NIH Chief Varmus, In His Second Year, Credited With Reinvigorating Agency

Questions remain about the low-key director's handling of clinical research, Congress, and scientific misconduct Not yet two years into his tenure as head of the National Institutes of Health, Harold E. Varmus is getting high marks from many scientists for his low-key, but thorough efforts to rejuvenate the agency's biomedical research effort. Initiatives to sharpen the basic science being done on campus and to streamline the peer review of proposals from outside researchers are bringing new energy to the health agency from top to bottom, they say. "Varmus has looked at NIH afresh from, I think, every perspective, both intra- and extramurally," says Samuel C. Silverstein, chairman of the physiology and cellular biophysics department at Columbia University College of Physicians and Surgeons and president of the Federation of American Societies for Experimental Biology (FASEB). Some scientists and others maintain that NIH director Harold E. Varmus has given short shrift to questions of research integrity generally, and has failed to concretely address long-standing cases of scientific misconduct involving agency researchers. In particular, a recent investigative report from former chairman Rep. John Dingell's (D-Mich.) subcommittee on oversight and investigations of the House Committee on Energy and Commerce, as yet officially unreleased, charges Varmus with failing to take appropriate steps to resolve the case involving NIH researcher Robert C. Gallo. The report finds that Gallo misappropriated the HIV virus from French researchers at the Pasteur Institute in Paris and was guilty of scientific misconduct, and that federal officials--not including Varmus--participated in a cover-up of evidence in the case. According to the report, Varmus was presented with new evidence in February 1994 demonstrating conclusively that the virus could only have come from the French labs to Gallo's lab. "Varmus failed to take action," says Suzanne Hadley, an NIH employee who helped prepare the Dingell committee staff report. "But it wasn't that he denied the truth. For example, in dealing with Dr. Gallo's use of the Pasteur virus, Dr. Varmus's response was to get impatient and say, 'Well, didn't we already know this? This is old stuff, isn't it?' That's quite an extraordinary kind of reaction, because, by implication, he was saying, 'Why is this important?' "The reason it's important for you, Harold Varmus, is because you are now the NIH director. You are now in a position to do something about this and to make it clear whether there is anything to all this stuff about science being self-correcting. Essentially, it was put up or shut up time--and he decided to shut up." Researchers who have seen the report agree that the time has come for firm, official action in the case. "The director of NIH should issue a public apology to the Pasteur Institute--that's number one," contends William A. Hagins, a neurophysiologist at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "Number two, they should make the committee staff report a part of the NIH annual report for this year, so it becomes an official printed government document that everybody can then read. And then the director of NIH should ask that the government remit all the royalties it's collected on the HIV [blood test] patent to the Pasteur Institute. "If Varmus were to take this course of action, the administration would probably fire him, in which case he would become a hero. He'd be known as the first director of NIH that actually stood for something and did the right thing when it was called for." According to Frederic M. Richards, a professor of molecular biophysics and biochemistry at Yale University, the genetic-sequencing evidence reported by the Dingell committee establishes crucial issues of timing in the case. Richards headed a National Academy of Sciences panel formed at then-NIH director Bernadine Healy's request to review an investigation of the Gallo case by the agency's now-defunct Office of Scientific Integrity. The panel's report, delivered in February 1992, affirmed the NIH investigation's assessment of wrongdoing in Gallo's lab but was essentially ignored by Healy. "I was disappointed that Varmus didn't take stronger action on this," Richards says. "Gallo is still running his laboratory, isn't he? I find that mind-boggling. The fact that he's still at NIH--well, maybe--but it does seem to me a little peculiar that he's still running the lab." "I haven't seen any remarkable leadership coming out of NIH on this front," remarks Robert L. Sprague, a professor of psychology at the University of Illinois. Sprague was the whistle-blower in a case in which a University of Pittsburgh psychologist, Stephen Breuning, pleaded guilty to fraud in United States District Court in Maryland in 1988. Sprague says that Varmus's inattention to misconduct cases represents an "insensitivity to the mood of the country" on these issues. "We have been running a real risk," Sprague asserts. "If we lose public confidence because of some of these things, science will be hurt badly." --F.H. Varmus's predecessor, cardiologist Bernadine Healy, was praised in the scientific community during her time in office for specific efforts, like her promotion of women's health issues and the appointment of Francis S. Collins to head the National Center for Human Genome Research. But her corporate-style strategic plan for the agency also engendered widespread displeasure among researchers (F. Hoke, The Scientist, April 19, 1993, page 