1 Challenges in the Early Years of the Human Genome Project at the National Institutes of Health

The Human Genome Project (HGP) began formally at the National Institutes of Health (NIH) in a small office in the attic of Building 1 on the NIH campus. On October 1, 1988, I moved into this office with my secretary. We had two empty desks, a pad of paper, and a pen. From this inauspicious beginning evolved the Office for Human Genome Research (OHGR), which became the National Center for Human Genome Research (NCHGR) in 1989 and, after the addition of an intramural program, eventually the current National Human Genome Research Institute (NHGRI).

We had no money. The money for genome research had been appropriated by Congress to the National Institute of General Medical Sciences (NIGMS). NIGMS had issued solicitations for grants and established a subcommittee of its Advisory Council (often referred to as simply “Council”) to help review them. We relied on NIGMS staff to do all the work of managing a grants program. This state of affairs did not last long, as we soon heard that Congress would appropriate genome funds to OHGR in the second and future years instead of to NIGMS. Although welcome, this did not mean we were out of the woods. Every year the appropriations process was a nail-biter. Would we be zeroed out? How much would we get? We spent much time briefing Office of Management and Budget and Congressional staff about the HGP. The genome community also educated staff and testified to the benefits of this program. All these efforts were successful in getting us the funding we needed after a rapid ramp up.

The Superconducting Supercollider was under consideration at the same time. It was cancelled in 1993 and never finished. We were often compared: two multibillion-dollar projects competing for the federal purse. Fortunately, we could truthfully argue that the HGP would not need to build an expensive machine before generating scientifically and medically relevant results. Useful results would be produced at every stage along the way. In addition to new technology, there would be maps and sequences of model organisms, all valuable even when incomplete (see Appell 2013; United States Congress 1994).

In order to manage the budget and be able to award grants, we had to quickly assemble a varied staff with expertise in the scientific and financial management of grants, personnel, budget, and other administrative areas. It was a very busy first year. To cap it all, we changed our name to the National Center for Human Genome Research, connoting that we had been appropriated our own budget by Congress and had authority to spend it and make grants (see NHGRI Internal History Archive. Scanned Francis Collins Files, Box 1366B file 001).

The administrative challenges were many, but with full support from NIH Director James Wyngaarden, we were able to meet them. We were fortunate to be able to recruit staff excited by the goals of the HGP and committed to making a success of this novel program. The staff brought a “can-do” attitude and a determination to make it work. The NCHGR was organized like a little typical NIH center. (For background, see Harden 1998 and NHGRI Internal History Archive, Scanned Francis Collins Files, Box 7076, file 031.) There were scientific staff called program directors, an executive officer, budget officer, grants management officer, information officer, and a personnel officer. Mark Guyer (see Guyer et al. contribution in chapter 2) came with me from NIGMS and became a kind of program coordinator, pulling all the program parts together; his first title was assistant director for scientific coordination. Other program staff were recruited gradually from both within and without NIH. The administrative staff all came from NIH because we needed people who knew how to operate in the NIH environment and could hit the road running.

However, many other challenges awaited us in the early years. The HGP was not universally welcomed. In fact, there was strong opposition to it in the scientific community, as reflected in articles and letters, as well as among the public, as reflected in the press. Scientists were afraid that the HGP would drain money from more deserving and creative areas of research. The HGP looked to them like a mundane repetitive endeavor of little scientific value. They were afraid it would change biology as we know it forever. They were partly right but did not appreciate how much it would change biology for the better and benefit their very own research. Many letters complaining about the HGP came to us, some stimulated by specific individuals who started letter-writing campaigns. Regardless of to whom they wrote, the letter was forwarded to us for response. If the letter was from a VIP, the response would be signed by an appropriately important person in the government, but if the letter was from a typical scientist, the response was signed by me. We were deluged. To help us cope, we developed a standard reply that went out to all writers. That helped a lot (see my responses to opponents of HGP in NHGRI Internal History Archive, Scanned CPLB, Box 5 31 Letters Opposing the Human Genome Project 1990).

