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An initiative is under way to make the center an NIH institute; critics, however, argue that unnecessary redundancy would result. The National Center for Human Genome Research (NCHGR), which directs the National Institutes of Health's part in the Human Genome Project (HGP), is poised to become an institute. The necessary steps to change the center's status are already in motion, according to director Francis Collins, who supports the move. PROS AND CONS: Supporters note progress in NIH’s Human Genome Project under the direction of Francis Collins; critics, however, question some of his actions. NIH officials say the status change would not make much difference in authority or power. While most centers and institutes may differ substantially in their structure and research sponsorship capabilities, "NCHGR essentially has the same authority as an institute already," comments Diane Wax, NIH associate director for legislative policy and analysis. Becoming an institute "is probably a bigger deal perception-wise," she states, adding that NCHGR differs from most NIH centers. It has an intramural research program and the authority to give intramural research training awards (IRTAs); most centers do not. The process of going from a center to an institute is not a simple one. According to NCHGR deputy director Elke Jordan, it can happen one of two ways: either by law or by an administrative act by the Secretary of Health and Human Services (HHS). In NCHGR's case, HHS Secretary Donna Shalala wrote in July to both Senate and House appropriations committees responsible for NIH. She sent letters to Senate Committee on Labor and Human Resources chairwoman Nancy Kassebaum (R-Kan.), and to the ranking member, Edward Kennedy (D-Mass.). In the House, letters were sent to Committee on Commerce chairman Thomas Bliley (R-Va.) and ranking member John Dingell (D-Mich.). The members of Congress have 180 days to consider the proposal. Though that waiting period is over this month, several bureaucratic hurdles remain before anything becomes official, according to Jordan. She cautions that the process is far from a sure thing: "You have to watch the political mood." With the Republicans' focus on reducing government, there's little enthusiasm for creating another institute, the deputy director points out. "More bureaucracy means a larger NIH, which creates additional budget overhead and is more difficult to manage." Collins and many others in the scientific community see the status change as important. Being an institute "presents certain advantages," he says. One of these concerns review of grants, programs, and major policies by an advisory board, which Collins calls "no small matter." An institute can award a grant of up to $50,000 without advisory council review, while a center requires council approval prior to awarding any grants or undertaking other ventures. Currently, if NCHGR wishes to help sponsor a conference or immediately begin funding additional work on a new scientific finding, it must wait for its advisory council to meet. At the same time, Collins maintains that aside from "subtle administrative issues, the scope of what we do and our funding would not change. That should be reassuring to those who worry that it would shift resources. . . to genome [research] and away from something else." ‘REASON FOR DOUBT’: William Haseltine says it’s too early to tell whether NCHGR has been successful. Yet critics believe a genomics institute is unnecessary. They contend that many institutes already have their own genomics research programs, so a separate genomics institute would be redundant. An institute devoted to cancer or heart, lung, and blood disease, for example, can combine genomics research with the institute's more specialized resources and expertise to study a specific disease or organ system. "The work of understanding genes goes across institutes," contends William Haseltine, president and CEO of Human Genome Sciences Inc., a genetic testing and genomic sequencing company in Rockville, Md. The former NIH scientist argues that "genomic mapping and sequencing techniques should be integrated into all efforts. Confining it to one institute would hamper medical research at NIH." A CONSIDERATION: David Sidransky thinks a genome institute might jeopardize research projects better done here. Cancer geneticist David Sidransky at Johns Hopkins Oncology Center agrees. He believes that cancer genetics-and its resulting ethical, legal, and social issues-should be studied in the National Cancer Institute (NCI). Sidransky, an associate professor of otolarygology, head and neck surgery, and oncology, notes that although NCHGR provides necessary genomics research tools, he would not want NCI-related projects to be centered there: "Technology developed at NCHGR should be integrated into all the institutes that would benefit, rather than setting up [a separate] institute around a center that is essentially technology-based." Most scientists and officials applaud NCHGR's leadership in the HGP. The $3 billion, 15-year international effort to identify and sequence some 100,000 human genes is ahead of schedule and under budget, according to Collins and others. "The HGP has gone remarkably well," says Maynard Olson, who directs one of six NCHGR-funded sequencing centers at the University of Washington. "It has had a much greater impact on biology than anyone expected." HGP officials hope to catalog all functional human genes, ushering in a