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Fauci: When I came down to what was the Laboratory of Clinical Investigation, of which Dr. Wolff was the laboratory chief as well as being the clinical director of the National Institute of Allergy and Infectious Diseases, I wanted to work on cellular immunology. But, interestingly enough, as popular as cellular immunology is now, there really were not very many cellular immunologists at the time, and certainly not in the Laboratory of Clinical Investigation. I went to work with Dr. John Johnson, who now practices rheumatology in Nashville, Tennessee. John was an immunochemist at the time, but he allowed me to work on problems in cellular immunology. I had to go around to different groups in different laboratories to learn the fundamentals of cellular immunology under the auspices of the Laboratory of Clinical Investigation. It was a great experience and a testimony to the flexibility of people like Dr. Wolff and Dr. Johnson, who allowed me to work in that field even though it wasn't their field of expertise. Dr. Wolff was mainly working on the pathogenesis of fever. I told him I didn't want to work on that, although it was a very interesting topic. I wanted to learn some basic cellular immunology with the ultimate aim of going into what has been my theme for the past twenty-one years–human immunobiology and the regulation of the human immune system. I was then, and still am, extremely interested in clinical medicine, and I have been successful in being able to mix and meld together the very fundamental, basic concepts of immunology with clinical medicine. It was Dr. Wolff who encouraged me. I worked on some projects looking at the regulation of the immune system in animals, with rabbit and guinea pig models. I learned from Dr. Baruj Benacerraf, who was down the hall in the Laboratory of Immunology; from [Dr.] David Katz, who worked with him; and from [Dr.] Carl Pierce and a few others. There were in the laboratory working with Dr. Johnson two people who have gone on to be very successful and prominent immunologists–[Dr.] Alexander Lawton, who is now at Vanderbilt [University] and chairman of pediatrics, and [Dr.] Herbert Reynolds, who is now chief of medicine at the Hershey Medical Center of the Pennsylvania State University. They were just Fellows with me at the time, and we taught each other immunology. However, though I liked it very much, my main desire was to get back to the New York Hospital/Cornell Medical Center and to be a clinician. That's what I really wanted to do. I liked the scientific environment, but my real love was taking care of patients.
Harden: Why did you go back to Cornell for another year, and what made you decide to come back to the NIH and pursue your career here rather than going on into a private practice or into academic medicine?
Fauci: I was at that very critical period in my second year as a Fellow in a three-year program having to make up my mind about what I was going to do “for the rest of my life.” Just about at that time things started to click in the laboratory. I was making some interesting observations, writing some papers that were turning out to be good papers. Virtually simultaneously, [Dr.] Alexander Bearn, who was the chairman of the Department of Medicine at Cornell at the time, asked me if I wanted to come back at the end of my third year to be chief resident in medicine. At the same time, Dr. Wolff offered me a job, which was one of those offers that you can't refuse. It was the position of senior investigator in the Laboratory of Clinical Investigation. I told him I wanted to go back and have another year in clinical medicine and make myself as excellent a clinician as I possibly could. His response was, “Fine, go back to New York; take a year as chief resident, and then come back; the laboratory will be waiting for you when you get back.” I made the decision, but when you make decisions like that, you're not really sure why you made them. I think it was a combination of the personality of Dr. Wolff, with whom I was developing a very strong friendship, and the fact that as the months were going by, my immunology research was becoming more successful. I didn't feel that I was giving up anything because I was going back to New York to cement my clinical training. I decided that I would do it. I would go back to New York and come back to NIH after a year to my own laboratory, in which I would have total independence. I think it is important to emphasize that quality of Dr. Wolff that has been responsible for the development of so many successful investigators over the years. It is important to recognize what he did with me as with many others. He could recognize early on in someone's career a person who had potential, who would succeed. Before that person did anything to make any kind of reputation, Dr. Wolff would give that person unqualified support. That was exactly what he did for me. Nobody knew who I was; nobody cared to know who I was. But Dr. Wolff said, “Here's your laboratory. You can have a technician. You can have a Fellow if you can attract a Fellow. So go ahead.” I said, “Fine, that's great.” I went to New York, came back to the NIH and started my own human immunobiology group. I was one of the few people at the time anywhere who was devoted exclusively to human immunobiology. There was [Dr.] Max Cooper in Alabama and Tom [Dr. Thomas] Waldmann at the NIH. Bob [Dr. Robert] Good and a few others were exclusively human. There were many excellent and great immunologists around who did either totally animal work or a combination of animal and human, but there were very few who were doing exclusively human immunobiology. That's when I started my work on immunoregulation of the human immune response, which I have continued throughout the past couple of decades. I am still working on it right now in 1989.
