AIDS Research's Intrepid New Navigator

by Seema Kumar

Earlier this year when William Paul, a noted immunologist (read hard-core scientist), accepted the politically charged job of heading the NIH Office of AIDS Research (OAR), a few eyebrows in the scientific and political communities rose a couple of inches: Some questioned whether Paul had the political pizzazz to pull this job off, and others wondered why he was putting himself under the microscope where his science belonged. Now six months later, the eyebrows are still raised, but with pleasant surprise at the way Paul has deftly weaved his way through the fiefdoms and bureaucracies surrounding AIDS politics, emerging unscathed.

"Bill Paul is one of the most thoughtful of an extremely talented group of laboratory chiefs at NIAID, and I was very happy that Dr. Varmus had the imagination to select him to head the OAR, even though he did not have a track record in AIDS research," says John Gallin, Paul's ex-boss and now Director of the Clinical Center and Associate Director for Clinical Research. "Bill seems to be applying the same careful and thoughtful approaches to leading OAR as he did at NIAID." So far, Paul seems to have won the approval and support of the various factions involved in the fight against AIDS -- policymakers, Congress, activists, and intramural and extramural researchers.

But some of the truly tough scrutiny that Paul must face is yet to come. As Director of the reorganized OAR with new funding powers, Paul holds a $1.3 billion purse string and has the power to direct which areas of AIDS research will be funded and how the money will be divided among the 21 institutes. But more importantly, Paul will be making global decisions about the direction AIDS research will take, and various groups in the scientific and political circles, including the intramural scientists at NIH, are anxious to see what those decisions will be. They will include how he sets the balance between clinical and basic research in AIDS, what he deems to be AIDS and AIDS-related research, and whether his office will control the intramural AIDS budget.

Clinical vs. Basic Research on AIDS

One of the most important issues that OAR faces is selecting the proper mix of clinical and basic research on AIDS. On the one hand, says Paul, there seems to be general agreement among the various stakeholders, including activists, that real progress in combating AIDS will result from basic research on the immune response to HIV-1 and on the pathogenesis of AIDS. On the other hand, says Paul, "there is also a desperate need to move rapidly in the clinical front.... We don't have the luxury of simply saying, 'All we are going to do is basic research and as soon as we have [that] well understood, we will turn our attention to a more clinically oriented program,' because this epidemic is decimating large parts of the world."

However, given that "money is not infinite, you have got to make choices," says Paul. Although many activists, disillusioned with inadequate current therapies for AIDS, now support substantial shifting of resources from clinical to basic research, Paul says his own view is a little more conservative. "I would prefer not to see large shifting in the level of effort" and resources from clinical to basic research, says Paul, because it won't be long before new generations of vaccines and drugs, such as the protease inhibitors, are ready to be tested. Instead, says Paul, OAR plans to streamline the clinical program, which grew too rapidly under emergency room-like conditions at a time when saving lives was the only priority. "When you are responding to a medical emergency, you not only grow rapidly but also in ways that are not very efficient," says Paul. By making the AIDS clinical program give "more bang for the buck," Paul hopes to free up funds for basic research.

But even for the basic research areas, Paul will have to make tough choices among the growing number of AIDS-related research subdisciplines -- an issue that has some NIH-supported scientists worried.

AIDS and AIDS-Related

Paul says that the decision to fund will be easy for "areas of research that provide fundamental insights into the nature of the disease, effective therapies, good vaccines, and other preventative approaches." Unfortunately, says Paul, there is no telling where those insights will come from; "they may come from a [non-AIDS] area." OAR will certainly fund research in related areas where a reasoned case for AIDS-relatedness can be made, but it will be harder to fund areas that show only peripheral or tangential connection to AIDS. To guard against the possibility that some currently unrelated but potentially important research may be squelched by the lack of OAR funding, "the research budget for the NIH as a whole will need to grow," says Paul.

"We believe that to support AIDS research generously and at the same time to starve the rest of biomedical research is a very unwise thing and will run the serious risk of slowing the progress in AIDS," says Paul. "The better the biomedical research program at NIH is supported, the less important it becomes for the AIDS research to start supporting things that are more and more difficult to show a direct connection to AIDS," he says.

