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This is an interview with Dr. Kenneth W. Sell, chairman, department of p= athology, Emory University School of Medicine, Atlanta, Georgia, November 3= , 1988. Dr. Sell was formerly the director of intramural research at the Na= tional Institute of Allergy and Infectious Diseases.
The interviewer is Victoria A. Harden, director of the National Institut= es of Health Historical Office.
Harden:  = ; Could you talk abou= t your training in pathology and immunology to help me understand how you a= nd other immunologists thought about AIDS?
Sell: &= nbsp; I'm a physician. I trained in pediatrics but = later became interested in the importance of the immune system, particularl= y as it related to immunity and the problems of infection in children. I tr= ained at the University of Cambridge in England with [Dr.] Robin Coombs. At= that time I was particularly interested in what was happening on the surfa= ce of cells, how cells recognized not only each other throughout the immune= system but other cells as well. This led me back to tissue transplantation= . The role that transplantation has played in the whole field of immunology= is very interesting. At the turn of the century all the people involved, s= uch as [Dr. Paul] Ehrlich and [Dr. Elie] Metchnikoff, looked at the immune = system as it related to infectious diseases, which is where my original int= erest was. Then [Dr.] Alexis Carrel developed techniques for vascular surge= ry, and later on in the 1950s, the actual transplantation of human kidneys = became possible. It then became imperative to understand how the immune sys= tem rejected organs. That caused a major spurt in research, investigation, = training, and education in immunology. Most of the advances in understandin= g how the immune system worked were the consequence of pressure by surgeons= who transplanted organs and wanted to know why they did or didn't work.
The whole area of tissue type and match ultimately turned out to provide= us with knowledge of proteins on the surface of cells which were not meant= to be there. They weren't there to recognize an invading kidney graft, but= were meant to provide recognition by finding proteins on other cells with = which the immune system could interact and could control both the response = and the adapting of responses in terms of immunity.
Around the turn of the century, as I've said, immunology developed, firs= t by studying humoral antibody-type reactions. I suppose that was because t= he technology that related to study of those kinds of antibodies was availa= ble. Tissue culture and the isolation of the lymphocytes were necessary bef= ore further progress in cellular immunity could be made=E2=80=94the work of= [Dr. James] Gowans and others in the early 1950s was especially important.= As a result, cellular immunity=E2=80=94the role of lymphocytes and macroph= ages and all the other specific cells of the immune system=E2=80=94began to= be studied.
That was about the time that I got into the field. I was interested in t= ransplantation. I got very involved with how cells worked or didn't work. T= he whole concept of T cells and cellular immunity, B cells and humoral immu= nity was developed during the time that I was involved in bone marrow, kidn= ey, and other kinds of transplants. Very quickly then, others became intere= sted and began to recognize how the immune system underwent dysfunction; au= toimmunity and other forms of dysregulation were identified. Within NIAID, = for instance, we had a program dealing with diseases that were the result o= f dysregulation of the autoimmune system. Wegener's granulomatosis and vari= ous other kinds of autoimmune diseases were studied. We began to understand= the problems of the immune system itself and various immunological and gen= etic deficiencies. That whole area began to develop on a parallel path with= the understanding of immunity and transplantation. To be sure, immunity in= infectious disease continued to benefit from this kind of knowledge, altho= ugh the direction of immunological thought developed an entirely new area o= f research: that was the IgA mucosal immunity system. Sixty to seventy perc= ent of all infections penetrate through the mucosal surface, so mucosal imm= unity became a separate specialty, if you will, and it still is. All these = wide-ranging immunological investigations developed in a parallel fashion.<= /p>
My own training was in cellular immunology, and I was particularly inter= ested in cell surface markers and how cells interact with one another. That= whole area developed during the time that I was in training and doing my o= wn laboratory work. That's my background; I think it answers where I fit in= and where the whole field of immunology fit during the 1970s as we were be= ginning to understand this network of immunity.
Harden:  = ; At the same time th= at there were the great strides in immunology, there was a widespread feeli= ng that infectious diseases were controllable, if not completely curable=E2= =80=94in fact, that we had seen the end of infectious diseases. Were you su= rprised when AIDS appeared as a new infectious disease?
