...

Sell: Yes. Richard Wyatt was then brought in to the intramural program of NIAID to coordinate all of these efforts. We also began to set up contracts with people, say for instance, in New York, who were seeing these patients. We set up a repository to collect specimens as well as epidemiological data from the patients and began to examine all types of specimens like urine, blood, and stool to see if we could isolate these viruses. Richard Wyatt was a very experienced infectious disease specialist working in [Dr.] Robert M. Chanock's laboratory. He was called in to coordinate a full program for the intramural NIAID. I think we did a fairly respectable job of looking at all these things. There were many moments of excitement when we thought we had found something new, and many moments when we felt we were really running down nothing but blind alleys. It turned out we were.

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.

There was an amazing amount of understanding in the public from the very earliest time. I felt there was a lot of responsible reporting about AIDS very early on. Almost weekly we had somebody in the office talking about AIDS, ranging from people at the U.S. television networks to those from newspapers. The vast majority of the reporting was very responsibly done. It is amazing how much good information comes out over the TV and in the press when the media deal with this subject. This responsible reporting has led the majority of the population to understand this particular disease, what is going on and the need for all kinds of research, not just treatment trials.

The people who are afflicted have bombarded the press with the need for instant cures, instant answers, instant vaccines, and immediate access to drugs that have not been proven yet. The afflicted are the ones who are really driving for things that cannot be done. They are driving for answers that we do not have. They are driving for drugs to be used that are not available or have not even been adequately tested for safety. It is understandable to do that if you have a disease that's 100 percent fatal. When people with cancer get to a stage that's 100 percent fatal, they do the same thing, just perhaps not so vocally. It is understandable. But I think that the general public understands the disease reasonably well, although it always bothers me when I see kids being ostracized in school because of ignorance in some families. At the same time I see many school districts turning around and welcoming those kids into their schools. Many parents and various school officials do understand. There are always a few misguided [people], but the understanding of the disease is pretty remarkable.

Harden: Following up on your comments about drugs, I recall a reporter asking me whether scientists were trying to hold up the release of potential therapeutic drugs from people with AIDS. I replied that I thought it was a regulatory question, that the Congress had decided that the U.S. would not permit people to market drugs without testing for safety and efficacy. Clinical trials, of course, take a long time. Is there any other way rather than having a proper clinical trial to tell if a drug is working?

Sell: Even when you have a proper clinical trial it is often difficult to know what value any particular drug is. I don't think any scientist is holding up anything. The regulatory agency [Food and Drug Administration] wants to be shown that one drug is better than another. It is the safety of the public that is important. There is also a huge financial burden. Take a look at what the federal government has paid for AZT [3'-Azido-2',3'-dideooxythymidine]. If we didn't have some data indicating it really did some good, it would be an incredible rip-off of society, of people dying with AIDS.

The primary concern about drugs is the safety of the individual. Even if people with AIDS are dying, that does not mean we should hasten their death or make their existence more unbearable. Even AZT has a huge problem with bone marrow depression and the need for blood transfusions. It is not an innocuous drug, and yet we are talking about using drugs that are more toxic but that we don't know much about. There is tremendous pressure from those who are dying to try anything, and there is pressure from the regulatory agency saying we cannot approve everything. We have to have at least some modicum of knowledge about the drug before we let the public use it. I don't think any scientist has held anything back in terms of treatment of patients. In fact, the doctors and the scientists are pushing on the patients' side. They are willing to try almost anything they can get their hands on to help the patients, because they feel just as helpless as the patients do.

Harden: Now that you have been at Emory for three and a half years, how is the academic approach to AIDS different from that of the NIH? What do you see happening here?

Sell: AIDS in Atlanta developed over the three years or so since I have been here. Although it was a problem, it was not as big a problem as it was in New York and San Francisco. The infectious disease physicians, and to some extent the oncologists, took care of those patients. There was not very much to offer them and interestingly, the local physicians were not very interested. This was different from almost all the other centers around the country, which were participating in the clinical treatment programs that were being funded out of NIAID.

The first year there was around $20 million in funds for a large number of centers for new drugs. The physicians here at Emory were not very interested in that because they could not see any new drugs of great interest for the community here. They felt the need was much more in the area of education, in dealing with partners and individuals who were exposed, and in trying to deal with the infection. It was more important to deal with the economics of this situation for the patients who were involved, the tremendously devastating effect on the families and the devastating effect it had on the hospital personnel when it moved from a few cases to ten or twenty on the floor. They were much more concerned about all of these problems. The university research division was much more concerned about precise evaluation of the mechanisms of the disease and not with treatment trials.

Here at Emory, we have a Yerkes Primate Center, and we tumbled into one of the best models for AIDS virus infection in the sooty mangabey monkey. It has an SIV virus which is homologous to HIV-2. It infects these monkeys, but they never get ill. They live with this virus without problems, and yet when you take blood out of that monkey, the mangabey, and put it into Asian monkeys like the macaques, they exhibit features of the AIDS-related complex (ARC), they develop a full-blown disease like AIDS, and they die of opportunistic infections. This provides us a model to study that is better than a human model. We don't have to inflict our studies on humans, and we can follow in a programmed and planned way a primate model. We had a virus that was living happily and not destroying a group of monkeys. This may have been the situation in Africa with HIV-1, which then moved to man. It was in this area that we submitted most of our research grants. We now have quite a few millions of dollars to study that primate model, so basic research can be done much more precisely, much more planned. The research is quite fascinating, although one disturbing thing has come out of it. One variant of this SIV retrovirus, when put into macaques, is now thought to kill them in a matter of weeks. If, in fact, this is substantiated, then it would suggest that this virus may under some circumstances be modified to become a acutely lethal virus. That is one of things we are currently studying.

It has also allowed us to develop what we think is the first understanding of cellmediated immunity in AIDS. It is difficult to measure cellular immunity in AIDS. There have been various attempts, more or less satisfactory, using this system to explore many different approaches. We now have what we think is a sensitive and specific cell-mediated immune assay that allows us to replicate it, so that we can take a look at this and other infections in the same animals–cytomegalovirus and other infections–to show specificity. So this model may, in the long run, provide more understanding of the whole AIDS process.

Now in our human populations, of course, we have been impressed, like everybody else has, that there is a tremendous neurological component to AIDS. It may be the first component of AIDS that appears in many of the patients. A lot of our attention has been directed that way. The most recent observation, moreover, is that more and more AIDS cases are occurring in drug addicts. We just happen to have had a program here to look at the effect of drugs on the immune system. We have shown clearly that surface receptors on T lymphocytes are modified by drugs. You can cause them to appear or disappear with various of amounts of cocaine or heroin. In fact, one of our graduate students just did his thesis on that subject in our department. So we are now concerned with drug usage and its effect on the susceptibility of progression of AIDS.

Harden: Thank you, Dr. Sell.