Harden: Your medical student years and just after marked the period of time when cellular immunology began to flower. Would you comment on what factors made immunology such a fruitful field?
Fauci: It was a combination of the emergence of technologies and the awareness of the extraordinary implications, if not tentacles, that the immune system had in controlling so many aspects of the human organism. For example, technology provided the ability to identify different types of cells and their subsets. There was the realization of the almost infinite possibilities of a repertoire of B-cells to recognize different antigens. The development of monoclonal antibodies and the ability to clone cells led to a virtual explosion in the delineation of the immune system, its structure and its function.
At the same time, scientists became aware that there were many immunologically mediated diseases. Diseases that were total mysteries years ago became understood as immune-mediated: lupus, rheumatoid arthritis, the connective tissue diseases, the organ-specific autoimmune diseases, and transplantation rejection are a few examples. This was also occurring during the emergence of molecular biology within the field of immunology. If you look at immunology, it has from the very beginning been inextricably linked to infectious diseases. Teleologically, what is the immune system for? The immune system protects you against invaders from without–microorganisms–as well as, in some cases, the emergence of certain tumors from within.
What was not realized until that period of explosive interest is that the immune system is an organ system just like any other system. It is an organ system like the cardiovascular system, the neurological system and the endocrine system. Initially, it was understood to be a response that the body had, but now, the immune system is viewed as a true organ system. It has structural components: there are lymphocytes; there are organs, such as the spleen; the blood is a lymphoid organ. The reticuloendothelial system, the bone marrow, the thymus and the lymph nodes are all parts of the immune system. This organ system has a way of communicating by a variety of soluble factors which we call cytokines. Knowledge about this has just emerged over the past decade. There are a large number of different molecules that have very specific functions, such as one cell's ability to talk to another cell. All of this started to emerge as the technology was developed that allowed the precise identification of the components of the immune system and their function.
Harden: Cell sorters, for example, were essential to this.
Fauci: Absolutely.
Harden: Some of the basic research in other fields, the work on protein chemistry and protein structure, for example, also facilitated the advances in immunological knowledge, I believe. It appears to be one of those “payoffs.”
Fauci: Absolutely. I think immunology, certainly is one of the major examples of something that we stress very often. Basic, fundamental undifferentiated research will inevitably, sooner or later, emerge into something that is very important; but very likely you would not have predicted that it would relate to this particular arena. You're working in one direction and then all of a sudden you find something else that you don't understand now, but ten years from now it solves problems in another direction. Immunology and basic research on the immune system really provide a classic example of this.
Harden: The 1956 research by [Bruce] Glick, [Timothy S.] Chang, and [R. George] Jaap on the bursa of Fabricius and antibody production in poultry seemed so far outside the mainstream of human immunology, if I remember correctly, that it could only be published in the journal, Poultry Science. Later, it turned out to be very important. Could you talk about your own work on Wegener's granulomatosis and some of the other problems to which you applied your knowledge?
Fauci: My research career at the NIH emerged in two parallel tracks. One was the very fundamental dissection of how the human immune system is regulated. The other parallel track was an examination of immune-mediated diseases and how one can classify and treat them. The work on the regulation of human immune system is what led me into AIDS research. What we performed in the late sixties and early seventies were probably “breakthrough” studies on the development of cures for formerly fatal diseases such as Wegener's granulomatosis and polyarteritis nodosa. Things emerged from those interesting quirks of science, things that you never would have predicted. Dr. Wolff, even before I came to the NIH, had been very interested in immunosuppression, such as some of the cytotoxic agents. His major interest was fever. This is really very interesting, a story that I tell the Fellows when they come. It is the classic example of how science is so beautiful because it is so unpredictable. Dr. Wolff had collected over the years–he had been at NIH for at least five or more years before I got there–a group of patients with prolonged fevers of unknown origin, not just five or six weeks, but a year long at least. He had a heterogeneous group of people which numbered literally in the hundreds. He had been collecting them for a few years because he wanted to study the pathogenesis of fever. Some of them had granulomatous hepatitis, a disease that had never before been described and that he described. Some of them had juvenile rheumatoid arthritis; some of them had connective tissue diseases; some of them had hematologic diseases; and others had immune-mediated vasculitic diseases. They were a very interesting group of patients–interesting because the diseases were interesting but also because most of them would die from their diseases–particularly those with Wegener's granulomatosis.
