adoption of a science policy initiative. This paper focuses on how those dedicated budgets were created. This case is not about the genome project itself, because that is still a nascent enterprise, but rather about the process by which it was conceived, formulated, and ratified at several levels in various federal science agencies. Describing this process is an exercise in contemporary history, retaining the advantages of direct access to the principal decision makers but necessarily suffering from a lack of perspective that only decades can bring. There are three main sources of information. Robert M. Cook-Deegan is a physician, formerly with the congressional Office of Technology Assessment and the Biomedical Ethics Advisory Committee. In 1991 he joined the Institute of Medicine as Director of the Division of Biobehavioral Medicine and Mental Disorders.

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BIOMEDICAL POLITICS First, I conducted interviews with the people involved. The first formal round of interviews occurred in January and February 1987, with most of them conducted during a two-month travel marathon spent visiting many western cities in the United States to gather facts for the congressional Office of Technology Assessment (OTA). Several more interviews took place later in 1987, principally in Boston, New York, and Washington, D.C. A second major round of interviews took place in July and August 1988. Since July 1986, I have also attended dozens of scientific symposia, administrative meetings, hearings, and other public events related to the genome project. At those events, I have spoken with the individuals cited in this paper, as well as several hundred more, many on a regular basis (once per quarter or more frequently). The second source of information consists of planning documents, memos, letters, and other information gathered first for OTA and later in preparation for a book funded by the Alfred P. Sloan Foundation. Many of the people I interviewed opened their files to me, and I have copied material from OTA, the National Research Council, the University of California at Santa Cruz (UCSC), Cold Spring Harbor Laboratories, the DOE genome offices in Germantown, Maryland, the Office of the Director, NIH, and the National Center for Human Genome Research at NIH. This study has been an extraordinary opportunity to sift through the history of a science program in its infancy. Staff in the agencies were extremely generous with their time and free in allowing me access to documents. I have by no means gone through all the material in all these places; rather, I copied those documents identified as critical by those who made the decisions, or I filtered out pertinent material from large file collections. Finally, I systematically surveyed the science and lay literature for articles referring to the human genome project through mid-1988. Press accounts document the story, but they are also a part of it, as the channels of communication are themselves mechanisms for producing action. The first section of the paper deals briefly with the origins of mapping and sequencing technologies. This topic is discussed because these technical capacities are the reason the genome project exists at all. Technical advances are not the focus of the paper but rather a backdrop to understand the ensuing story about policy formation; consequently, the technical background section is brief but dense, and it may be rough going for nonscientists or scientists outside molecular biology and genetics. If this is the case, the NRC or OTA reports on mapping and sequencing explain the technical background at greater length in lay language (National Research Council, 1988; U.S. Congress, OTA, 1988a). The new technical means led to bureaucratic adaptations in the science agencies, and the paper's second section describes the history of

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BIOMEDICAL POLITICS the numerous individuals who originated different conceptions of systematic genome-scale research. It also tracks how the technical ideas were translated into science programs at DOE, NIH, and the Howard Hughes Medical Institute (HHMI). This history is mingled with the concomitant process by which these science programs were funded by Congress. Securing a budget for a new program is the first step that requires justification to a community beyond the science agencies, because the budget processes within the executive branch and the justification of budgets to the appropriations committees in Congress both entail considerable effort. Securing a budget requires convincing those with broad-ranging responsibilities well beyond a particular scientific community not only that something new is needed but that it is needed more than other items competing for funds in the federal budget. Programs must contend not only with other life science programs but also with broader national priorities within science and with any federal programs that entail annual appropriations. In the case of the genome project, the legislative and bureaucratic developments hinged on arguments, made principally by scientists themselves, about the merits of the enterprise. Some of the principal arguments and issues raised in the process of persuasion are teased apart in the final section of this paper. The justifications proffered for public funding of the genome project generated a set of obligations that the project will have to meet, and I briefly note these and discuss whether keeping such promises matters. Four brief appendices elaborate on certain specific issues mentioned only briefly in the text. The future of the genome project remains in doubt. Public fears of how genetic information might be handled, discomfiture with the power of such intimate knowledge, and democratic distrust of powerful elites are all elements that could disrupt the working consensus that currently favors public support. Opposition to a new style of biology and research management has been intense since the beginning and shows little sign of abating. There is no disease-oriented constituency supporting the program, and so the genome program is largely a creature of the molecular biologists and human geneticists who conceived it and supported it in its early stages. The human genome project is thus, more than many other areas of biomedical research, under pressure to produce results, and it is likely to be held to greater standards of accountability than other projects for the initial promises made on its behalf. Whether the genome project is judged a social benefit is contingent on how its results are used, and there will be considerable uncertainty about this for several years at least. The genesis of the human genome project highlights the complex interplay between people and the institutions in which they work, illumi-