Sell: &= nbsp; I was not surprised that a new infectious dis= ease could appear. I never supported the idea that we had really conquered = infectious disease. You're absolutely right, however. There was a widely he= ld belief that we had the strength to control bacterial infections and with= vaccines, to prevent most of the important viral infections. We were at a = stage when certainly there was a de-emphasis of research and attention to i= nfectious disease problems, but the infectious disease problems never reall= y went away. There were many infectious diseases that we obviously couldn't= deal with in this country.
We also tended to ignore the vast amount of uncontrolled infectious dise= ase that occurred all over the world. Take malaria and schistosomiasis= , for instance. They caused huge mortality and morbidity throughout the ent= ire world. It was almost as though these weren't important because they wer= e not major issues within our country. They didn't count as a major issue t= o our scientists, except for those interested in international health in de= veloping countries. I never shared the idea that we had reached a point at = which infectious diseases were not important. I agreed that, in general, th= ere was less of an emphasis there, but new diseases popped up all the time.= When AIDS appeared, it also popped up as a new disease. It reminded me of = all sorts of new diseases in animals and in man that had occurred in the pa= st. The classic one was in animals. The parvovirus that occurred in o= ne species of mink underwent some genetic changes, and all of a sudden it b= ecame a disease specific for cats. It underwent more mutations and it becam= e a specific parvo disease in dogs. Each genetic change caused a world- wid= e epidemic in the new species to which it adapted itself. I don't mean to s= ay that AIDS virus has mutated or jumped from one species to another. All I= 'm saying is that new diseases can occur, and most often they occur because= the etiological agents have left one species and gone into another. When t= hey do this, the disease they cause becomes a rampant epidemic infection be= fore the organism settles down to some sort of equilibrium with its new hos= t. That may even be the case in AIDS. There is speculation that this could = be a primate virus that has jumped to man as a new host. The unfortunate th= ing, if this is true, is that an equilibrium state, in which the organism d= oesn't kill the host, hasn't yet been reached.
Harden:  = ; How would physician= s have viewed the disease if it had struck in 1955, before we knew what we = now know about the immune system?
Sell: &= nbsp; We would have been very bewildered, because i= n 1955 we were just beginning to understand the cellular aspects of the imm= une system. We didn't have any of the phenyotypic markers, we didn't really= know how T cells interacted with other T cells, or how T cells interacted = with B cells. This is the whole basis for our understanding of AIDS. We wer= e able to determine fairly quickly that this virus was interfering with the= immune system. Within the first year, we knew which cell was involved=E2= =80=94the T-4 helper cell. We knew what the primary attack target was and t= hat the AIDS agent was interfering with all sorts of signals that that this= cell provided to the rest of the immune system. In 1955 virtually none of = that was known. If the disease had occurred then, we would have seen the in= fections; we'd have seen the complications of cytomegalovirus and other kin= ds of opportunistic infections, infections of the lung, but we really would= not have known how to ascribe this infection nor would we have known where= to focus our attention in terms of the infection because we wouldn't have = recognized the disease as it developed. It was that development of our unde= rstanding of the immune system, particularly cellular immunity, that allowe= d the quick focusing of our attention on the aspects of the immune sys= tem that were involved.
Harden: Woul= d you link that to public policy support for basic research?
Sell: &= nbsp; Of course. Generally, I feel that basic resea= rch has provided the basis for increasing our understanding=E2=80=94not jus= t of the infectious disease area but in every aspect=E2=80=94of understandi= ng and treating disease. Certainly, support of basic research was essential= . As we began to understand the immune system, we could understand the path= ogenic mechanism in AIDS and the pathogenic mechanism in autoimmune disease= s. We could begin to understand how tumor immunity in cancer works. One nee= ds basic research to stimulate new ideas about immune system interactions t= hat may cause or influence disease processes. I think most scientists would= agree that you make much less progress when you are disease- focused than = when you try to go back and establish some basic understanding of fundament= al biochemical, physiological and cell biological reactions.
