Epilogue T I HE JANUARY 1,1993, issue of Science announced that Francis S. JL Collins of the University of Michigan had agreed to direct the NIH genome program,1 confirming rumors that had persisted since midsum- mer. Collins agreed to join NIH on condition that a significant intramural genome research capacity be created on the NIH campus in Bethesda, Mary- land, so he would not have to give up active laboratory work. Collins agreed to make the move despite a cut in pay and the disruption of one of the most secure scientific empires in human genetics. Several members of his group, including himself, were funded by the Howard Hughes Medical Institute. This highly prestigious and financially stable base was buttressed by an NIH- funded genome research center linked to the University of Michigan. The University of Michigan combined one of the best state-supported universities with a medical school that had chosen soon after World War II to emphasize human genetics. Stanford geneticist David Botstein, for one, be- lieved that his unusually broad and deep training at Michigan—with exposure to excellent molecular biology and world-class human genetics, including pop- ulation genetics—gave him the requisite background to prepare him for the 1978 insight about the importance of a human genetic linkage map.2 Con- struction of just such a map helped spawn the revolution in human genetics that began in the 1980s. Why would Collins leave such an enviable position to direct a federal program? His answer: "Because there is only one human genome program. It will only happen once, and this is that moment in history. The chance to stand at the helm of that project and put my own personal stamp on it is more than I could imagine."1 Recruiting Collins was a major coup for NIH director Bernadine Healy.3 She had to go to considerable lengths to secure precious laboratory space on NIH's campus, displacing other research groups and thus engendering strong antipathy among those who had waited for years to get it. Healy's own future became quite cloudy with the election of President Bill Clinton, and she an- nounced on February 26,1993, that she would leave the NIH directorship by June 30.4 In her statement, Healy singled out among the major initiatives she 342 The GENE WARS hoped would continue after the end of her two-year tenure the NIH strategic plan, women's and minorities' health initiatives, recruitment of scientific tal- ent, and an expanded Human Genome Project. It seemed likely that attracting Francis Collins, as part of the expansion of the genome project, would be an important part of her legacy. Collins was on everyone's short list for the job, probably the only person about whom that could be said. His scientific qualifications were unques- Francis S. Collins was successfully recruited by Healy to head the NIH genome program, following Watson's resignation. Collins, a leading re- searcher in the field, had been at the University of Michigan, where he directed the team that found genes for several hereditary diseases, including cystic fibrosis. Courtesy National Center for Hu- man Genome Research tioned. Together with Lap-Chee Tsui of the University of Toronto, Collins had directed the team that first found the cystic fibrosis gene,5"7 and his was one of two teams that found the gene for neurofibromatosis, type I.8"11 (The other group was directed by Ray White at the University of Utah; while the two groups had initially collaborated, they parted company, only to cross the finish line almost simultaneously.) Collins was an integral part of the collab- orative team organized by Nancy Wexler to search for the Huntington's dis- ease gene,12 and his group was in the hunt for an early-onset familial breast cancer gene mapped to chromosome 17, near the neurofibromatosis gene. Collins and his group were thus in the thick of some of the most conspicuous gene quests. That work, in turn, was coming to define a deep current in the mainstream of biomedical research. Collins continued to work in medical genetics and genetic counseling, one of but a few first-rank molecular biologists to maintain clinical skills. The clinical work gave him an instinctive feel for the impact of genetic information on families. He had a keen appreciation of and support for the ethical, legal, and social issues program. He had followed the ELSI working group's efforts Epilogue 343 on cystic fibrosis pilot-testing programs. People who worked closely with him at the University of Michigan were tracking several issues in close collabora- tion with the ELSI research program, especially those related to Huntington's disease and breast cancer. Collins was also rare among genome scientists in accommodating religious interests. He was comfortable speaking publicly about his religious beliefs, as when he spoke to a group of theologians at a March 1990 conference, noting how