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BIOMEDICAL POLITICS nating how much difference a few individuals can make but also demonstrating how constrained those individuals are, how persistent they have to be, and how little power any one person has in the great march of science. A few individuals independently conceived a large-scale genome project, a much larger number of scientists reformulated the initial plans in a way that commanded greater support within the scientific community, and policymakers ratified the judgments made by scientists, thus providing resources to begin work. The genome project is now poised to begin in earnest, and its results over the next few years, and the uses to which those results are put, will determine the success or failure of the endeavor. TECHNICAL AND SCIENTIFIC BACKGROUND The genome project coalesced from a number of independent developments. Historical strands can be traced to evolutionary and population genetics, medical genetics, molecular biology, detection of mutations, advances in instrumentation, and computational biology. The principal factor was a meeting of the fields of human genetics and molecular biology. One field has long been largely clinical and descriptive; the other has been highly reductionist and focused on mechanics. As these two worlds came together in the 1970s and 1980s, each was fundamentally transformed, a process that continues today. The human genome project is a result of this collision. Human gene mapping began in 1911, when researchers deduced that, because of its pattern of inheritance, color blindness lay on the X chromosome. For five decades thereafter, study of the odd inheritance patterns of X-linked disease was the only reliable mapping method. In the late 1960s, two technical developments occurred. First, somatic cell hybridization became a mapping strategy. This method mixed chromosomes by fusing together cells from humans and other organisms. The mixed chromosomes fragment and reorganize into metastable cell lines that retain various amounts of human deoxyribonucleic acid (DNA). It turned out that rodent-human cell lines, after a few generations, generally retained 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 clever ways to select only those cells that contained functional genes of interest, it became possible to map genes. During this period, it also became possible to differentiate the 24 distinct human chromosomes under the light microscope by staining them with DNA-binding dyes, producing a karyotype (normally 22 pairs of autosomes and either a pair of Xs, in females, or an X and Y, in males). In a photograph of the nucleus of a cell, the chromosomes

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BIOMEDICAL POLITICS could be directly seen and large-scale deletions, rearrangements, and duplications detected. Somatic cell hybridization and karyotyping launched human geneticists on their 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 for selectively cutting and copying DNA 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 spinoff: mapping by linkage to DNA markers. The idea was to find landmarks along the human chromosomes that would allow geneticists to determine which parts of which chromosomes were inherited from which parent. Once located, the markers could be used to trace the inheritance of bits of chromosomes through families, so that the inheritance of markers could be compared with the inheritance of diseases or other traits. There are, very roughly, 3 million differences in DNA sequence “spelling” between any two people. Most of these differences have no detectable effect on the individuals, but they can be measured by direct analysis of DNA. If there are enough markers and enough people in a family to do the statistics, one can “link” the inheritance of a genetic character (a disease or trait) to the inheritance of a chromosomal marker. The closer a gene is physically to the marker being studied, the less often it will be separated in the process of producing sperm and egg cells, and the greater the statistical linkage to the marker. Because the marker's chromosomal location is known, at least approximately, this information locates the gene nearby. Kan and Dozy first used linkage to a sequence difference to detect different variants of hemoglobin in 1978 (Kan and Dozy, 1978). The first published suggestion that a systematic collection of such markers be made occurred in 1979 (Solomon and Bodmer, 1979). A landmark paper published a few months later (Botstein, 1980) elaborated the idea in considerably more detail, initiating an explosion of genetic linkage mapping in the 1980s. Methods of studying the inheritance of markers and genetic characters harken back to the mathematical genetics developed late in the last century and early in this one. The scientific approach is 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 relies 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

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BIOMEDICAL POLITICS medical geneticists who were comfortable with the statistical techniques of linkage. When the method yielded success in locating the gene responsible for Huntington's disease in 1983 (Gusella et al., 1983) and the gene responsible for polycystic kidney disease in 1985 (Reeders et al., 1985), clinical genetic research quickly adopted it. By the mid-1980s, genetic linkage mapping was part of the mainstream of human genetics. Newsweek magazine quipped in late 1987 that there was a disease a week being mapped by genetic linkage (Begley et al., 1987). Technical advances further extended the ability to work backwards from an 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 that causes the rare condition chronic granulomatous disease (Royer et al., 1987). This achievement was soon followed by location of the Duchenne's muscular dystrophy gene (Koenig et al., 1987) and retinoblastoma (Friend et al., 1986; Lee et al., 1987). In these cases, however, the location was known from patterns of inheritance (on the X chromosome for Duchenne's muscular dystrophy and on chromosome 13 for retinoblastoma), or from human-hamster hybrids, and the study of individual patients who had lost specific portions of the X chromosome. The process of going from chromosomal location to isolated gene is slow, tedious, unreliable, and often frustrating. (Intensive work over seven years failed to produce the Huntington's disease gene, for example.) But many prevalent disease-causing genes have been isolated in this way, most notably the gene that causes cystic fibrosis (Kerem et al., 1989; Riordan et al., 1989; Rommens et al., 1989). Cystic fibrosis was the first case in which the gene was mapped initially by genetic linkage; then the regional DNA was studied until a gene was found and its product identified, a membrane protein thought to be involved in the regulatory flow of chloride ions into cells. The idea that mapping can be the critical first step in understanding genetic disease has thus been confirmed in principle and in practice, but there is a long way to go before the more than 4,000 known disorders have been correlated with genes and gene products. The late 1980s were the period that saw human genetics, and with it the study of genetic diseases, joined with molecular biology in happy matrimony. Molecular biology is largely a post-World War II phenomenon. Its two seminal events are Avery, MacLeod, and McCarty's discovery in late 1943 of DNA as the “transforming principle,” conferring heritable traits (Avery et al., 1944), and Watson and Crick's revelation in 1953 of the double helical structure of DNA (Watson and Crick, 1953). These