new era of molecular medicine. This would provide new opportunities to diagnose, treat, and prevent disease. The project has already contributed to the discovery of genes involved in Alzheimer's disease, Huntington's disease, cystic fibrosis, breast cancer, and amyotrophic lateral sclerosis. Among other accomplishments, NCHGR has helped to develop sophisticated new genetic maps that shed light on the potential locations of thousands of genes, and to create genetic databases. Its division of extramural research, established at the center's inception in 1989, funds HGP research in chromosome mapping; DNA sequencing; database development; and ethical, legal, and social issues in institutions across the United States. A PLAN: Jeffrey Trent sees NCHGR’s intramural mission as using the genome project’s findings to improve human health. In 1993, the center expanded, establishing the intramural research division. According to NCHGR intramural scientific director Jeffrey Trent, the intramural division's mission is to "take the fruits of the HGP and apply them to human health problems." Its aim is to find human disease genes and to develop diagnostics and gene therapies. The division has established programs in gene therapy, among other areas. It recently opened a Center for Inherited Disease Research to focus on the genetics of complex disorders, such as diabetes and Parkinson's disease. NCHGR scientists have contributed to some notable discoveries. In November, for example, NCHGR's researchers, along with colleagues at Johns Hopkins University and Umea University in Sweden, found the location of a prostate cancer gene (J.R. Smith et al., Science, 274:1371-4, 1996). Earlier, scientists at NCHGR, the National Institute of Neurological Disorders and Stroke, the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, and the Istituto de Scienze Neuologiche in Naples reported the location of a Parkinson's disease gene (M.H. Polymeropoulos et al., Science, 274:1197-9, 1996). NCHGR scientists have been instrumental in unraveling the complex nature of inherited breast cancer in the Ashkenazi Jewish population. ONE HAPPY FAMILY: Barbara Weber sees a genome institute as the focal point for research collaborations. A genome institute would be fine with Barbara L. Weber, an associate professor of medicine and genetics at the University of Pennsylvania and a former collaborator of Collins's. Weber sees NCHGR as both an information resource and a focal point for research collaborations with other institutes and researchers. "Whether it becomes an institute or not, it will have to tie the [genomics work of many] institutes together. Right now, researchers at NHLBI [the National Heart, Lung, and Blood Institute] don't necessarily have to talk to NCI scientists, for example. But NCI and NCHGR work very closely together," because of NCI's interest in cancer genetics. Similarly, NCHGR scientists might work with other NIH researchers in identifying genes and developing diagnostics for diseases such as Alzheimer's disease and diabetes. Peter D. Meldrum, president and CEO of Myriad Genetics Inc., a genetics testing company in Salt Lake City, also sees a place for a genome institute. "[An institute] demonstrates the importance of genomics in most areas of biomedical research," he says. Its work "will help yield new therapeutics for disease." Yet some see a genome institute as unwarranted because it would be technology-based. "Traditionally, institutes haven't been established around technologies; they've been focused on disease and organ systems," explains Olson, a professor of medical genetics and genetics at the University of Washington School of Medicine. MULTIPLE PLAYERS: Craig Venter notes that researchers outside of NCHGR have also contributed to the genome project. Former NIH scientist J. Craig Venter, president of The Institute for Genomic Research (TIGR) in Gaithersburg, Md., a nonprofit research organization that is also an NCHGR-funded HGP sequencing center, acknowledges NCHGR's contributions to the HGP. Yet he points out that NCHGR is only one player in the genome-sequencing game. TIGR scientists, for example, have sequenced several bacterial genomes, he notes. Other institutes, such as the National Institute of Allergy and Infectious Diseases, have sequenced the malaria genome. NCHGR, he says, appropriately is "a center aimed at a specific goal. It's a technology-driven program aimed at generating data." This, he says, is hardly the typical description of an NIH institute. Some scientists say it's too early to determine if the center's efforts have been successful. Collins and others contend that there is little doubt that available technology will enable scientists to meet the 2005 deadline for sequencing the genome. Yet Haseltine points out that NCHGR, with only 1 percent of the genome sequenced to date, "still hasn't proven that [the HGP] can accomplish its task." He's also critical of NCHGR's efforts to sequence the genome of the common bacterium E. coli. The fact that this project has yet to be completed is "reason for doubt" over whether NCHGR can sequence the entire human genome, he contends. It takes researchers at his company "about three weeks to sequence a bacterial genome and a couple of months to analyze it. NCHGR hasn't done one." In addition, Haseltine sees an "intrinsic conflict of interest" in Collins's role as center director. He calls it "unusual" that Collins manages external development, which includes managing the funding of his potential competitors, as well