his Christian values reinforced his commitment to biomedical research.13 This breadth of clinical and scientific background and appreciation for the broader context in which the science was being performed made him an ideal candidate to direct the NIH genome research effort. Even as Collins began to grab the reins, the NIH part of the genome project was on its way to becoming a fully entrenched part of the bureaucracy. The NIH authorization bills, S. 1 in the Senate and H. R. 4 in the House, both formally authorized the National Center for Human Genome Research. The genome center had been created by administrative action within the De- partment of Health and Human Services, with agreement of the appropriation committees. The new authorization statute gave the genome center more permanent status, so that a future Secretary of Health and Human Services could not simply dissolve it. The bills also mandated that at least 5 percent of the budget go to the ELSI program. The House and Senate NIH bills were put on the fast track in 1993, largely because they had been vetoed by President Bush the previous year over provisions concerning fetal-tissue research. Sev- eral members of Congress promised during the 1992 presidential campaign to pass the law early in a Clinton administration if Bush lost the election. Bush did lose, and the NIH bill did indeed receive early attention from Congress. The Senate went so far as to introduce NIH authorization as its first bill for the new Congress. President Clinton signed it into law as Public Law 103-43 on June 10,1993. This special attention to NIH authorization ironically posed a problem for Collins. He aspired to transform the National Center for Human Genome Research into the National Institute for Genomics and Medical Genetics, making clear its broad mandate and conferring full institute status upon it. Collins was not yet the director of the genome center as the bills were transiting Congress, however, and AIDS research and fetal-tissue research provisions commanded almost all the political energies of the bills' congressional cham- pions. He was thus poorly positioned to succeed in effecting last-minute changes in the NIH bill. The NIH genome center would have to wait a few more years, until the next authorization cycle, before it could become an NIH institute by statute. (An agreement to pursue institute status through action within the administration, however, was part of the recruitment package that brought Collins to NIH.)14 When Healy resigned as NIH Director on June 30, Ruth Kirschstein replaced her as Acting Director on July 1, 1993. As the transition began at NIH, David Galas at DOE also announced he was departing, to U.S. budget for genome research grew sharply from 1987 onward, before leveling off at a total of about $170 million per year, as shown in this bar chart, representing the two main U.S. programs. Figures for the Department of Energy (DOE) are for its Human Genome Initiative. The 1987 budget reflects funds reprogrammed from other areas; earmarked budgets within DOE began in 1988. The National Institutes of Health (NIH) figures for 1988 and 1989 correspond to earmarked funds spent at the National Institute for General Medical Services and coordinated by the Office for Genome Research, part of the NIH Director's office. The National Center for Human Genome Research was established at the beginning of fiscal year 1990 and acquired its own budget. Figures for 1993 are estimates based on congressional appropriations. Figures for 1988-1992 are based on appropriations, adjusted for actual expenditures. 110 DOE NIH 1 100 1987 1988 1989 1990 1991 1992 1993 FISCAL YEAR Epilogue 345 become part of the scientific team at Darwin Molecular, Inc., a new biotech- nology company based in Seattle. In August, President Clinton announced his nomination for NIH Director: Harold Varmus, a Nobel laureate cancer re- searcher from the University of California, San Francisco. While the NIH genome center was attaining statutory sanction, the ge- nome project as a whole became the exemplar of yet another major policy debate, this time over commercial investments. Private corporate investment in genome research became fashionable in 1992 and 1993. The prospects for attracting private capital had changed dramatically in five years. Whereas Wal- ter Gilbert had great difficulty in finding venture capital to launch the Genome Corporation in the spring of 1987, a symposium devoted to solicit interest among pharmaceutical firms, organized by Craig Venter and Gilbert, drew a respectable audience in September 1990.15 Translating intellectual interest into direct financial investment, however, took several more years. By early 1993, in contrast, many of the most prominent genome researchers were being approached by venture capital firms, major pharmaceutical houses, and other sources of private funding.