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BIOMEDICAL POLITICS are, indeed, two of the high points in twentieth-century science and culture. The distinctive signature of molecular biology is its approach to understanding function through the study of molecular structure. The double helical structure of DNA is the touchstone of this approach, explaining at once how information can be transmitted from generation to generation or from cell to cell during development, and also how information can be decoded into cellular processes through DNA-directed synthesis of proteins and ribonucleic acid molecules. One tenet of molecular biology is to study simple systems of living things, and early work in molecular biology, Delbrück and Luria's “phage” group in particular, focused on the simplest—viruses that infect bacteria (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 and resulted in the discovery of oncogenes. The first disease characterized at the molecular level was sickle cell anemia. In 1949, genetic studies by Neel showed that it was a recessive genetic disease, and biochemical studies by Pauling and colleagues (1949) indicated that it was caused by a chemical change in the structure of hemoglobin. In the mid-1950s, Ingram identified the difference between sickle and normal hemoglobin by breaking the protein into small fragments and looking for differences. He was able to establish that in the sickle cells a single glutamine amino acid had been replaced by valine in one of the two pairs of protein chains that make up hemoglobin (Ingram, 1957). This difference suggested a mutation in the DNA encoding of the beta chain of hemoglobin. Until the past few years, most of the tools of molecular biology were applied following this paradigm, that is, studying individual genes, one at a time, by biochemical analysis. Application of molecular techniques to chromosome mapping came from pushing molecular biological techniques at both ends—on the one hand, forcing chromosomal mapping to higher resolution, ultimately enabling direct decoding of the DNA base pair sequence, and on the other hand, developing techniques to separate and clone larger and larger fragments of DNA, culminating in reproduction of megabase stretches of DNA. Before the development of these techniques, the handling of large fragments of DNA was difficult for several reasons. First, the manipulations involved in preparing it for analysis often sheared the long, fragile strands. Second, the widely used analytical techniques could only separate fragments of up to thousands of base pairs in length. Finally, because of the modified viruses and plasmid vectors used, the length of DNA that could be cloned was also limited to a range of from several

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BIOMEDICAL POLITICS thousand to a few tens of thousands of base pairs. 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. It also became possible to separate DNA molecules of up to several million base pairs in length using pulsed-field gel electrophoresis, first developed by Schwartz and Cantor, who pioneered several innovations in electrophoretic separation methods (Schwartz and Cantor, 1984). Moreover, cloning vectors that could consistently contain 30,000 to 40,000 base pairs became standard fare through incremental improvements in 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. If such a tool had been available for the tip of chromosome 4, for example, those searching for the Huntington's gene in that region could have studied the DNA directly as soon as they located the gene. Having the DNA cloned would make the search for closer markers and candidate genes much simpler and faster. The DNA sequence would be another leap forward. Work on both fronts is now proceeding. Two groups began independently to apply the cloning and ordering strategy to make ordered maps of yeast, in Olson's laboratory at Washington University, and of nematodes, in Sulston and Coulson' s laboratory in Cambridge, U.K., and Waterston's at Washington University. Work began in the early 1980s and began to show promising results by 1986 (Coulson et al., 1986; Olson et al., 1986). The genome of the nematode is roughly the same size— 100 megabases—as a small human chromosome, and it thus became conceivable to map the human genome by extension of the nematode method. Such an extension followed a tradition in molecular biology to focus on a new problem an order of magnitude greater than one that has been solved before. (The exact size of the leap was open to discussion, but the principle was widely accepted.) DNA sequencing was developed by groups located in both Cambridges, more or less simultaneously, using entirely different approaches. Sanger's group in Cambridge, U.K., developed DNA sequencing after a dedicated and deliberate effort that started with protein sequencing, progressed to the sequencing of ribonucleic acid, and culminated in DNA sequencing. Sanger presented a partial sequence of a virus to an awestruck audience in May 1975 (Judson, 1987) and published a modified, simpler method in 1977 (Sanger et al., 1977). Maxam and Gilbert, working in Cambridge, Massachusetts, developed DNA sequencing from their at-

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BIOMEDICAL POLITICS tempts to study directly the regulation of gene expression in bacteria. Gilbert's group had been early pioneers in the field. They isolated their first DNA segment and deduced their first DNA sequence during 1972-1974. This first sequence consisted of 24 base pairs and took two highly competent investigators two years to achieve (W. Gilbert, Harvard University, personal communication, July 1988). The next step was to use chemical modifications of DNA bases to study directly the DNA protein-bound segments that regulate gene expression. Maxam and Gilbert realized they had come upon an approach that, with some further work, would permit direct DNA sequencing (Kolata, 1980). By August 1976, they were ready to distribute the chemical recipes used in their sequencing reactions at a Gordon conference (one of many small, closed gatherings of scientists held in New Hampshire colleges each summer). They also published their method of DNA sequencing in 1977 (Maxam and Gilbert, 1977). Molecular biology thus generated a cornucopia of technological tricks that allowed scientists to think seriously about constructing physical maps of chromosomes and determining their DNA sequence. Some human geneticists were quick to apply the developing techniques to study diseases, but with a few exceptions, molecular biology was a separate field from human genetics. Nonetheless, the two disciplines were rapidly converging, as molecular biology worked its way into yet another field ripe for the picking. The early to mid-1980s also saw two other important technological developments: diffusion of the personal computer and automation of microchemical manipulation. The computer revolution was imported from other areas but quickly adapted to the needs of biologists. It was important because it put personal computers in thousands of laboratories that were unacquainted with them. It permitted more analysis of raw data, and there was a natural harmony with the 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 use computers more and more. 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 that either were already selling instruments to biologists or had been newly formed to do so. Instruments were devised first to sequence and synthesize proteins for analysis of their amino acid building blocks. Analysis of DNA was the next step. Serious efforts to synthesize short segments of DNA, a capability essential to developing highly sensitive probes for analyzing genetic experiments, began in the late 1970s; they had by 1980-1981 proved successful.