as internal resources, including his own laboratory. These issues "would need to be addressed if the center became an institute." Collins's managerial skills have been questioned as well. He recently admitted that a University of Michigan graduate student who had worked in his NCHGR laboratory fabricated data. As a result, Collins retracted several published studies (Notebook, The Scientist, Nov. 11, 1996, page 30). While many note that Collins's scientific credibility has not been shaken, some question his ability to oversee NCHGR, particularly while maintaining his own lab. "It's a serious question," says TIGR's Venter. In a letter to the New York Times (Nov. 7, 1996, page A32), Lowell M. Greenbaum, vice president, emeritus, for research at the Medical College of Georgia, rebuked Collins for not checking experimental results sooner. "The mentor deserves chastisement for this failure to conduct checks, especially if the results will have great consequences," he wrote. AGAINST THE GRAIN: Maynard Olson says a genome institute goes against the traditional NIH model. Scientists see many challenges facing NCHGR. Collins says the biggest one is to put the genome-sequencing effort into high gear by the end of 1997. "We don't know how much trouble we may have with certain parts of the genome-we've only done 1 percent to date," he acknowledges. Collins discussed what he terms "Genome 2" and the future of the HGP at a Washington, D.C., conference titled "Science in Crisis at the Millennium" in late September (S. Benowitz, The Scientist, Oct. 14, 1996, page 3). At the meeting, he noted that a challenge for NCHGR and medicine in general will be to confront the period of a decade or more in which scientists will have mapped and cloned disease genes. Society will be in an "unknown area between sequencing the gene and understanding the basic biological defect involved, and then developing diagnostics and medicines," he said. Collins adds that "we should identify opportunities, based on the whole genome sequence soon existing, for other institutes. We shouldn't compete, but find those gaps." He believes that NCHGR's role is likely to evolve as more involved relationships develop with institutes. Some observers think the center should broaden its focus and study not only disease genes, but also the normal functions of genes. Haseltine faults NCHGR and the HGP for "a limited view of biology. It [HGP] focuses on heritable disorders, and not the major focus of biology, which is what the genes do in normal tissues." He would like to see a new specialty he calls "genomic biology" integrated into every institute. "What does genomic science tell us about cancer, for example, or the workings of the nervous system or the heart, lung, and blood?" he asks. In the meantime, genetic mapping and sequencing continue. Collins explains that "there's discussion of designing the ultimate genetic map, much denser than now, where you could find more variations-polymorphisms-in the sequence. It would take a lot more investment." He contends that DNA chips-a technology that synthesizes short segments of nucleic acids that correspond to the gene under study and binds them directly to silicon computer chips-will allow researchers to sample sequence information rapidly. DNA chip technology essentially allows large numbers of genetic mutations to be identified simultaneously. The chips and their attached probes are incubated with copies of the patient's gene being tested. If the gene has the same sequence as the probe, it will bind and be detected. While some criticize NCHGR for its lack of technology development, Weber credits NCHGR with helping speed the development of DNA chip technology. On the other hand, she feels that NCHGR needs to increase the development of "faster, better technologies." "It would be unfortunate if sequencing technologies did not meet the need," says Collins. "We will continue to push [the development of] new technologies." Another major challenge is the future of NCHGR's Ethical, Legal and Social Implications (ELSI) program, which Collins says is a source of constant criticism from scientists and others. ELSI's charge is to identify and make recommendations on matters dealing with the use of genetic information. Yet many question its specific role, if any at all, in policymaking, and the usefulness of identifying issues and sponsoring scholarly studies rather than specifically addressing appropriate policies. A recent report released by an advisory group, the Joint NIH/DOE Committee to Evaluate the Ethical, Legal, and Social Implications Program of the Human Genome Project, suggests replacing the ELSI Working Group, an advisory body, with two other committees. One would make recommendations on the ELSI research agenda, the other on policy. The report also urges Shalala to charter a new federal panel as an advisory committee on genetics and public policy. Few of NCHGR and HGP's achievements will be appreciated if the ethical, legal, and social consequences of genetic information regarding privacy, discrimination, and testing, among other issues, are not adequately addressed, Collins agrees. As the center lurches toward institute status and the HGP gallops to completion, Collins is pleased with the scientific progress, but he is concerned about the ability to protect people against misuses of genetic information. Efforts to thwart such misuses must continue, he concludes.

Plan For NCHGR Receives Mixed Reaction

Jan 19, 1997

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