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VARMUS: LIKE A ROLLING
by Fran Pollner
In the last month of the twentieth century, Harold Varmus took his leave of NIH. He offered "valedictory thoughts" to his scientific advisory committee at his final meeting with them; he bid fond adieu to the NIH community gathered in Masur Auditorium to laugh away the pangs of parting (see "Coda," below); and he obliged reporters from The NIH Catalyst, the NIH Record, Nature, Science & Government Reports, Washington Fax, and the Blue Sheet with a farewell interview.
Time To Go
Why are you leaving? asked a reporter. "It began to feel repetitive," Varmus said, especially the annual appropriations process. And, he added, there was also the matter of "timing": "To have gone deeply into my sixties would have reduced the chances of getting another really good joband this particular job became available now," he said of the opportunity to head the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. "In an ideal world, I probably would have left [NIH] one year after the next administration came in"in which case he would have gone through two more of those appropriations shuffles he does not relish but which he counts among the priorities for the NIH leadership.
Its up to NIH leaders to chart and promote the "right flight path" for future budgets, he said. Its also up to them to recognize that technologic advances and the "genomic revolution" could drive "deeper divisions in access," in which case, he told his advisory group, "we wont have achieved the NIH mission of improving the public health and we will look like an institution that serves the elite." Similarly, he told reporters of his concern that "were going to cut a significant proportion of the population out of the benefits of certain approaches to health that are paid for with public money and that ought to be publicly accessible." Current NIH initiatives related to research into health disparities should help, as should tapping the wisdom of the NIH directors Council of Public Representatives (COPR), an activity his successor would be well-advised to engage in seriously and often, he said.
"I was slow to appreciate the importance of a nonsectarian council like COPR, a good sounding board," he said, for scientific, political, and ethical matters, especially equity and health disparity issues.
Varmus repeated his suggestion that NIH be reconfigured into perhaps five "clusters" that would logically organize existing centers and institutes and discourage add-ons, but such a proposal from him or any NIH official, he said, would appear self-serving. Rather, he hopes Congress or the National Academy of Sciences will some day arrive at a similar conclusion based on independent study, and then such a reorganization could be accepted and implemented. His own dim view of proliferating NIH institutes is well known, he noted. Far better, from both scientific and administrative viewpoints, are NIHs new interdisciplinary Neuroscience Center and the new transinstitute Office of Bioimaging and Bioengineering (asked for and received in the appropriations bill).
But there are still some components of the intramural research program that "are too far removed from the centers of activity. These [geographically] outlying groups are a worry," he said.
Nearly out the NIH door, Varmus nonetheless used the word "we" frequently in addressing future courses of action for NIH. It was also clear, however, that his future at the biomedical complex on New Yorks East Side was close upon him and he was eager for it.
The Varmus Lab
"I will be at a place," he said, "where cancer research and cancer treatment coexistat a strong institution, with interesting neighbors (New York UniversityCornell Medical Center, Rockefeller University) and many good friends and colleagues." And, of course, hell be taking his lab with hima lab, he proudly said as the interview opened, that had "just received a quite favorable review" from NCI. He noted with bemusement that someone had asked, "Whos going to run the Varmus lab now?" as if it were a permanent entity at NIH and not the work-in-progress of the person who brought it to NIH and would be taking it with him when he left.
Indeed, at the MSKCC, Varmus will have more time to spend in that lab than he did at NIH, where, he said, he really couldnt "settle in" in the hour or so a day and off-hours that he had there. Half his time in New York, he said, will be in his hospital executive office and the other half will be in his lab. The administrative aspects of the new job may actually be more onerous than his counterpart tasks as NIH director, which dealt less with administrative details than with the broader policy issues he enjoys grappling with. Nonetheless, its the science thats most compelling, and the science in the Varmus lab, he said, has been centered on "two major themes":
Getting better models for studying human cancer in the mouse. No longer confined to making transgenics and crossing them with knockouts, the Varmus team has been using viral vectors to deliver conditional genes to organs expressing target receptors. The repertoire has included oncogenes, tumor-suppressor genes, marker genes, and recombinases, or genes programmed to be rearranged. Theyve been working with tumors characteristically hard to grow in cell culture, such as gliomas and breast tumors, and are crafting models for lung, pancreatic, and ovarian cancer. Ultimately, knowledge of gene abnormalities in human cancer should yield therapeutic and preventive interventions that are less toxic and more effective than currently available agents. It should also yield a more profound understanding of metastasis.
Understanding how growth and differentiation factors (such as WNT proteins, fibroblast growth factors, and hedgehog and TGF-b genes) signal the cell nucleus to alter the way the cell behaves. Varmuss interest in signaling was "activated" about 20 years ago, he said, when he and his colleagues discovered the first WNT gene and traced the role of WNT1 in cancer development after the insertion of viral DNA from the mouse mammary tumor virus.