I also think that almost every investigator, including myself, would agr= ee that basic research is truly serendipitous, because you don't know what = direction you're going in. Many great discoveries have been made quite unkn= owingly, in terms of the original intent of the research. If we had to thro= w out all knowledge that was discovered accidentally while we were doing ex= periments, we'd have to throw out most of what we know about the biology of= man. Basic research is essential; free- ranging basic research is even mor= e essential. It's good to have aims and objectives, but what really comes o= ut of research often has nothing to do with the original aim or objective o= f the research. I think the public knows this to some extent, but people re= ally need to know it. I hope Congress knows it, and I hope that NIH continu= es to push basic research that allows the investigator to pursue the new li= nes of thought that always come out of basic research. There is a ter= rible tendency nowadays to focus in on a specific target=E2=80=94to focus i= n on AIDS or to focus in on cardiovascular disease, for example. Basic rese= arch is more likely to bring us new ideas that will solve these problems th= an is targeted, focused research. It permits examination of the subject wit= h only the knowledge we currently have available, which is never enough.
Harden: The = CDC [Centers for Disease Control and Prevention] reported the first cases o= f AIDS in 1981. Focusing on the years 1981 to 1983, could you please recall= when you first learned about the unusual cases that later became called AI= DS? How did you first think about the disease? What issues were discussed i= n the NIAID intramural program? How did your thinking evolve in these early= years?
Sell: &= nbsp; The first case of AIDS at NIH was admitted on= our clinical service=E2=80=94NIAID's 11th floor. The disease was not known= as AIDS when the patient was admitted, but he had the unusual combination = of infections and the impairment of the immune system. At first = we didn't know what the disease was. Then there were the reports from= New York and California. [Dr.] John Fahey's group in California published = their findings in several patients. Almost immediately we began to hear at = meetings about this group of patients. Similar symptoms were also being rec= ognized in patients in New York. So we had a patient in-house, and we began= to hear reports from these two areas. The whole thing proved to be a virtu= al avalanche of discovery. NIH, of course, has a constant ferment of meetin= gs=E2=80=94 everyone comes to sit on the study sections. There were several= meetings on the campus that dealt with this unusual infection, and we bega= n site visits. It was just a matter of months until everyone was aware of t= he fact that there appeared to be a new constellation of illnesses or a new= syndrome or new disease. It got publicized very quickly in 1981-82. Almost= immediately, the people involved felt that most likely it was an infectiou= s disease, and with all of the epidemiological data collected by CDC, it wa= s thought to be a sexually transmitted infectious disease.
Very early on we called a meeting, bringing together people who had deal= t with new infectious diseases, with the discovery of new viruses and with = vaccine development. We asked [Dr. Albert] Sabin to chair that meeting. We = spent time talking about the characteristics of the disease. We also talked= about what approach to take if, indeed, it was a new infectious agent, how= to identify it.
It didn't take very many months of review with various members of the in= tramural staff and of my own personal review of the problem to realize that= it potentially could be anything. Almost every virus that we looked at cou= ld cause components of this infection and could mimic some portion of what = was happening to the immune system. I previously mentioned parvoviruses in = animals. Parvoviruses had caused diseases which had some of the characteris= tics of AIDS. There were certain minute virus diseases in mice=E2=80=94caus= ed by peculiar CMV [cytomegalovirus] or other viruses=E2=80=94that caused s= imilar diseases. There was a whole range of viruses and even some bacteria = that were thought to be related to immunosuppressive illness, and they coul= d possibly have been the basis for what was going on.
We made the decision intramurally to look for every viral and bacterial = infectious agent that we possibly could. We excluded retroviruses because w= e knew that the cancer institute [National Cancer Institute, NCI] had been = looking carefully at retroviruses as a cause of tumors and had a very large= program with retroviruses. We had a small program with retroviruses. Mal [= Dr. Malcom] Martin and Wally [Dr Wallace] Rowe, two brilliant scientists, h= ad been looking at retroviruses in mice, but the scale of our program was m= uch smaller than NCI's. So by convention=E2=80=94not by a formal agreement= =E2=80=94we decided we'd look at everything else while NCI would look at re= troviruses. We searched everything. We did every kind of technique and cult= ure method we could trying to isolate the culprit.
Harden: Is t= his the program with which Dr. Richard Wyatt was involved?
