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Harden: Would you explain to me how the theory of amyl nitrites as a cause of AIDS fit in scientifically and intellectually? I believe that for a brief period it was considered very important.
Sell: The general theory was that an infectious agent could penetrate more easily if there was laxity or expansion of the blood vessel system. This occurs with amyl nitrites, which causes laxity of blood vessels, meaning that an infection could spread more easily once it penetrated. It was thought that populations that used amyl nitrites were more susceptible to the infection than other people. Early on, when we didn't know what the virus was, there was a proposed link with amyl nitrites, but it turned out to be simply a link between amyl nitrite use and the population which was most at risk, the homosexual population. They were the main target of the infection, the main source of transmission to each other, and some ninety plus percent of them apparently used amyl nitrites.
Harden: But amyl nitrites themselves do not cause immune depression?
Sell: There was even some suggestion that there was some modification of immunity by amyl nitrites. It could not sufficiently explain it anyway. There is some potential link between the use of amyl nitrite, however, in the development of Kaposi's sarcoma in AIDS patients once they are infected. I don't know if that is valid or not, but it would make some sense because Kaposi's sarcoma is a disease in which there is blood vessel change and that could be related to the use of agents that cause expansion and laxity in blood vessels. That, however, has not been substantiated. To my knowledge, the effect of these agents on the immune system never was sufficient to explain either susceptibility or spread.
Harden: You have talked about the beginning of the NIAID intramural AIDS program. Could you describe the work of some of your key investigators?
Sell: In those early days, Dr. Anthony Fauci had just been made laboratory chief of the Laboratory of Immunoregulation. The first patient was admitted on his service, and very quickly he began to do some innovative clinical activities like transplanting bone marrow from one normal identical twin to his twin with AIDS. He also entered into several treatment trials, using things that would modify the immune system. We spent several hundred thousand dollars for new immunological agents that were just then becoming available in order to look at things that could modify the immune system in these patients. So he was involved in seeing patients, studying them to confirm the immunological damage that was occurring and then conducting an extensive treatment trial. [Dr.] Clifford Lane was the main person in his laboratory who took care of these patients. There were several Fellows in the laboratory who did a lot of the investigative work, but Lane was intimately involved as a full-time participant in these programs.
We asked people in some of the other laboratories to assist–I already mentioned Richard Wyatt. We asked people in Dr. Chanock's laboratory to look at specimens to see whether or not parvovirus or serum parvo-like viruses were present in the tissues. They were not. Mal Martin is a physician and an infectious disease person, a molecular virologist who had switched his attention to retroviruses. He became interested in AIDS early on. I can remember one conference at which we had a young lady, Dr. Françoise Brun-Vezinet/Barré, who came from Montagnier's lab in France. She had just presented some data at a meeting in New York and then came down to NIH. We had a weekly session in our intramural program, in which we talked about in-house research or invited outside speakers to come in and talk about things that might relate to the AIDS issue. She came and presented her evidence of having isolated the first retrovirus from a patient who didn't have AIDS but who had enlarged lymph nodes. Mal Martin was very interested, and subsequently, he developed the contact with Montagnier's laboratory, which then led Montagnier to provide us with the virus to examine. This was about the same time he was giving the virus to the people at the CDC for them to begin to develop assays and tests with the viruses the French had isolated.
What strikes me as fascinating is that the French, Montagnier's group, wasn't looking for the AIDS virus when they found this virus. They were really interferon people. When they were isolating the virus, they used anti-interferon in their isolation culture, and they happened to use transformed lymphocytes in their culture medium. It turns out that interferon does interfere with this virus and so it potentially makes it more difficult to culture the virus. It turns out also, however, that it takes transformed, not normal, cell cultures to provide the necessary medium on which to grow the virus. Serendipity allowed them to grow that virus, which could not have been grown in any other conventional cultures–that is why it did not show up in any of our cultures. It was also serendipitous since we were preparing cells from peripheral blood using high-density gradients. We looked at the cells that occurred to see if there were viruses present. We examined them and tried to culture them. This particular virus, however, caused a syntycial reaction that allowed multi-nucleated cells to develop. They were all being lost in the gradient–they all went down as heavy cells in the gradient and didn't show up with the monitor for cell population that we were studying. If we had looked at the whole blood we would have seen these masses of multi-nucleated cells much earlier on and would have recognized the significant abnormality in these patients. In this case new technology, that is gradient technology used to examine mononuclear cells, interfered with the recognition of the abnormality in the peripheral blood.
This latter work of isolation of the virus, of examining the multi-nucleated cells was worked out by Tom [Dr. Thomas] Folks, who at that time was a NIAID postdoctoral fellow. He ran a little laboratory that I had near my office. That, by the way, constituted my one attempt to try to do a little bit of science while doing administration about ninety-nine percent of the time. Tom Folks has now been recruited by CDC. He is running a retrovirus laboratory at CDC, so his career in the field continues. His interest, however, has expanded to include retroviruses that may be important for other diseases. That may turn out to be a very important field in the future. It involves not just the AIDS virus but retroviruses associated with other illnesses, many of which may perhaps be associated with neurological illnesses.