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BIOMEDICAL POLITICS Automation of DNA sequencing began around this time in both Japan and the United States. In the United States, the first efforts leading to the current generation of DNA sequenators began in 1980 at the California Institute of Technology, or Caltech, under a five-year grant from the Weingart Institute. The first government support, through the National Science Foundation (NSF), came only in 1984 after a successful prototype was developed. In Japan, the Science and Technology Agency in 1981 began to support a project to automate DNA sequencing that involved several corporate sponsors (Fuji Photo, Seiko, and Matsui Knowledge Industries). The automation effort at the European Molecular Biology Laboratory in Heidelberg began several years later, supported by several European governments. All of these technological developments surged during 1980-1985. In their wake came ideas for a concerted genome project, and several farsighted people independently brought them forth. ORIGINS OF DEDICATED GENOME RESEARCH PROGRAMS The idea of a systematic gene map of human chromosomes was not new. Human geneticists had talked of it for decades. The notion of large-scale sequencing was also discussed soon after sequencing techniques became widespread in 1977. Several groups talked of sequencing the HLA region involved in immune regulation and the regions encoding antibody protein genes. The European Molecular Biology Laboratory seriously discussed a dedicated project to sequence Escherichia coli in 1980-1981. Solomon and Bodmer (1979) mentioned the benefits of finding DNA markers throughout the chromosomes, and Botstein and colleagues analyzed in detail the significance of a systematic effort in this area (Botstein, 1980) in a landmark 1980 paper. Yet none of these ideas for a collective effort took hold within the federal government. DNA sequencing was widely used, but it remained the province of thousands of small laboratories focused on small regions. The Cambridge, U.K., group, under Sanger and then Barrell, were almost alone in sequencing the entire genomes of progressively larger organisms. The key idea in genome projects was a dedicated effort to map and sequence whole organisms or significant parts of their genomes (e.g., an entire chromosome or chromosomal region). Government support for such technically focused efforts was slow to develop. Several 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 considered highly suspect because, in part, they had been used to support cancer research of only marginal usefulness. One corporation, Collaborative Research, Inc., and a private philanthropy,

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BIOMEDICAL POLITICS the Howard Hughes Medical Institute, stepped in to fund laboratories dedicated to generating DNA markers. These two laboratories, under the direction of Helen Donis-Keller (Collaborative Research) and Ray White (HHMI, Utah), contributed more than half the DNA markers that existed on the human genetic map in 1987 (Donis-Keller et al., 1987). The idea of focused mapping received some support when it fit into the format of a small scientific project, as in the case of physically mapping yeast, but several proposals to apply these methods to human chromosomes were rejected by scientific review groups in the mid-1980s. In 1985 and 1986, however, several groups began to buck the tide. The first discussion of a large dedicated genome project came at a workshop convened at the University of California at Santa Cruz in June 1985. In the fall of the same year, Norman and Leigh Anderson proposed 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). By a curious twist, the history of the genome project is connected to the Keck telescope that now graces Mauna Kea, joining the cluster of other large telescopes on a Hawaiian mountaintop. The story behind this connection merits a digression because it is a classic example of how the quest for funds breeds scientific entrepreneurship and how thinking about Big Science infiltrated the field of biology. Robert Sinsheimer was chancellor of UCSC in the fall of 1984. He 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. ” He was also faced with a problem: he knew about a pot of money but had no way to spend it. The events leading to this development were initially tied not to biology but to astronomy. The UCSC astronomy department had become extremely enthusiastic about building the largest optical telescope in the world. (UCSC had an excellent international reputation in astronomy, which was a great source of pride for the university.) One problem, however, was the prohibitive cost of producing the mirror for such a telescope. This problem was solved in principle by packing together 36 small hexagonal mirrors, rather than producing a single large mirror, which lowered the estimated costs from $500 million to $70 million. With this development, UCSC decided to seek funding for a telescope from private donors. A story was run in the San Jose Mercury, and the university received a call from a person familiar with the newly formed Hoffman Foundation, created after the death of Max Hoffman, the U.S. importer of Volkswagen and BMW automobiles. After further inquiry, the foundation indicated that Hoffman's wife might be interested in