At that time, I came as a Fellow and I wanted to stay involved in some clinical work while I was doing basic research in the laboratory. This is essentially what I'm doing now–doing clinical work while I'm doing very fundamental cellular and molecular work in the laboratory. I asked him, “Could I start collecting these Wegener's and vasculitic patients and put them on a set protocol, and look at these cytotoxic agents, particularly cyclophosphamide”? I was interested in this because the agent had been used successfully in one or two patients in a manner that was not very well organized since it was given to a patient as a last resort. Dr. Wolff, as usual, was extremely accommodating, and said, “Fine. I'll support you on that. Let's do it. We'll do it together and I'll help you out.”
To make a long story short, we started a protocol that gave cyclophosphamide in low doses. Previously it had been developed as an anticancer drug and was given predominantly to individuals with leukemia in very high doses that would wipe out the bone marrow. We figured from animal studies, particularly those performed by investigators such as Bob [Dr. Robert] Schwartz and others in Boston, that low doses of a cytotoxic agent could suppress the immune system without wiping out the bone marrow. We then did something that was very unorthodox. We gave low doses of this cytotoxic agent, equivalent to the amount that in animals suppressed immunological function but didn't cause very severe toxic side effects like neutropenia.
The disease that we targeted at first was Wegener's granulomatosis. The cytotoxic agent completely shut off the disease, so much so that we've now treated over the years hundreds of patients with Wegener's granulomatosis, and the disease is essentially curable. We now have a 93% remission rate, whereas when I came to the NIH in 1966, 100% of the patients died. We have fine-tuned the regimen now, writing and informing physicians that if the dose is maintained at a level that keeps the white count above a certain level, then there will be very little trouble with secondary infection. If the patient is simultaneously treated with alternate-day prednisone as opposed to daily prednisone, which has toxic side-effects, infection will be largely avoided. So, the combination of alternate-day prednisone with daily low-dose cyclophosphamide essentially was responsible for essentially curing Wegener's granulomatosis, or at least putting it into prolonged remission.
Once it became clear from the first several patients that it worked with Wegener's, we then tried it with similar diseases–polyarteritis nodosa, cerebral vasculitis, lymphomatoid granulomatosis and Takayasu's arteritis. We had a series of seven or eight diseases that formerly were completely fatal but now people were coming to the hospital, and four to six weeks later, they were walking out and going back to their jobs. It was a heady and exciting period of time–both clinically and in research. At the same time we were looking at regulation of the human immune system at the very basic level, which emerged in the 1970s from cellular phenomenological research to work at the molecular level.
Harden: It must have been very gratifying to achieve such results.
Fauci: It was gratifying not only because I could do some good but because I actually saved the lives of some people. That is the epitome of what you want to do in medicine. I've always wanted to be involved with diseases that were very, very serious. I would rather be involved with patients who have fatal diseases than those with diseases that are just an annoyance. That just happened to be my bent. I wanted to be where the action was. So there it was, we had a disease that was formerly fatal and we made a major impact on it. The other thing that was so gratifying about that experience was that we were able to do something that people said you can't do–you can't do clinical medicine at the same time that you do very basic research. That is absolutely incorrect, if you organize your time correctly. If you ask the right questions, get the right training, you can do work that is very, very basic in its approach and yet has important clinical consequences.
Harden: In our next interview I want to examine how you as a clinical immunologist responded to the first cases of AIDS that you saw. But, before we stop today, I want to pose a hypothetical question. If AIDS had struck in 1955, before we knew about T-cells and other aspects of the immune system, how do you think the medical community would have responded to it?
Fauci: I think it would have been much more frightening than it is now, and it is frightening now. I think we would not have had a clue as to how to combat this disease from a basic scientific standpoint. I think we would have realized just on epidemiological grounds that it was an infectious agent of some sort that was sexually transmitted and transmitted by blood. But about pathogenic mechanisms, we wouldn't have had a clue. We wouldn't have known how even to go about thinking about the virus, much less clone it and develop drugs against it. So within the framework of the catastrophe of AIDS, we're lucky in the sense that it came at a time when retrovirology, molecular biology, molecular immunology, and immune system studies were at that stage where we could very quickly identify the agent, how it works, the pathogenic mechanisms, its effect on the immune system, etc. If it had happened in 1955, we would have been in very serious trouble.
Harden: Thank you, Dr. Fauci. I look forward to the next interview.
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