Sell: &= nbsp; Yes. Richard Wyatt was then brought in to the= intramural program of NIAID to coordinate all of these efforts. We also be= gan to set up contracts with people, say for instance, in New York, who wer= e seeing these patients. We set up a repository to collect specimens as wel= l 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 coord= inate a full program for the intramural NIAID. I think we did a fairly resp= ectable job of looking at all these things. There were many moments of exci= tement 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 w= e were.
Harden:  = ; Would you explain t= o me how the theory of amyl nitrites as a cause of AIDS fit in scientifical= ly and intellectually? I believe that for a brief period it was considered = very important.
Sell: &= nbsp; The general theory was that an infectious age= nt could penetrate more easily if there was laxity or expansion of the bloo= d vessel system. This occurs with amyl nitrites, which causes laxity of blo= od vessels, meaning that an infection could spread more easily once it pene= trated. It was thought that populations that used amyl nitrites were more s= usceptible to the infection than other people. Early on, when we didn't kno= w 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 targe= t 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: &= nbsp; 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 nit= rite, however, in the development of Kaposi's sarcoma in AIDS patients once= they're infected. I don't know if that's valid or not, but it would make s= ome sense because Kaposi's sarcoma is a disease in which there is blood ves= sel change and that could be related to the use of agents that cause expans= ion 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'= ve talked about the beginning of the NIAID intramural AIDS program. &n= bsp;Could you describe the work of some of your key investigators?
Sell: &= nbsp; In those early days, Dr. Anthony Fauci had ju= st been made laboratory chief of the Laboratory of Immunoregulation. The fi= rst patient was admitted on his service, and very quickly he began to do so= me innovative clinical activities like transplanting bone marrow from one n= ormal identical twin to his twin with AIDS. He also entered into several tr= eatment trials, using things that would modify the immune system. We spent = several hundred thousand dollars for new immunological agents that were jus= t then becoming available in order to look at things that could modify the = immune system in these patients. So he was involved in seeing patient= s, 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 s= everal Fellows in the laboratory who did a lot of the investigative work, b= ut Lane was intimately involved as a full-time participant in these program= s.
We asked people in some of the other laboratories to assist=E2=80=94I al= ready 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 v= iruses were present in the tissues. They were not. Mal Martin is a physicia= n and an infectious disease person, a molecular virologist who had switched= his attention to retroviruses. He became interested in AIDS early on. I ca= n remember one conference at which we had a young lady, Dr. Francoise Brun-= Vezinet/Barre, who came from Montagnier's lab in France. She had just prese= nted 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-hous= e research or invited outside speakers to come in and talk about things tha= t might relate to the AIDS issue. She came and presented her evidence of ha= ving isolated the first retrovirus from a patient who didn't have AIDS but = who had enlarged lymph nodes. Mal Martin was very interested, and subsequen= tly, 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, w= asn't looking for the AIDS virus when they found this virus. They were real= ly interferon people. When they were isolating the virus, they used anti-in= terferon in their isolation culture, and they happened to use transformed l= ymphocytes in their culture medium. It turns out that interferon does inter= fere with this virus and so it potentially makes it more difficult to cultu= re the virus. It turns out also, however, that it takes transformed, not no= rmal, cell cultures to provide the necessary medium on which to grow the vi= rus. Serendipity allowed them to grow that virus, which could not have been= grown in any other conventional cultures=E2=80=94that is why it did n= ot show up in any of our cultures. It was also serendipitous since we were = preparing cells from peripherial blood using high-density gradients. We loo= ked 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=E2=80=94they all went down as hea= vy cells in the gradient and didn't show up with the monitor for cell popul= ation that we were studying. If we had looked at the whole blood we would h= ave seen these masses of multi-nucleated cells much earlier on and would ha= ve recognized the significant abnormality in these patients. In this case n= ew technology, that is gradient technology used to examine mononuclear cell= s, interfered with the recognition of the abnormality in the peripherial bl= ood.