A different set of concerns motivated the non-scientific public, including the bioethicists. They feared we would create monsters, designer babies, and all manner of unnatural creatures. We assured them that was not our goal and there was no evidence that would happen. Our best defense against these concerns was the effort all HGP supporters made to give talks around the country on what the HGP was really about. Jim Watson was a prime contributor to this publicity campaign, but many others participated too. At one of these occasions, Watson had the brilliant idea that we should set aside a small percent of our budget for studies of the ethical, legal, and social ramifications of genome research. In one stroke, this changed the tenor of the discussion. Instead of writing complaining letters, the community now set to work writing grant applications. Our small budget allocation (5 percent of the Center’s budget) for Ethical, Legal and Social Implications (ELSI) of the Genomics Research Program made a big difference to the field of bioethics. In fact, the program announcement for the ELSI specifically discussed funding proposals from investigators, which reflected bioethical concerns on, among other topics, “The uses and misuses of genetics in the past and their relevance to the current situation,” which included “the eugenics movement in the U.S. and abroad” and “the misuse of behavioral genetics to advance eugenics or prejudicial stereotypes” (NHGRI Internal History Archive, Scanned Francis Collins Files, Box 1380, file 010).

We were fortunate to be able to recruit a young bioethicist to head the new ELSI program, who also was well grounded in science. Eric Juengst had a BS in biology and a PhD in philosophy of medicine from Georgetown University. He had the confidence of the bioethics community as well as our confidence that the grants funded under this program would be based on accurate research. Eric has since become the Director of Social Medicine and Director of the Center for Bioethics at the University of North Carolina and continues to work on the ethical aspects of genetics.

The ELSI program became well known and is viewed as a model for how socially sensitive research should be conducted, that is, by including the study of ethical, social, and legal issues in the research design. The science must be cognizant of the ethical issues, as the ethics research must be based on accurate science and not pure speculation. For more details, see the contribution of Joy Boyer and Jean McEwen in chapter 10.

Watson was a part-time consultant to the NIH, but based in Cold Spring Harbor, New York. He was busy traveling the country with two goals: recruiting scientists to work on the HGP and giving lectures to clarify exactly what the project was going to do and what it was not. He called the office frequently to share his findings and ideas, but aside from occasional visits, he left day-to-day management to the NCHGR staff. When he called, you could be sure your plans for the day were upended.

The HGP was envisioned as an international program and coordination of all the components was a challenge. Early on, the NIH executed a Memorandum of Understanding with the Department of Energy (DOE) (for the memorandum see NHGRI Internal History Archive. Scanned Francis Collins Files, Box 1366A-024). This proposed an “inter-agency working group” as well as spelling out how information on the progress of mapping and sequencing would be shared and joint activities undertaken, including the shared management of an early genomics data resource the “Genome Data Base.” The DOE had actually started a genome project at two of their National Laboratories before the NIH program came on the scene. Their early efforts at technology development and bioinformatics as well as mapping remain underacknowledged. The DOE had been studying the biological effects of atomic radiation since the atom bombs were dropped on Japan in World War II. The DOE expected the human DNA sequence to assist in these studies. Over time, NIH took the lead, but throughout the period of the HGP there was close collaboration with DOE on all aspects of the project. Congress appropriated money to both NIH and DOE to manage this program jointly. On the historical role of the DOE in radiation research and its connection to the HGP see Lindee (2008).

This took some ingenuity, as the cultures of the two agencies were so different. DOE funded research mostly through its National Laboratories, which are operated under contract with DOE. NIH was accustomed to funding research under grants, which are generally much more investigator led. Our funding cycles during the fiscal year were different. NIH could fund grants on the last day, whereas DOE needed to make funding decisions several months before. However, as we gained knowledge and understanding of each other’s requirements, we managed to live in relative harmony.

Collaboration internationally was less formal. There was widespread interest in many countries in participating in the HGP, particularly England, Germany, France, Japan, and the former USSR, which were just emerging from communism (see NHGRI Internal History Archive, Scanned Box 013, file 006). Watson hoped to set up an international advisory group that would be called Human Genome Organization (HUGO) and would coordinate all these pieces. Watson worked hard to interest the Howard Hughes Medical Institute in taking this on, but it never happened for a variety of reasons (on HUGO and Howard Hughes, see Maynard Olson interview 2016).