1). For the current director, however, something like the reverse appears to be the case--he is being applauded for his systemic changes at NIH and criticized, instead, for a handful of perceived oversights. Among these are concerns that he may be short-changing clinical research in his push to reinvigorate basic science at NIH and that he has neglected his crucial relationship with Congress. In addition, there are charges that he has failed to adequately address issues and specific cases of research misconduct, especially the case of NIH researcher Robert C. Gallo (see accompanying story). The view of most scientists, patient advocates, and others interviewed for this article is of a top biomedical scientist--Varmus shared the 1989 Nobel Prize in physiology or medicine--bringing long-needed changes to one of the leading institutions of his profession. Varmus declined to be interviewed for this article, although spokeswoman Anne Thomas provided information about his programs. "He's activated a lot of interest within the NIH itself, and within the community at large," reports Ira Mellman, a professor of cell biology at Yale University and chairman of one of the NIH study sections responsible for reviewing extramural grant proposals. "Even bureaucrats who I thought were brain dead for years have, all of a sudden now, really gotten into the process of administrating and looking for new ways to do things. "It reflects what happens when you have a true scientist in charge of such an organization. A lot of the civil-servant types are coming out of the woodwork now, with just fantastic ideas." Some scientists, however, contend that Varmus, who came to NIH never having run an organization larger than his own lab, has become overly reliant on a small group of NIH career bureaucrats to administer the gangling agency (see story on page 7). In moves generally welcomed as long overdue by scientists and that belie the image of an inexperienced federal administrator, Varmus has launched broad plans of renewal in both the intramural and extramural programs at NIH. The aim, partly, is to correct some of the agency-wide problems--with recruitment and retention, for example--consistently identified by critics. Changes to the intramural program, now being implemented by deputy director for intramural research Michael Gottesman, respond in large measure to a congressionally mandated review of the program begun before Varmus's appointment and completed last April, only a few months after his confirmation. The review was conducted by a committee chaired by Memorial Sloan-Kettering Cancer Center president Paul A. Marks and University of Alabama microbiology department head Gail Cassell. Though not obligated to act on the so-called Marks-Cassell report, Varmus has chosen to expedite the vast majority of the recommendations. A number of changes suggested by the report to strengthen the intramural research program have already been made and others are in process. Among these are the implementation of more uniform, rigorous reviews of intramural scientists and institute scientific directors to more closely tie promotions and additional resources to scientific merit. While other reforms have gone forward as suggested, and reviews of scientists are widely seen as improved, one central change in this area has not been implemented, for a combination of regulatory and other reasons, according to NIH officials. The report had suggested that to bolster the independence of the institutes' boards of scientific counselors, who perform the reviews, new members be selected by a vote of current board members, rather than by the institute scientific directors, as is currently the case. Some intramural scientists feel that the lack of this procedural reform is unfortunate. "The review process has gotten more rigorous, there's no question about that," says one cell biologist, speaking on condition of anonymity. "And that, I think, is good. That's the way it should be, because then you get rid of the junk. But it hasn't been smooth sailing. NIH is still an institution where merit is not the basis for things. It's your relationships with people that are the basis for things. So, I don't think the power shift has happened--if anything, the scientific directors may be stronger now." Varmus has pushed forward a number of detailed administrative changes that, taken together, are expected by supporters to make recruitment and retention of top scientists at the institutes more successful. For example, he recently arranged for an extension of Title 38 authority to NIH. Title 38 of the United States Code, Chapter 74, is a federal law, primarily used by the Veterans Administration, the Bureau of Prisons, and the Department of Defense, that allows physicians in the civil service to receive a salary boost of up to $100,000 to compensate them for choosing government service over more lucrative careers. The provision will be used to augment the salaries of clinicians at NIH. National Institutes of Health director Harold E. Varmus is too dependent on the counsel of a small group on veteran agency bureaucrats, according to some researchers. "There's no reason to believe that having been a co-winner of a Nobel Prize is going to make you into a person of vision or a person who is going to a be a gifted administrator," observes one biochemist with more than two decades' experience in NIH research labs, now in the private sector and speaking on condition of anonymity. "What happened was that Varmus came in and all of the serpents crept out of the cracks in the walls and took him