This latter work of isolation of the virus, of examining the multi-nucle= ated 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 o= ffice. That, by the way, constituted my one attempt to try to do a little b= it of science while doing administration about ninety-nine percent of the t= ime. Tom Folks has now been recruited by CDC. He is running a retrovirus la= boratory at CDC, so his career in the field continues. His interest, howeve= r, has expanded to include retroviruses that may be important for other dis= eases. That may turn out to be a very important field in the future. It inv= olves not just the AIDS virus but retroviruses associated with other illnes= ses, many of which may perhaps be associated with neurological illnesses.= p>
Harden: How = were the intramural and extramural efforts at NIAID coordinated? It's been = said that NIH's response to AIDS was the classic situation for which the NI= H intramural program was set up.
Sell: &= nbsp; It was ruled that we could transfer resources= to the AIDS problem and so we did, almost immediately. We expanded our int= ramural program just as fast as we had new ideas. There was no limitation i= n 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 thin= gs they could do. Most of the things that they identified were in the epide= miological sphere. They were things that to some extent were being done at = CDC, but they had more to do with specimen gathering and obtaining informat= ion from which the infectious nature from the disease could be more clearly= demonstrated. We worked very closely with several of the people in the ext= ramural program and, in fact, helped them develop contracts. Some of the in= itial contracts involved five centers that studied groups of people who eit= her 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. Wi= thin a matter of time, however, the extramural program became very large. T= hey did a lot more on their own, and even though there was a lot of communi= cation 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've 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: &= nbsp; I was primarily intramural NIAID and so that = I didn't have much responsibility for intra-institute interactions or inter= actions between various agencies. To some extent we participated and when C= DC held any kind of a meeting regarding AIDS, we were also invited to atten= d. 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 inst= itutes became involved and vice versa. Every meeting that was held by an in= stitute at NIH always had representation from all the concerned institutes.= The three most commonly concerned institutes at NIH were, of course, NCI a= nd NIAID and then the Heart Institute [National Heart, Lung, and Blood Inst= itute] 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. I= t also allowed us to talk at a very basic scientific level about what was g= oing on in each of the organizations. We had good communication.
Our communications were a little less good with NCI, which was conductin= g research on retroviruses. That was not coordinated with what NIAID was do= ing during the early years. In fact, we were somewhat surprised when the fi= rst announcement came saying that a virus associated with the disease had b= een isolated in the U.S. We had not met to discuss the progress toward the = identifica- tion of that virus.
Harden: Shou= ld it have been better?
Sell: &= nbsp; You always like to think that institutes, sci= entists, and agencies will cooperate and communicate particularly when ther= e's a problem of such magnitude and epidemic proportions. Ideally you alway= s want better communication and I certainly would have liked to see it= even better. I'm 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 u= nderstanding. I don't think that it interfered in any way with what we did.=
Harden:  = ; That's a very impor= tant statement. There have been many criticisms in the press and in books t= hat the response to AIDS was too slow. Many people seemed to express the at= titude that scientists should have had instant communications and instant a= nswers. I think it's important that you believe that progress against AIDS = was not slow.
Sell: &= nbsp; My own view is that from the early days we pr= ogressed 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; Reque= st for Applications] were funded at a payline level much lower than anythin= g else we were planning at NIH=E2=80=94that is, the scientific merit of the= se 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. O= ur understanding of the disease, the agent, and the epdemiology developed m= ore rapidly than any other new infection in the history of biomedical scien= ces. It's a serious epidemic and, therefore, wanting to know all the answer= s immediately is understandable, but blaming the scientific community for n= ot progressing fast enough is totally irresponsible.
Furthermore, I never saw anyone refraining from the pursuit of this scie= ntific investigation because they thought that the people at risk weren't w= orth studying. This is another claim that's made sometimes. I certainly nev= er 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 e= ven hinted at. That isn't to say there isn't a single scientist anywhere wh= o is anti-gay, but I never saw that at NIH.
Harden:  = ; Your funding came f= rom Congress, which influenced what you could do with your resources. Do yo= u think that Congress, the administration, and the public understand well e= nough how biomedical science works, and if not, how can scientists get the = message across?
Sell: &= nbsp; I think Congress really does understand that = basic science is important. The people in Congress that I spoke to understo= od 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 syste= m. Congress is relatively sophisticated, and even though members like to ta= rget money towards pet projects, they understand that basic science=E2=80= =94R01 grants, fundamental research=E2=80=94is very important. I think= we need to harp on that constantly, but they have an amazing amount of und= erstanding.