Nevertheless, coordination did happen on a scientist-to-scientist level. We had a steady stream of visitors from abroad in our offices wanting to learn our plans and how they could participate. Our response was that there was no central body controlling who could participate, but this should be worked out by scientist-to-scientist negotiations. There was plenty of work to go around. However, each country would have to come up with its own funding. The Wellcome Trust in England became one of the major contributors of funding outside the US government and became a key partner with NIH and DOE. They funded the Sanger Centre in 1992, which became one of the big sequencing centers, as well as a number of international meetings.

Some countries decided to take unusual roles for their participation. For example, Spain decided to host international meetings emphasizing the ethical, legal, and social implications of genome research. The meetings were held at Valencia in very lovely surroundings (see NHGRI Internal History Archive. Scanned Subject Files, folder 26, Hearing on Coop of Int Human Genome Project, 19 Oct 1989 [1 of 2]). At one of those meetings, Watson met Nancy Wexler and after talking to her decided that she should be appointed to the NCHGR Advisory Committee. As a person with a family history of the genetic condition known as Huntington’s Disease and a genome researcher herself, she filled an important role and became a primary spokesperson for us on ELSI issues. She gave talks, granted interviews that were televised, and was a resource to us for our ELSI program.

The need for an Advisory Committee for the HGP was identified early on and was endorsed by the “Ad Hoc Program Advisory Committee on Complex Genomes,” a group convened by the NIH director to advise him on how to proceed with the HGP. We set to work right away to recruit members. Norton Zinder became the chair. He was a longtime friend of Watson’s and a devoted supporter of the HGP. It was determined that his committee would provide the best possible assistance and advice. The committee met for the first time in early 1989. Watson saw the committee as giving legitimacy to the HGP and recruited a wide range of the most prominent scientists available. (For materials related to these early meetings, see NHGRI Internal History Archive, Scanned Francis Collins Files, Box 1211, folder 014.)

The first order of business for the Advisory Committee was to create a robust plan for the HGP. This was not going to be investigator-initiated research as the NIH customarily funded, but plan-driven research with quantitative goals. It was believed that only that way would the exceedingly ambitious goals be met. Fortunately, some of the planning was already done for us by two groups that preceded the formal establishment of the HGP at NIH. The first was the National Research Council Committee on Mapping and Sequencing of the Human Genome, which published its report in 1988. The second was the Office of Technology Assessment, which issued its report “Mapping our Genes” (Office of Technology Assessment 1988) also in 1988. Both of these groups determined that the HGP should start by mapping and sequencing some key model organism genomes and focusing on technology development. The “Ad Hoc Program Advisory Committee on Complex Genomes” meeting in February 1988 also endorsed the general approach of the other groups. The latter committee further advised the NIH director to establish a special entity, apart from any institute, to manage the HGP, so it would not be perceived as competing with other programs. These recommendations led to the recruitment of Watson and resulted in my sitting in the attic of Building 1 to start the ball rolling (see the “Administrative Plan” for the Office of Human Genome Research NHGRI Internal History Archive, Scanned Francis Collins Files, Box 1210, folder 044).

Our new Program Advisory Committee on the HGP also endorsed the previous recommendations as to the general approach. But the broad guidelines of these prior groups were not sufficient to guide a funding program; more quantitative measures were seen as necessary. After much heated debate and soul searching, goals for the first five years emerged. Finding the right balance between realism and ambition was a challenge. The goals had to be ambitious but not impossible. We were guided by the prior estimates that the HGP would cost $200 million per year and take fifteen years. The first five-year plan was published as a pamphlet in April 1990 with appropriate appendices and explanatory text. It became a very popular document worldwide and had to be reprinted several times. The five-year plan and its successors became the guiding principle for the international project (National Center for Human Genome Research et al. 1990).

A major topic of debate from the beginning was how quickly data should be publicly released by the laboratories that produced it. Several of the early proponents of the HGP were scientists working on model organisms. Those communities were accustomed to sharing information with each other rapidly and found that this approach expedited research and ultimately benefited all. They brought this worldview to the HGP and lobbied for a similar approach to data release in the HGP. There was also strong belief among HGP scientists that DNA sequence data must remain in the public domain (on early data sharing policy see NHGRI Internal History Archive, Scanned Box 443, folder 12).