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BIOMEDICAL POLITICS Bodmer, W. F. 1986a. Human genetics: The molecular challenge. Pp. 1-3 in Molecular Biology of Homo sapiens. Cold Spring Harbor Symposia on Quantitative Biology, Vol. 51. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Bodmer, W. F. 1986b. Two cheers for genome sequencing. The Scientist October 20:11-12. Botstein, D. 1980. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. American Journal of Human Genetics 32:314-331. Cook-Deegan, R. M. 1989. The Alta summit, December 1984. Genomics 5:661-663. Coulson, A., J. Sulston, S. Brenner, et al. 1986. Toward a physical map of the genome of the nematode Caenorhabditis elegans. Proceedings of the National Academy of Sciences (USA) 83:7821-7825. del Guercio, G. 1987. Designer genes. Boston Magazine August:79-87. DeLisi, C. 1988. The human genome project. American Scientist 76:488-493. Donis-Keller, H., P. Green, C. Helms, S. Cartinhour, B. Weiffenbach, K. Stephens, T. P. Keith, D. W. Bowden, D. R. Smith, E. S. Lander, et al. 1987. A genetic linkage map of the human genome. Cell 51:319-337. Dulbecco, R. 1986. A turning point in cancer research: Sequencing the human genome. Science 231:1055-1056. Elmer-DeWitt, P., with A. Dorfman and J. M. Nash. 1989. The perils of treading on heredity. Time March 20:70-71. Friend, S. H., R. Bernards, S. Rogelj, R. A. Weinberg, J. M. Rapaport, D. M. Albert, and T. P. Dryja. 1986. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643-646. Gilbert, W. 1986. Two cheers for human gene sequencing. The Scientist October 20:11. Gilbert, W. 1987. Genome sequencing: Creating a new biology for the twenty-first century Issues in Science and Technology 3:26-35. Gusella, J. F., N. S. Wexler, P. M. Conneally, S. L. Naylor, M. A. Anderson, R. E. Tanzi, P. C. Watkind, K. Ottina, M. R. Wallace, A. Y. Sakaguchi, A. M. Young, I. Shoulson, E. Bonilla, and J. B. Martin. 1983. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306:234-238. Hall, S. S. 1988. Genesis: The sequel. California (July):62-69. Holtzman, N. A. 1989. Proceed with Caution. Baltimore, Md.: Johns Hopkins University Press. Holzman, D. 1987. Mapping the genes, inside and out. Insight May 11:52-54. Hood, L., and L. Smith. 1987. Genome sequencing: How to proceed. Issues in Science and Technology 3:36-46. Ingram, V. M. 1957. Gene mutation in human haemoglobin: The chemical difference between normal and sickle cell haemoglobin. Nature 180:326-328. Jaroff, L., with J. M. Nash and D. Thompson. 1989. The gene hunt. Time March 20:62-67. Jenks, S. 1989. Gene map budget given a boost. Medical World News February 13:94. Joyce, C. 1987. The race to map the human genome. New Scientist March 5:35-40. Judson, H. F. 1979. The Eighth Day of Creation: The Makers of the Revolution in Biology New York: Simon and Schuster. Judson, H. F. 1987. Mapping the Human Genome: Historical Background (Mapping Our Genes contractor reports, Vol. 1, NTIS Order No. PB 88-160-783/AS). Office of Technology Assessment, U.S. Congress. Kan, Y. W., and A. M. Dozy. 1978. Polymorphism of DNA sequence adjacent to human beta-globin structural gene: Relationship to sickle mutation. Proceedings of the National Academy of Sciences (USA) 75:5631-5635. Kanigel, R. 1987. The genome project. New York Times Magazine December 13:44, 98-101, 106.

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BIOMEDICAL POLITICS Kerem, B.-S., J. M. Rommens, J. A. Buchanan, D. Markiewicz, T. K. Cox, A. Chakravarti, M. Buchwald, and L.-C. Tsui. 1989. Identification of the cystic fibrosis gene: Genetic analysis. Science 245:1073-1080. Kevles, D. J. 1985. In the Name of Eugenics. Berkeley, Calif.: University of California Press. Koenig, M., E. P. Hoffman, C. J. Bertelson, A. P. Monaco, C. Feener, and L. M. Kunkel. 1987. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50:509-517. Kolata, G. B. 1980. The 1980 Nobel prize in chemistry. Science 210:887-889. Lee, W. H., R. Bookstein, F. Hong, L. J. Young, J. Y. Shew, and E. Y. Lee. 1987. Human retinoblastoma gene: Cloning, identification, and sequence. Science 235:1394-1399. Lewin, R. 1986a. Molecular biology of Homo sapiens. Science 233 July 11:157-160. Lewin, R. 1986b. Proposal to sequence the human genome stirs debate. Science 232:1598-1600. Lewin, R. 1986c. Shifting sentiments over sequencing the human genome. Science 233:620-621. Lifton, R. J. 1986. The Nazi Doctors. New York: Basic Books. Maxam, A. M., and W. Gilbert. 1977. A new method for sequencing DNA. Proceedings of the National Academy of Sciences (USA) 74:560-564. McAuliffe, K. 1987. Reading the human blueprint. U.S. News and World Report (December 28, 1987/January 4, 1988):92-93. McKusick, V. A. 1986. The gene map of Homo sapiens: Status and prospectus. Pp. 15-27 in Molecular Biology of Homo sapiens. Cold Spring Harbor Symposia on Quantitative Biology, Vol. 51. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. McKusick, V. A. 1988. The morbid anatomy of the human genome: A review of gene mapping in clinical medicine. Bethesda, Md.: Howard Hughes Medical Institute. Muller-Hill, B. 1988. Murderous Science. New York: Oxford University Press. National Institutes of Health and Department of Energy. 1990. Understanding Our Genetic Inheritance. The US Human Genome Project: The First Five Years, FY 1991-1995. Document DOE/ER-0452P. Washington, D.C.: National Institutes of Health, U.S. Department of Health and Human Services; and U.S. Department of Energy. National Research Council, Committee on Mapping and Sequencing The Human Genome. 1988. Mapping and Sequencing the Human Genome. Washington, D.C.: National Academy Press. Neel, J. W. 1949. The inheritance of sickle cell anemia. Science 110:64-66. Nelkin, D., and L. Tancredi. 1989. Dangerous Diagnostics: The Social Power of Biological Information New York: Basic Books. Olson, M. V., J. E. Dutchik, and M. Y. Graham. 1986. Random-clone strategy for genomic restriction mapping in yeast. Proceedings of the National Academy of Sciences (USA) 83:7826-7830. Olson, M. V., L. Hood, C. Cantor, and D. Botstein. 1989. A common language for physical mapping of the human genome. Science 245:1434-1435. Palca, J. 1987. Human genome sequencing plan wins unanimous approval in US. Nature 326:429. Palca, J. 1989. Gene mappers meet on strategy. Science 245:1036. Pauling, L., H. A. Itano, S. J. Singer, and I. C. Wells. 1949. Sickle cell anemia: A molecular disease. Science 110:543-548. Pines, M. 1986. Shall We Grasp the Opportunity to Map and Sequence All Human Genes and Create a ‘Human Gene Dictionary.' Bethesda, Md.: Howard Hughes Medical Institute. Proctor, R. 1988. Racial Hygiene. Cambridge, Mass.: Harvard University Press.