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 AI= DS, ranging from people at the U.S. television networks to those from newsp= apers. The vast majority of the reporting was very responsibly done. It's a= mazing how much good information comes out over the TV and in the press whe= n the media deal with this subject. This responsible reporting has led the = majority of the population to understand this particular disease, what's go= ing on and the need for all kinds of research, not just treatment trials.= p>
The people who are afflicted have bombarded the press with the need for = instant cures, instant answers, instant vaccines, and immediate access to d= rugs that haven't been proven yet. The afflicted are the ones who are reall= y driving for things that cannot be done. They are driving for answers that= we don't have. They are driving for drugs to be used that aren't available= or have not even been adequately tested for safety. It's understandable to= do that if you have a disease that's 100 percent fatal. When people with c= ancer get to a stage that's 100 percent fatal, they do the same thing, just= perhaps not so vocally. It's understandable. But I think that the ge= neral public understands the disease reasonably well, although it always bo= thers 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 scho= ol officials do understand. There are always a few misguided, but the under= standing of the disease is pretty remarkable.
Harden:  = ; Following up on you= r comments about drugs, I recall a reporter's asking me whether scientists = were trying to hold up the release of potential therapeutic drugs from peop= le with AIDS. I replied that I thought it was a regulatory question, that t= he Congress had decided that the U.S. would not permit people to market dru= gs without testing for safety and efficacy. Clinical trials, of course, tak= e a long time. Is there any other way rather than having a proper clinical = trial to tell if a drug is working?
Sell: &= nbsp; Even when you have a proper clinical trial it= 's 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= 's the safety of the public that's important. There's also a huge financial= burden. Take a look at what the federal government has paid for AZT [3'-Az= ido-2',3'-dideoxythiamidine]. If we didn't have some data indicating it rea= lly did some good, it would be an incredible rip-off of society, of pe= ople 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 deat= h or make their existence more unbearable. Even AZT has a huge problem with= bone marrow depression and the need for blood transfusions. It's not= an innocuous drug, and yet we're talking about using drugs that are more t= oxic but that we don't know much about. There's tremendous pressure from th= ose who are dying to try anything, and there is pressure from the regulator= y agency saying we can't 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 patie= nts. In fact, the doctors and the scientists are pushing on the patie= nts' side. They're 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 b= een in Emory for three and a half years, how is the academic approach to AI= DS different from that of the NIH? What do you see happening here?
Sell: &= nbsp; AIDS in Atlanta developed over the three year= s or so since I've been here. Although it was a problem, it was = not as big a problem as it was in New York and San Francisco. The infectiou= s disease physicians, and to some extent the oncologists, took care of thos= e patients. There was not very much to offer them and interestingly, the lo= cal physicians were not very interested. This was different from almost all= the others centers around the country, which were participating in the cli= nical 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 weren't very interes= ted in that because they couldn't see any new drugs of great interest for t= he community here. They felt the need was much more in the area of educatio= n, 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 economi= cs of this situation for the patients who were involved, the tremendously d= evastating 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 f= loor. They were much more concerned about all of these problems. The univer= sity 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. I= t has an SIV virus which is homologous to HIV-2 It infects these monkeys, b= ut 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 ha= ve 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 qu= ite a few millions of dollars to study that primate model, so basic researc= h 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's one of things we are currently stu= dying.
It's also allowed us to develop what we think is the first understanding= of cell- mediated immunity in AIDS. It's difficult to measure cellular imm= unity in AIDS. There have been various attempts, more or less satisfactory,= using this system to explore many different approaches. We now have what w= e 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=E2=80=94cytomegalovirus and other infections=E2=80=94t= o show specificity. So this model may, in the long run, provide more unders= tanding of the whole AIDS process.
Now in our human populations, of course, we've been impressed, like ever= ybody 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 observa= tion, moreover, is that more and more AIDS cases are occurring in drug addi= cts. We just happen to have had a program here to look at the effect of dru= gs 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 disappea= r with various of amounts of cocaine or heroin. In fact, one of our graduat= e students just did his thesis on that subject in our department. So we're = now concerned with drug usage and its effect on the susceptibility of progr= ession of AIDS.
Harden: Than= k you, Dr. Sell.