The human genome was felt to be the property of all mankind and therefore must remain free of commercial entanglements such as patents claiming ownership of any parts of the sequence. On the one hand, the data producers argued they should have a chance to look at their data before publishing; on the other hand, scientists using the data wanted it as soon as possible and argued this would speed research. Once large-scale sequencing began, this issue was all resolved by the adoption of the Bermuda Principles (agreed to at a meeting in Bermuda in 1996), which laid down rules for rapid data release for all who participated in the HGP. By mandating rapid release, the Bermuda Principles also addressed the patenting issue: There would not be time to file patents before data were released (see Guyer et al. in chapter 2).

We adopted our own policy on data release for those grants that were not large-scale data producers. We asked applicants to describe their plans for sharing data and materials. These plans were peer reviewed and if not satisfactory were negotiated prior to any grant award.

Rapid data release also had side benefits. As the sequence of model organisms was released, the value of the sequence became evident to even the ardent critics. Everyone turned to lobbying for their favorite sequence to be determined next. Criticism of the HGP as a frivolous endeavor ceased for the most part.

Rapid data release in large-scale projects was subsequently adopted in other areas of research and has been widely endorsed. Along with ELSI, these two science management policies emanating from the HPG have had broad impact.

In order to release large quantities of data rapidly, you need someplace to release it to that can handle customer demand. Here, the National Center for Biotechnology Information (NCBI) of the National Library of Medicine at NIH played a leading role along with similar centers in Europe and Japan. The recruitment of David Lipman as head of the NCBI was a key contribution to the HGP.

The director of NIH is a political appointee and so subject to dismissal whenever there is a change of administration. When George Bush became president in 1989, Wyngaarden unfortunately had to leave and was eventually replaced by Bernadine Healy. Both Wyngaarden and Healy were physicians, but their styles could not have been more different. Where Wyngaarden was thoughtful, modest, and warm, Healy came determined to fix the NIH. She particularly believed that the NIH budget should be supplemented by private funds to make it less dependent on Congressional appropriations.

At this time Craig Venter, who was an NIH employee at the time, came up with a novel way of identifying genes. He proposed that small snippets of the coding region of genes, named expressed sequence tags (ESTs), could uniquely identify genes without the need to know the whole gene sequence. Craig and Bernadine together developed a proposal to patent ESTs and use the patents to enrich NIH. Most scientists were appalled, because they believed DNA sequence free of patent protection was the best way to maximize research productivity. They also saw genes as a product of nature that was not an invention under patent law.

Foremost among the opponents of Healy’s plan was James Watson, and he freely expressed his misgivings. At a Congressional hearing where both he and Venter were witnesses, Watson opined that ESTs could not be patented because any monkey could produce them. This was obviously in direct opposition to Healy’s position and ultimately led to Watson’s resignation in 1992. Having two such strong-willed people vying for the limelight at NIH was never going to be a stable situation. (For more discussion of this controversy, see NHGRI Internal History Archive, Scanned Francis Collins Papers, Box 7096, folder 021.)

Fortunately for us, Healy was an admirer of the HGP. It was the kind of bold, ambitious project she liked, even if she did not care for the people managing it. We were given an acting director, Michael Gottesman, and carried on without Watson. Michael spent his time assuaging the concerns of our grantees and shielding the staff from direct confrontations with Healy. One positive outcome of this stressful time was that Bernadine Healy recruited Francis Collins to become the full-time permanent director of NCHGR in 1993. At last, we were on a solid footing. Francis negotiated as part of his recruitment that NCHGR would add an intramural component and lobbied to make NCHGR a full-fledged NIH Institute, the NHGRI. Jim Watson had already argued for that, but it took several years to come to fruition in 1997. At the next general election, Healy was replaced by Harold Varmus, a reliably strong supporter of the HGP. The challenges were not over, but they entered a new phase.

Finally, I want to mention one area that was not a challenge but a huge benefit. Developments in computer hardware and software were coming at least as fast as the HGP, and without them the HGP could not have succeeded. Remember there was no reliable email, no readily accessible internet, no Google when we started. PCs were big and clunky, cell phones, let alone smartphones were only a dream. All these technological wonders, as well as sophisticated developments in software, came along and worked synergistically with the HGP to make it all possible. Sophisticated email allowed rapid communication around the globe, and the internet allowed scientists to share data rapidly and easily and enabled the Bermuda Principles to be implemented. Computers became faster and smaller, as sequencing machines were challenged to handle ever larger amounts of data.