over. And he fell under their spell. "They have all the answers for him, and he lets them solve his problems. All of the policy that he's supposed to have made was not actually made by him but rather by some of the denizens of Building One [NIH administrative headquarters]. They're the only people he listens to." Other scientists call this an uncharitable view of the facts of life in a federal agency and of a director, perhaps unused to administration, making the best use of an experienced staff to quickly take control of and run the NIH. "He's essentially getting his advice from the insiders who have been running the place for many years," says William A. Hagins, a neurophysiologist in the laboratory of chemical physics at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "Insiders run any big institution, year in and year out, and they're still the ones being consulted. But I suspect that he knows that and has ways of getting alternative views." Hagins says that Varmus is more visible on campus and more accessible than was former NIHhead Bernadine Healy, lending a "less uptight" air to his directorship. Varmus occasionally attends scientific lectures on campus, intramural researchers note, and meets for lunch with small groups of scientists to talk about their research. Patient advocates, too, say they see more of the current director than they did of his predecessor. Varmus has reached out to include their views, they report. "The patient community was not invited to participate or have any input at NIH before Dr. Varmus got there," says Abbey S. Meyers, executive director of the National Organization for Rare Disorders in New Fairfield, Conn. "[Healy] didn't want to hear from patients." New York-based AIDS activist Larry Kramer, however, presents a different view of Varmus. "The man is invisible," Kramer says. "My own personal problems concern AIDS, which, as far as Varmus is concerned, doesn't seem to exist at NIH. It's not a subject that interests him." Overall, many scientists express surprise at and disagree strongly with the perception of the NIH director as being under the influence of insiders, noting that Varmus has consistently reached out for independent advice. "His decisions are not predicated upon the advice of any single group within the NIH," asserts Ira B. Black, chairman of the department of neuroscience and cell biology at the Robert Wood Johnson Medical School of the University of Medicine and Dentistry of New Jersey and a past president of the Society for Neuroscience in Washington, D.C. "What's impressed me is that [Varmus] has not hesitated to ask a number of us to come down and give him our opinion about various directions, both strategic and tactical, that he and the NIH should be taking." --F.H. "That will go a long way toward stabilizing the situation with our clinical investigators, for whom the salary differential between NIH and the medical schools is particularly great," observes Edward Korn, scientific director of the National Heart, Lung, and Blood Institute. Korn notes, too, that Varmus is working to create a Senior Biomedical Research Service that would allow for somewhat higher salaries for nonclinical researchers at NIH. The new service would also offer a portable retirement plan, so that, for example, scientists coming from academia would be able to retain their university retirement plans. Varmus also was able to arrange for the authority to make appointments to the Senior Executive Service, the top level of civil service, to be delegated to him from higher in the Department of Health and Human Services. In addition, a newly enhanced tenure-track program is expected to help with recruitment and retention. "He's had a positive effect on the morale of the intramural research staff," Korn says. "People like myself who didn't know him but just knew that he'd never been an administrator for any group bigger than his own research group, wondered whether he could really take on something the size of the NIH and the interactions at all levels of government that are required. But he's done it very well." Like intramural NIH science, extramural activities have also come under Varmus's scrutiny. Many of the changes he is directing find their impetus in Vice President Albert Gore Jr.'s initiatives to "reinvent" government, NIH officials say. Under deputy director for extramural research Wendy Baldwin, several experiments to improve and streamline the peer-review process for grants have been tested. These include the so-called triage and just-in-time procedures. In triage, initial reviewers identify applications--up to 50 percent of the total--that they consider unlikely to win funding. These then are not discussed and scored by the full study section, allowing more time for in-depth assessments of the remaining proposals. If a single member of the section objects to the classification of a given proposal as noncompetitive, it receives full discussion. Beginning this month, triage will go into effect throughout the extramural review process. Some researchers have complained that, given the level of effort that goes into a proposal, potential investigators deserve a thorough review by the full study section. They also suggest that the feedback from the full review process increases the likelihood of improved future proposals. But reviewers note that all submissions receive a detailed critique by a qualified reviewer, even when they are not considered by the full study section. A goal of triage, NIH officials stress, is to contribute to an improved review. "The work load that had been placed