Harden: How were the intramural and extramural efforts at NIAID coordinated? It has been said that NIH's response to AIDS was the classic situation for which the NIH intramural program was set up.
Sell: It was ruled that we could transfer resources to the AIDS problem and so we did, almost immediately. We expanded our intramural program just as fast as we had new ideas. There was no limitation in terms of dollars. We could always reassign or get additional dollars. Our problem was trying to think of new things to do and new people to do them so that we could expand our intramural program.
At the same time, people in the extramural program began to look at things they could do. Most of the things that they identified were in the epidemiological sphere. They were things that to some extent were being done at CDC, but they had more to do with specimen gathering and obtaining information from which the infectious nature from the disease could be more clearly demonstrated. We worked very closely with several of the people in the extramural program and, in fact, helped them develop contracts. Some of the initial contracts involved five centers that studied groups of people who either had the disease or were at risk of the disease. They examined all sorts of specimens and other data from the participants. We worked together very closely with the extramural people as they developed that program. Within a matter of time, however, the extramural program became very large. They did a lot more on their own, and even though there was a lot of communication back and forth, we were much less involved in the administration of their programs, because we were no longer needed in that capacity.
Harden: I would like you to describe the federal coordinating processes. You have mentioned briefly the relationship between NIAID and NCI. Perhaps you could talk more about that and then about the relationships with other public health service agencies. What are the things that went right and went wrong?
Sell: I was primarily intramural NIAID and so I did not have much responsibility for intra-institute interactions or interactions between various agencies. To some extent we participated and when CDC held any kind of a meeting regarding AIDS, we were also invited to attend. I can remember when the whole issue came up regarding the spread of the infection. There were meetings in Atlanta in which we participated. We were invited to participate in every area of new concern that CDC or other institutes became involved in and vice versa. Every meeting that was held by an institute at NIH always had representation from all the concerned institutes. The three most commonly concerned institutes at NIH were, of course, NCI and NIAID and then the Heart Institute [National Heart, Lung, and Blood Institute] to some extent because of the blood supply. So we had that kind of a coordination. The CDC was very open, and information went back and forth. I often asked senior people like Walter Dowdle at CDC to serve on the Board of Scientific Counselors for intramural projects at NIAID. They would come up to examine our programs and could see at the time what we were doing. It also allowed us to talk at a very basic scientific level about what was going on in each of the organizations. We had good communication.
Our communications were a little less good with NCI, which was conducting research on retroviruses. That was not coordinated with what NIAID was doing during the early years. In fact, we were somewhat surprised when the first announcement came saying that a virus associated with the disease had been isolated in the U.S. We had not met to discuss the progress toward the identification of that virus.
Harden: Should it have been better?
Sell: You always like to think that institutes, scientists, and agencies will cooperate and communicate particularly when there is a problem of such magnitude and epidemic proportions. Ideally you always want better communication and I certainly would have liked to see it even better. I am not sure it would have made a difference in the rapidity of the progress of our understanding of the disease or the quality of our understanding. I don't think that it interfered in any way with what we did.
Harden: That is a very important statement. There have been many criticisms in the press and in books that the response to AIDS was too slow. Many people seemed to express the attitude that scientists should have had instant communications and instant answers. I think it is important that you believe that progress against AIDS was not slow.
Sell: My own view is that from the early days we progressed as fast as anyone had a good idea to support. Ideas that came from the outside in response to our RFPs and RFAs [Request for Proposals; Request for Applications] were funded at a payline level much lower than anything else we were planning at NIH–that is, the scientific merit of these proposals, as judged by the study sections reviewing them, could be much lower than usual grants and still be funded. That decision was an obvious attempt to try to get resources committed to the problem.
I totally disagree with people who say things didn't progress rapidly. Our understanding of the disease, the agent, and the epdemiology developed more rapidly than any other new infection in the history of biomedical sciences. It is a serious epidemic and, therefore, wanting to know all the answers immediately is understandable, but blaming the scientific community for not progressing fast enough is totally irresponsible.
Furthermore, I never saw anyone refraining from the pursuit of this scientific investigation because they thought that the people at risk were not worth studying. This is another claim that is made sometimes. I certainly never saw that attitude the entire time I worked closely with the problem, and I worked quite a few years at NIAID. It just never came up and was never even hinted at. That is not to say there is not a single scientist anywhere who is anti-gay, but I never saw that at NIH.
Harden: Your funding came from Congress, which influenced what you could do with your resources. Do you think that Congress, the administration, and the public understand well enough how biomedical science works, and if not, how can scientists get the message across?
Sell: I think Congress really does understand that basic science is important. The people in Congress that I spoke to understood that it was basic science that allowed us to understand this disease as early as we did. We understood the disease because we knew the immune system. Congress is relatively sophisticated, and even though members like to target money towards pet projects, they understand that basic science–R01 grants, fundamental research–is very important. I think we need to harp on that constantly, but they have an amazing amount of understanding.
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