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BIOMEDICAL POLITICS Reeders, S. T., M. H. Breunig, K. E. Davies, R. D. Nicholls, A. P. Jarman, D. R. Higgs, P. C. Pearson, and D. J. Weatherall. 1985. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317:542-544. Reilly, P. 1977. Genetics, Law, and Social Policy. Cambridge, Mass.: Harvard University Press. Riordan, J. R., J. M. Rommens, B.-S. Kerem, N. Alon, R. Rozmahel, Z. Grzelczak, J. Zielenski, S. Lok, N. Plavsic, J.-L. Chou, M. L. Drumm, M. C. Iannuzzi, F. S. Collins, and L.-C. Tsui. 1989. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245:1066-1072. Roberts, L. 1987. Human genome: Questions of cost. Science 237:1411-1412. Roberts, L. 1989. New game plan for genome mapping. Science 245:1438-1440. Rommens, J. M., M. C. Iannuzzi, B.-S. Kerem, M. L. Drumm, G. Melmer, M. Dean, R. Rozmahel, J. L. Cole, D. Kennedy, H. Hidaka, M. Zsiga, M. Buchwald, J. R. Riordan, L.-C. Tsui, and F. S. Collins. 1989. Identification of the cystic fibrosis gene: Chromosome walking and jumping. Science 245:1059-1065. Rothstein, M. A. 1989. Medical screening and the employee health cost crisis. Washington, D.C.: Bureau of National Affairs. Royer, B., L. Kunkel, A. Monaco, S. Goff, P. Newburger, R. Baehner, F. Cole, J. Curnutte, and S. Orkin. 1987. Cloning the gene for an inherited human disorder—chronic granulomatous disease—on the basis of its chromosomal location. Nature 322:32-38. Sanger, F., S. Nicklen, and A. R. Coulson. 1977. DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences (USA) 74:5463-5468. Schwartz, D. C., and C. R. Cantor. 1984. Separation of yeast chromosome-sized DNAs by pulsed field gel electrophoresis Cell 37:67-75. Sinsheimer, R. 1989. The Santa Cruz workshop, May 1985. Genomics 5:954-956. Solomon, E., and W. F. Bodmer. 1979. Evolution of sickle cell variant gene [letter]. Lancet 1:923. U.S. Congress, House. 1987a. Fiscal Year 1988 DOE Budget Authorization: Environmental Research and Development (No. 58). Subcommittee on Natural Resources, Agriculture Research, and Environment of the Committee on Science, Space and Technology, U.S. House of Representatives. U.S. Congress, House. 1987b. Departments of Labor, Health and Human Services, Education, and Related Agencies Appropriations for 1987 (Part 4A). Subcommittee of the Committee on Appropriations, U.S. House of Representatives U.S. Congress, House. 1988. Departments of Labor, Health and Human Services, Education, and Related Agencies Appropriations for 1989 (Part 4A). Subcommittee of the Committee on Appropriations, U.S. House of Representatives U.S. Congress, House. 1989. Hearing on International Cooperation in Mapping the Human Genome. October 19, 1989, 2325 Rayburn House Office Building. Subcommittee on International Scientific Cooperation, Committee on Science, Space, and Technology. U.S. Congress, Office of Technology Assessment. 1984. Commercial Biotechnology: An International Analysis. OTA-BA-218. Washington, D.C.: U.S. Government Printing Office. U.S. Congress, Office of Technology Assessment. 1986. Technologies for Detecting Heritable Mutations in Human Beings. Washington, D.C.: U.S. Government Printing Office. U.S. Congress, Office of Technology Assessment. 1988a. Mapping Our Genes—Genome Projects: How Big? How Fast? OTA-BA-373, Washington, D.C.: U.S. Government Printing Office. U.S. Congress, Office of Technology Assessment. 1988b. Medical Testing and Health Insurance. Washington, D.C.: U.S. Government Printing Office. U.S. Congress, Senate. 1982. Nominations. Committee on Labor and Human Resources.

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BIOMEDICAL POLITICS U.S. Congress, Senate. 1987a. Department of Energy National Laboratory Cooperative Research Initiatives Act (S. Hrg. 100-602, Pt. 1). Subcommittee on Energy Research and Development of the Committee on Energy and Natural Resources. Washington, D.C.: U.S. Government Printing Office. U.S. Congress, Senate. 1987b. Workshop on Human Gene Mapping (100-71). Committee on Energy and Natural Resources. Washington, D.C.: U.S. Government Printing Office. U.S. Congress, Senate. 1988. Departments of Labor, Health and Human Services, and Education and Related Agencies Appropriation Bill, 1989, Report (Report 100-399, pp. 83-84). Senate Committee on Appropriations. U.S. Congress, Senate. 1989. The Human Genome Project and the Future of Biotechnology. Subcommittee on Science, Technology, and Space, Committee on Commerce, Science, and Transportation. (S. Hrg. 101-528). Senate Committee on Commerce, Science and Transportation. Washington, D.C.: U.S. Government Printing Office. Watson, J. D. 1986. Foreword. Pp. xv-xvi in Molecular Biology of Homo sapiens. Cold Spring Harbor Symposia on Quantitative Biology, Vol. 51. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Watson, J. D. 1988. The NIH Genome Initiative. Los Angeles: Molecular Biology Institute, University of California. Watson, J. D. 1990. The human genome project: Past, present, and future. Science 248:44-49. Watson, J. D., and F. H. C. Crick. 1953. Genetical implications of the structure of deo xyribonucleic acid Nature 171:737-738.

