Kenneth Sell M.D. Interview

Transcripts

Harden: Could you talk about your training in pathology and immunology to help me understand how you and other immunologists thought about AIDS?

Sell: I'm a physician. I trained in pediatrics but later became interested in the importance of the immune system, particularly as it related to immunity and the problems of infection in children. I trained at the University of Cambridge in England with [Dr.] Robin Coombs. At that time I was particularly interested in what was happening on the surface 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, such as [Dr. Paul] Ehrlich and [Dr. Elie] Metchnikoff, looked at the immune system as it related to infectious diseases, which is where my original interest was. Then [Dr.] Alexis Carrel developed techniques for vascular surgery, and later on in the 1950s, the actual transplantation of human kidneys became possible. It then became imperative to understand how the immune system rejected organs. That caused a major spurt in research, investigation, training, and education in immunology. Most of the advances in understanding 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, first by studying humoral antibody-type reactions. I suppose that was because the technology that related to study of those kinds of antibodies was available. Tissue culture and the isolation of the lymphocytes were necessary before further progress in cellular immunity could be made–the work of [Dr. James] Gowans and others in the early 1950s was especially important. As a result, cellular immunity–the role of lymphocytes and macrophages and all the other specific cells of the immune system–began to be studied.

That was about the time that I got into the field. I was interested in transplantation. I got very involved with how cells worked or didn't work. The whole concept of T cells and cellular immunity, B cells and humoral immunity was developed during the time that I was involved in bone marrow, kidney, and other kinds of transplants. Very quickly then, others became interested and began to recognize how the immune system underwent dysfunction; autoimmunity and other forms of dysregulation were identified. Within NIAID, for instance, we had a program dealing with diseases that were the result of dysregulation of the autoimmune system. Wegener's granulomatosis and various other kinds of autoimmune diseases were studied. We began to understand the problems of the immune system itself and various immunological and genetic 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, although the direction of immunological thought developed an entirely new area of research: that was the IgA mucosal immunity system. Sixty to seventy percent of all infections penetrate through the mucosal surface, so mucosal immunity became a separate specialty, if you will, and it still is. All these wide-ranging immunological investigations developed in a parallel fashion.

My own training was in cellular immunology, and I was particularly interested 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 own 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 beginning to understand this network of immunity.

Harden: At the same time that there were the great strides in immunology, there was a widespread feeling that infectious diseases were controllable, if not completely curable–in fact, that we had seen the end of infectious diseases. Were you surprised when AIDS appeared as a new infectious disease?

Sell: I was not surprised that a new infectious disease could appear. I never supported the idea that we had really conquered infectious disease. You're absolutely right, however. There was a widely held 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 infectious disease problems, but the infectious disease problems never really 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 disease that occurred all over the world. Take malaria and schistosomiasis, for instance. They caused huge mortality and morbidity throughout the entire world. It was almost as though these weren't important because they were not major issues within our country. They didn't count as a major issue to our scientists, except for those interested in international health in developing countries. I never shared the idea that we had reached a point at which infectious diseases were not important. I agreed that, in general, there 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 past. The classic one was in animals. The parvovirus that occurred in one species of mink underwent some genetic changes, and all of a sudden it became a disease specific for cats. It underwent more mutations and it became a specific parvo disease in dogs. Each genetic change caused a worldwide epidemic in the new species to which it adapted itself. I don't mean to say 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 they do this, the disease they cause becomes a rampant epidemic infection before the organism settles down to some sort of equilibrium with its new host. 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 thing, if this is true, is that an equilibrium state, in which the organism doesn't kill the host, hasn't yet been reached.

Harden: How would physicians have viewed the disease if it had struck in 1955, before we knew what we now know about the immune system?

Sell: We would have been very bewildered, because in 1955 we were just beginning to understand the cellular aspects of the immune system. We didn't have any of the phenotypic 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 were able to determine fairly quickly that this virus was interfering with the immune system. Within the first year, we knew which cell was involved–the T-4 helper cell. We knew what the primary attack target was and that 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 infections; we would have seen the complications of cytomegalovirus and other kinds 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 understanding of the immune system, particularly cellular immunity, that allowed the quick focusing of our attention on the aspects of the immune system that were involved.

Harden: Would you link that to public policy support for basic research?

Sell: Of course. Generally, I feel that basic research has provided the basis for increasing our understanding, not just of the infectious disease area, but in every aspect, of understanding and treating disease. Certainly, support of basic research was essential. As we began to understand the immune system, we could understand the pathogenic mechanism in AIDS and the pathogenic mechanism in autoimmune diseases. We could begin to understand how tumor immunity in cancer works. One needs basic research to stimulate new ideas about immune system interactions that 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 fundamental biochemical, physiological and cell biological reactions.

I also think that almost every investigator, including myself, would agree that basic research is truly serendipitous, because you don't know what direction you're going in. Many great discoveries have been made quite unknowingly, in terms of the original intent of the research. If we had to throw out all knowledge that was discovered accidentally while we were doing experiments, we would have to throw out most of what we know about the biology of man. Basic research is essential; free ranging basic research is even more essential. It is good to have aims and objectives, but what really comes out of research often has nothing to do with the original aim or objective of the research. I think the public knows this to some extent, but people really need to know it. I hope Congress knows it, and I hope that NIH continues to push basic research that allows the investigator to pursue the new lines of thought that always come out of basic research. There is a terrible tendency nowadays to focus in on a specific target–to focus in on AIDS or to focus in on cardiovascular disease, for example. Basic research is more likely to bring us new ideas that will solve these problems than is targeted, focused research. It permits examination of the subject with only the knowledge we currently have available, which is never enough.

Harden: The CDC [Centers for Disease Control and Prevention] reported the first cases of 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 AIDS? How did you first think about the disease? What issues were discussed in the NIAID intramural program? How did your thinking evolve in these early years?

Sell: The first case of AIDS at NIH was admitted on our clinical service–NIAID'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 recognized 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 virtual avalanche of discovery. NIH, of course, has a constant ferment of meetings–everyone comes to sit on the study sections. There were several meetings on the campus that dealt with this unusual infection, and we began site visits. It was just a matter of months until everyone was aware of the 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 infectious disease, and with all of the epidemiological data collected by CDC, it was thought to be a sexually transmitted infectious disease. Very early on we called a meeting, bringing together people who had dealt 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 intramural 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 could 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 characteristics of AIDS. There were certain minute virus diseases in mice–caused by peculiar CMV [cytomegalovirus] or other viruses–that caused similar diseases. There was a whole range of viruses and even some bacteria that were thought to be related to immunosuppressive illness, and they could 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 we 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, had been looking at retroviruses in mice, but the scale of our program was much smaller than NCI's. So by convention–not by a formal agreement–we decided we would look at everything else while NCI would look at retroviruses. We searched everything. We did every kind of technique and culture method we could trying to isolate the culprit.

Harden: Is this the program with which Dr. Richard Wyatt was involved?

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.