The World at Large
Asked if he would miss his role in the international arena, working on such problems as malaria, he replied: "Id miss it if I lost it, but I dont think I will." Hell likely be a consultant to the World Health Organization and will soon be traveling to India; hell also continue his involvement in PubMed Central, which, he said, is an "important issue in international health and the support of science in the developing world."
Beyond that, hell be rejoining the steering committee of the American Society for Cell Biology, from which, he said, he was apparently granted a "six-year leave of absence." And hes been asked to join the "p53 Club" in New York, as well as many other clubs, athletic and scientific, that he will consider once he figures out how much time his job leaves him for other pursuits. Among other things he looks forward to are New Yorks artistic offerings, having to answer to "fewer bosses," and "more flexible interactions with the private sector," although he intends to "serve only on nonprofits."
But he will leave behind the NIH intramural program, which "from the first day I arrived here, Ive really enjoyed" his scientific collaborations, the seminars, the interest groups, the "esprit," and the campus building boom. He lauded the speed with which NIH was able to respond to a perceived national needboth physically and intellectuallywith the building of the Vaccine Research Center and recruitment of Gary Nabel as its director.
For none of these aspects of NIH for which he expressed appreciation did Varmus take credit. He even punctuated his praise of the Clinical Centers activity level and clinical research on campus in general with an aside that though he himself did not contribute to the clinical side of NIH studies, his research had benefited from its resources, such as the small animal imaging facility.
But he had some good things to say for his handling of several matters as NIH director.
On patents: "I chose not to pursue intellectual property rights on anonymous cDNAs, and I think that was the right decision. Why prosecute a claim you dont think should be made? Im pleased the Patent Trademark Office is closer to our position now: that the specific utility must be known in order to patent a squence."
On material transfer agreements: "Were not trying to lay down a strict law but to move the scientific community to a more generous mode of behavior. We had a major success with Cre-Lox technology, and although our hold is less secure with corporate entities that dont have NIH funding, the movement is in the direction of greater sharing."
On PubMed Central: "Once its unveiled, the public interest will soar."
On stem cell research: "This issue will continue to heat up. I look back with a sense of pride at the Human Embryo Research Report of 1994, which was prescient [regarding issues raised in 1999]."
On his past actions to recast the role of the NIH Recombinant DNA Advisory Committee (RAC): "I have no objection to its being put on the table [that RAC again approve gene therapy protocols], but I think its the wrong way to go. Jesse Gelsingers death would not have been prevented if the RAC had approval authority, and NIH is not a regulatory agency [see Catalyst coverage of the RAC meeting in December on these matters, Gene Therapy Trial and Errors, this issue]. I dont think we should respond to this unfortunate episode by returning RAC to what was a somewhat dysfunctional state. Now its working well."
Asked if he had any disappointments, he said he rued his lack of visible success in increasing the numbers of investigators from minority backgrounds. "I havent seen major changes. . . . Perhaps you couldnt in just six years."
The Partys Over: As the NIH troops filed out, a few remained for parting photos (left to right): HHS secretary Donna Shalala, Tracey Rouault (NICHD, keyboardist), now acting NIH director Ruth Kirschstein, Chuck Allerson (NICHD, drums), NIAID director Tony Fauci, Francis Collins (NHGRI director, "lead guitar"), Harold Varmus, Connie Casey, Richard Klausner (NCI director, "lead guitar"), Steve Katz (NIAMS director, "lead guitar"), and John OShea (NIAMS, bass, "the only one who knows how to play a guitar").
band hierarchy provided by Richard Klausner
Celebrating Harold Varmus and, at the same time, saying goodbye to him is what "bittersweet" is all about, said Tony Fauci, NIAID director and emcee at a farewell sendoff for Harold Varmus in the month before the NIH director would officially leave his position to head to New York City and the Memorial Sloan-Kettering Cancer Center.
"Its been "six years and 23 days and counting," Fauci said, as if when that ball dropped 15 days laterat midnight in Times Squarethe roar from the crowd would not be "Happy New Year" but "Welcome, Harold!"
Paeans mixed with jokes for a couple of hours as farewell messages rained down upon Harold Varmus. HHS Secretary Donna Shalala was on hand to voice her deep respect for Varmus brillianceand his unique sense of fashion.
And a videotaped "documentary" from the "troops" showed that however much Varmus may inspire awe from the world at large, hes more than fair game for the inspired wit of his NIH colleagues, about a dozen of whom deadpanned hilarious answers to such questions as: "Why did Harold Varmus hire you?"
The event rocked to a close with a stellar performance by "The Directors," NIHs unparalleled rock band, and their doctored lyrics of sixties hits that ended with the exhortation "Oh, wont you stay . . . just a little bit longer . . . . please, please, please, please . . . say-ay you-ou will. . . ."
But he wouldnt.
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