on study sections before the initial screening process actually tended to interfere with adequate review of those applications that really did stand a chance of being approved and funded," according to Ira B. Black, chairman of the department of neuroscience and cell biology at the Robert Wood Johnson Medical School of the University of Medicine and Dentistry of New Jersey and a past president of the Society for Neuroscience in Washington, D.C. "So, I would say that triage actually sharpens the process." The just-in-time procedure, being tested in several NIH divisions, allows a grant candidate to postpone submitting certain types of data not needed for a review of the proposed science, such as complete supporting budgetary details, until an award seems likely. At that time, data would be requested "just-in-time" for final consideration. The aim of this effort is to lessen the paperwork burdens associated with both preparing and reviewing applications. "The extramural community is very pleased by the just-in-time grants submission process and by the triage type of review," FASEB's Silverstein declares. "There are a number of areas in which he's been as innovative in this job as he has been in his science," observes Black. While basic scientists in both the intramural and extramural community praise Varmus's efforts to improve their lot, clinicians are concerned that they may not be getting their fair share of support. Indeed, a recent NIH study found that patient-focused extramural studies were the least likely of any research category to receive NIH funding, with an overall proposal success rate of only 13 percent. "There's a general fear out there that [Varmus's] focus on basic research is doing great harm to clinical research," says Abbey S. Meyers, executive director of the National Organization for Rare Disorders in New Fairfield, Conn. "Especially in the rare disease community, that is of utmost importance and perceived as a real threat. The reason is that with orphan diseases there is no commercial interest in clinical trials of a new treatment, so we've always counted on NIH to do those clinical trials." Meyers's group defines orphan diseases as those affecting 200,000 or fewer U.S. citizens. Some NIH veterans agree that clinical studies at the agency are due for a revitalization. "It's not clear anymore what the role of clinical research is at the NIH," observes George R. Martin, scientific director of the National Institute on Aging until joining the biotechnology startup FibroGen Inc. in Sunnyvale, Calif., late last year. "My feeling is that it's essential if we're going to get translation of anything that we're doing [in the basic research labs] into practical [therapies]. You have to have the NIH supporting clinical research, and that's something that it seems to me we've fallen away from." Martin adds that, in so strongly advancing fundamental research at NIH, Varmus may be "losing track of the fact that it's the National Institutes of Health, not the National Institutes of Basic Biology." Here again, however, Varmus's supporters maintain that he has been responsive and is moving to address criticisms. Late last month, he named Lawrence Shulman, former director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, to serve as an "emissary" to the clinical research community. Shulman is expected to play a role similar to that of Howard Schachman, Varmus's ombudsman with extramural basic scientists. Also, a high-level "blue-ribbon panel" is being organized at Varmus's direction to review the entire range of clinical research supported by NIH, and the director of the clinical center at NIH, John Gallin, has begun a new effort to upgrade clinical training at the institutes. "Are we doing as good a job in clinical research as the world acknowledges that we are doing in basic research?" asks Black. "[Varmus] is well aware of the importance of clinical research, and he's really pursuing [that question] seriously." One criticism that detractors have leveled at Varmus is that he has failed to make NIH's case strongly enough on Capitol Hill, preferring to work among his fellow scientists at NIH and in academia. "I'm sure he could do more, and perhaps that's what he should do," Mellman says. "But I don't think that he's been completely invisible, by any stretch of the imagination. And you can also make the argument that he is putting a priority on more effectively spending the funds that have already been awarded and, as a result, has concentrated on getting the NIH's house in order." "This is a difficult time to expect anyone to do much in terms of the budget, given the economic climate and the change in the Congress," notes Korn. "We can't expect miracles." Many scientists are satisfied with the emphasis Varmus has placed on science at NIH rather than on politics. Although he has, at times, become entangled in highly charged national debates--for example, during his recent effort to establish funding policy for human embryo research--his primary focus has been on facilitating innovative research, they say. "The director of the National Institutes of Health should not be a politician, but should be a scientist," Black contends. "We don't need more politicians involved in science. We need scientists at the helm who are articulate, thoughtful, and can represent fairly and adequately to the Congress exactly what it is that we have been able to achieve. And I think [Varmus] is doing that."

NIH Chief Varmus, In His Second Year, Credited With Reinvigorating Agency

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