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BIOMEDICAL POLITICS Commentary Paul Berg This case study abounds with interesting opportunities for both retrospective and prospective analyses of science policymaking. Moreover, the study 's chronicle of the personalities, events, and decisions that led to the creation of the genome project provides a valuable record for evaluating the wisdom and effectiveness of the actions taken. Cook-Deegan's analysis also points out those policy decisions whose validity will have to be judged by events yet to come. Thus, this case study fulfills the purpose for which it was commissioned. It provides a record that is worth scrutinizing to determine how the policy and funding decisions were made and whether there are general and applicable lessons to be learned for advancing other biomedical programs. Any new initiative in science funding needs a highly visible, easily understandable goal, and champions who can articulate that goal persuasively in the offices of influence and power. By almost anyone's criteria, mapping and solving the human genome's sequence was viewed as a bold and exceedingly ambitious scientific and technical challenge, but one that would very likely be expensive in terms of resources, personnel, and funding. Aside from its initial influential group of proponents —Sinsheimer, DeLisi, Gilbert, Dulbecco, Hood, and Cantor—the plan to sequence the entire human genome, when it Paul Berg is the Willson Professor of Biochemistry and Director of the Stanford University Medical School's Beckman Center for Molecular and Genetic Medicine.

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BIOMEDICAL POLITICS became known, was met with considerable consternation and resistance. After some vacillation, Watson emerged as the genome project's chief advocate and proceeded to orchestrate support from several practicing and committed scientists. Concomitantly, DeLisi and Wyngaarden managed the legislative and budgetary complexities characteristic of governmental bodies. Senator Domenici, concerned for his DOE and state constituencies, and Senator Chiles, protective of the NIH, dominated the congressional debate and its outcome. Another influential participant was the NRC Committee on Mapping and Sequencing the Human Genome. Their report expressing unanimous support (including that of previously skeptical or opposing members) carried a great deal of weight with the scientific community and helped persuade Wyngaarden, the OMB, and the congressional bodies dealing with the proposal. The report prepared by OTA (Mapping Our Genes—Genome Projects: How Big? How Fast?; 1988a) also helped move the genome proposal toward acceptance by supporting its feasibility and emphasizing the wisdom of a phased program. The report also provided a more reasoned estimate of its costs and the ways they could be apportioned. However, the NRC and OTA reports diverged in their recommendations as to who should manage the project. The NRC chose not to express a preference for the managing agency, while OTA preferred a joint NIH-DOE management structure —a solution that may become a stumbling block in later stages of the project. However, the recently published NIH-DOE combined plan for the first five years of the project, harbors well for a cooperative collaborative research effort. This arrangement should also alleviate the often-voiced suspicions about the quality of DOE research and its peer review systems. But competition for funding and recognition between DOE's national laboratories and NIH-sponsored genome centers could threaten the presently well intentioned cooperation. Mutual understanding of research activities and a strong spirit of team play will be important ingredients of that partnership. A puzzling feature of the discussions concerning management of the genome project is why the NSF never emerged as a contender, especially as the project is indisputably science and technology based. Was this because of NSF's lack of interest or lack of competence to manage such a project? Or was it because of the project's decidedly biomedical slant? One aspect of the scientific debate is worth noting. As initially conceived, the human genome project's goal was to obtain the sequence of the 3 billion base pairs comprising the haploid genetic complement. But the debate among scientists broadened the scope of the project in several significant ways. One was to include a moderate resolution map of linked restriction fragment length polymorphism (RFLP) markers for use in locating disease genes. A second modification was to obtain a physical map of cloned DNA segments spanning the entire genome. Moreover, it soon became apparent

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BIOMEDICAL POLITICS that the sequencing efforts would have to await the completion of the first two objectives, as well as the development of faster, more accurate, and far less expensive sequencing technologies. Such a reformulation of the project was inevitable once fine scientific minds turned to developing a coherent and workable strategy. Another major modification of the original plan was to increase the number of genomes to be included in the project. This modification was not intended to add funds to an already large project, but was a result of the recognition of the close correspondence in genetic structures and functions between even distantly related organisms. Furthermore, it was evident that such relatedness would inform and speed the work on the human genome. Additionally, research with yeast, Drosophila, nematode, and mouse genomes provides experimental models with which hypotheses and technologies can be tested without resorting to human experimentation. Cook-Deegan points up several innovations in government-supported science. Besides the somewhat novel joint and coordinated sponsorship of genome research by NIH and DOE, there is the acknowledgment that ethical and cultural values need to be reconciled with the program 's objectives and applications. Including public education in that function would be helpful because one of the ingredients lacking from the debate so far has been any evidence of significant public awareness of the human genome initiative's costs and implications. The amount of funding for education and ethical studies is not as important as the fact that an ethics panel exists and that congressional support is contingent on attention to such issues. Whether ethical acceptability becomes a significant factor in judging the permissibility of initiating certain lines of basic research remains to be seen. Judging the ethical value of basic research prospectively and preemptively would be a considerable departure from current practices. Cook-Deegan's record of the project's prenatal history identifies the contending forces that shaped the debate. These include the competing research interests and priorities among the “power” and “fringe” scientists, the similar tensions in the executive agencies governing biomedical research, and the jurisdictional sensibilities of congressional committees. Even though the project gained official sanction, debate over it lingers and threatens to flare up and polarize the constituencies needed for the project's support. One of the most disturbing threats stems from the biomedical science community's still divided views concerning the project's merit, particularly in view of its perceived impact on traditional ways of supporting science; the simplistic view of this challenge is “Big Science versus Little Science.” This debate is exacerbated by the current dismal research funding situation and the bleak prospects for any remedies. The present and next year's genome budgets can hardly be responsible for the current crisis. We can anticipate that unless the virtues and benefits of the early-phase mapping studies, the