Paul also points out that whether or not a given area of research has a valid connection to AIDS is very subjective. "Each individual [has] a different view of what is AIDS-related, and that view is going to be predicated on their vision of the key factors in the pathogenesis of AIDS." For example, says Paul, for a researcher who believes that HIV's crossing of mucosal barriers is a key step in sexual transmission of HIV, any research that sheds light on mucosal barriers would be important to AIDS. But for a researcher from an alternative school of thought, who believes that the virus does not cross the mucosal barriers at all but only enters through wounds or abrasions, mucosal barriers would constitute an area unrelated to AIDS.

Paul says that he would prefer not to have to make these choices, but since he must, he relies on OAR's coordinating committees and representative members of the various factions in the AIDS community to provide him with the knowledge base on which to make the decisions. OAR's five coordinating committees, each with 10 extramural and intramural NIH scientists, meet for one to two months to produce a draft plan that is distributed to the institutes for comment. OAR then convenes a two-day workshop in which the coordinating committees meet with scientists from universities, research institutes, and pharmaceutical and biotech firms and with members of various community and activist organizations to review and revise the plan to reflect a consensus. OAR then reviews the plan with a smaller ad hoc group, consisting mainly of outside scientists, to look at the balance of clinical and basic research and at AIDS vs. AIDS-related research and to prepare the final version of OAR's strategic plan. The plan is submitted to the NIH Director, HHS, and Congress. "We did this last year and we will do it again this year. We really feel that the only way to have any broad support for this effort is by the reality and the perception that the scientific community as a whole has a strong input into this plan," says Paul.

OAR and the Intramural AIDS Budget

One issue that has not been fully resolved is whether OAR will control the intramural AIDS budget. The answer, says Paul, is no -- at least for the moment. Paul explains that the legislation gives OAR responsibility for funds over and above those needed for the continuation of ongoing research. Money that is already committed to ongoing research, such as grants and contracts that are not up for competitive renewal, for example, must be transferred promptly to the institutes. The entire intramural program has been interpreted, at least for this year's budgeting process, as falling within the purview of already-committed money. However, says Paul, "this interpretation is an issue that needs to be discussed."

Paul argues that the legal interpretation that the intramural program falls into the commitment base is, for intramural scientists, a double-edged sword. Although it may simplify life and make resources more predictable, "It does have a potential bad point, however, and that is that because funds committed to the intramural program will never be reviewed again, it makes the OAR inherently more conservative about increasing funding to the intramural program compared to the extramural program." Paul says that in the extramural setting, if increased funding in a given area turns into a dead end, OAR has the authority to change the level of funding when the grant or contract comes to an end. But any increase of funds to the intramural program remains there, even if the project is no longer fruitful. "Clearly, then, we would be much more willing to try [a risky] experiment outside of NIH because if it doesn't work, we can redirect the money. Inside, we cannot. That is a problem," says Paul. "In the long run, being considered part of the commitment base may not be good for the intramural program."

Paul suspects that many people will disagree with him, and he wants to tread softly on this matter "because it is a very tender area and we certainly don't want to give the idea that this is a power grab." However, says Paul, "the logical consequence seems to me inescapable: it is not necessarily in the intramural program's interest to be fully isolated." Paul would like to see the institutes and OAR jointly devise a solution that gives OAR a voice in the intramural AIDS funding but is at the same time as unintrusive as possible.

No Regrets

In the meantime, Paul has no regrets about accepting the position. He says he took the job simply because he thought it was a very important one and he owed it to NIH -- where he has been since 1968 -- to try to help if he could. "Very few of us who work in the lab, no matter how successful we are, [get a chance] to make such a direct contribution to human health," says Paul. "Here was a challenge of a very high order to make a great impact on the health of many people. If you can make a contribution, you have a responsibility to try. So while I might not have sought the position, I had great difficulty [turning it down]." The decision, says Paul, was made easier because "the new leadership at NIH made me believe that there would be a kind of setting in which one could really carry out this work."

Paul admits that his job does encroach on the time he can spend at his lab, where he has retained his research group and remains Chief of the Laboratory of Immunology at NIAID. "I accepted the position [as head of OAR] with the agreement that I would do it for a limited period of time and return to the lab. I am still interested in doing that." Paul says that being the OAR Director does not present any conflicts of interest with doing his own research at NIAID. "I don't do AIDS research, so I don't get any AIDS money," he says.

Paul says he has already profited from his current position which has given him an appreciation for the challenges and difficulties that people in the administration face and the creativity it takes to solve the problems. "I have a better appreciation than those of us who work in labs often do of how important and difficult and challenging the roles of people who do administration are. And it is very exciting and new, and it is very important," says Paul.