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BIOMEDICAL POLITICS availability of clone banks, and the development of improved sequence technology are seen to benefit all scientists, the sniping will continue. Moreover, if the genome budget rises to its projected steady state —$200 million per year—while the research grant crisis worsens, the project's continuation will be jeopardized. Alternatively, funding for the genome project could be stretched out, as was done in the space program. The case study does not indicate the extent to which the scientist activists, various advisory panels, or government agencies seriously considered the consequences of a fiscal crisis on Congress's ability or willingness to support the genome initiative. Perhaps this is because throughout the debate it was assumed that the project would be funded by supplemental (incremental) appropriations to NIH and DOE. Even though explicit assurances of the validity of those assumptions were never made, discussions and negotiations seemed to proceed as if the project's funding would not detract from support of investigator-initiated research in areas unrelated to the genome project. The current funding crisis for projects unrelated to the genome project and the subsequent reactions of scientists and Congress indicate that neglecting the possibility and consequences of a funding shortfall was a serious deficiency in the planning. Perhaps that oversight stems from the pace with which the project was launched. Hindsight suggests that a more deliberate review, particularly by “disinterested ” participants, could have led to contingency planning to contend with present or future difficulties in biomedical science funding.

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BIOMEDICAL POLITICS Commentary Ernest R. May This story begins in the mid-1980s. More or less at once, a number of geneticists and molecular biologists saw the possibility of mapping and sequencing the entire human genome. A few developed visions of an immense and expensive project, making an analogy with the space program. The analogy the case brought to my mind was the opening of Africa in the nineteenth century and the response of Victorian imperialists such a Cromer, Curzon, and Rhodes. For these visions to become reality, several things were needed. One was wide approval among knowledgeable scientists. Another was evidence that something appropriate could be done both bureaucratically and politically. Could any agency do it? Would the taxpayers countenance it? The first requirement was satisfied. Despite reserved commentary in Science and Nature, the visionaries succeeded in winning wide backing from their peers. An NAS panel, together with advisory committees in both DOE and NIH, helped measurably. Meanwhile, DOE-NIH competition helped both agencies come to readiness to do something on a large scale. OTA, abetted by or abetting key congressional staffers, worked out means such that the competition could end in cooperation rather than paralysis. In the larger world, local interests of New Mexico, Florida, and California enabled congressional leaders to push the project. Appeals to the sense of Ernest R. May is Charles Warren Professor of History at Harvard University.

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BIOMEDICAL POLITICS what might make a legislator's name live in history also helped. Watson's inspired decision to commit a percentage of project budgets to the study of ethical issues defused possible opposition. If this is the story—more or less—what are its lessons? Henry Kissinger used to say that no proposition was interesting unless one could imagine an intelligent person arguing the exact opposite. One way of asking about the lessons of the genome case is to ask what interesting propositions it speaks to. I see three. The first is the proposition that there should be consensus among scientists before efforts are made to construct science policy. The affirmative brief would say that otherwise, policy could be constructed on erroneous premises and/or be vulnerable in the public arena because of evidence of expert differences. The negative brief would argue, among other things, that policy may never get made if it waits for scientific consensus and perhaps science policy is too important to be left to scientists. The genome case seems to support this latter brief. The development of policy proceeded while scientists were still actively disagreeing. DOE/Office of Energy Research and OMB defined objectives, mechanisms, and tentative funding levels at a time when, according to the case, a poll of attendees at the Cold Spring Harbor conference would have voted against any early undertaking. Of course, the policy choices defined in mid-1986 were later to change, but the later effort would have been slower and different without this spadework. The second proposition is that scientists, in the process of developing a large, pathbreaking project, should think about the bureaucratics of the project as well as about the science. Affirmative: the key question is not just what to do but how, in what sequence, and by whom. Negative: what to do is a large enough question, and it is the only one that most scientists are competent to consider. Here, too, the genome case seems evidence for the negative. The efforts of the NAS panel to deal with bureaucratic implementation were, says the case, appallingly naive. It didn't matter. The bureaucracy, OTA, and congressional committees understood implementation issues. They dealt with them. The third proposition is that, in developing such a project, scientists should think about politics—that is, about the types of citizen concerns that might surface once commitment of public money enters open debate. The affirmative case is summarized in the charter for this Institute of Medicine committee. The negative case is rather like that for the second proposition—too complicated, not scientists' strong suit, someone else (more expert) should carry the can. On this third proposition, the genome case testifies for the affirmative as well as the negative. DeLisi got as far as he did in part because he recognized,

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BIOMEDICAL POLITICS and could take advantage of, New Mexicans' concern about the future of Los Alamos. Watson clearly pushed a hurdle out of his way by manifesting awareness of fears that the genome project might awaken. But the case, as written, does not show that thought about politics needed to be a major component of debate among scientists. So long as a few key figures kept the public in mind, that sufficed.