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Robert B. Nussenblatt
April 25, 1990
Oral History Interview
This is an interview of Dr. Robert B. Nussenblatt of the National Eye In= stitute (NEI), of the National Institutes of Health (NIH), at Bethesda, Mar= yland. The interview takes place on April 25, 1990, in Dr. Nussenblat= t's office at the Clinical Center at NIH. The interviewers are Dennis= Rodrigues, program analyst and Vicky Harden, director of the NIH Historica= l Office.
Rodrigues: First of all, to set the stage for things,= we've been asking why people decided to go into medicine? What= was your motivation to become a physician?
Nussenblatt: Probably the major reason for going into medicine is = the fact that there really are no two "rights." That is, there isn't = a game of sophistry that's played in medicine. It's one real goal:&nb= sp; the ideal of treating patients. I find that ideal very attractive= and one that's worth devoting one's life to. So, it's a very simple = goal.
Rodrigues: Could you tell us more about y= our training?
Nussenblatt: All my training was done in New York State.&nb= sp; I went to school in New York City. I went to the State University= of New York. I interned in internal medicine at Bellevue Hospital in= New York City. I did a first-year residency in medicine there, and t= hen continued on at Bellevue and New York University Hospital in ophthalmol= ogy. I finished my ophthalmology training in 1977 and then came here = to the NIH as a clinical associate in the Public Health Service and have st= ayed here ever since.
Rodrigues: During that period of time wha= t were your research interests?
Nussenblatt: Well, my research interests, in a generic sens= e, have really always stayed fairly stable. They revolved around ques= tions of immunology and inflammatory diseases. The internal medical b= ackground that I had helped me put some of the ocular problems that we've s= een into perspective. When I was in internal medicine, the interests = that I had, revolved around the rheumatologic diseases and immune-mediated = diseases. In ophthalmology, there is a separate area of ophthalmology= that deals with inflammatory diseases of the eye, or uveitis is sometimes = the term that one uses. So this goal has kept constant over the years= . Certainly, or at least I hope, our ability to ask and to answer som= e of the questions, has become more sophisticated with time. The goal= s however have remained fairly constant.
Harden: How have = those claims shifted from internal medicine to ophthalmology?
Nussenblatt: Probably not for specific reasons. I can't say = that they're absolutely logical. I think one of the problems or aspec= ts of internal medicine, at least in the way that I perceived it, was that = though I enjoyed very much the excitement of Bellevue, it was quite clear t= hat the practice of internal medicine would not be the same on the outside.= Additionally, internal medicine required you to sub-specialize, and = I didn't like the idea of not being involved in the whole area--the whole d= iscipline. Ophthalmology was something that I found very attractive w= hen I was a student. Actually, I had intended to go into ophthalmology, but= at the same time intended to stay in internal medicine longer than people = usually do. What I found attractive about ophthalmology was the abili= ty to deal with the whole discipline, and also the combination of both surg= ery as well as medicine. It offers a great deal. It's a very gr= atifying sub-specialty.
Rodrigues: Now, could you take us up to t= he point when you first became aware of this disease that was eventually re= cognized and called AIDS?
Nussenblatt: The first patient to my recollection that we s= aw through the Eye Clinic was a patient that was originally referred to Dr.= [David] Cogan who is a professor emeritus at Harvard and has been here at = NIH now for many, many years. He is one of the great ophthalmologists= of our century, who has trained many of the leading figures in ophthalmolo= gy from the United States. I've had the great fortune and the great b= enefit to have interacted with him. He is a man with many great talen= ts. Initially, when he came here he was involved in neuro-ophthalmolo= gy as well as pathology, but his abilities span almost every area of ophtha= lmology. An interesting patient came to the NIH who had a poorly-defi= ned illness that manifested itself in the eyes. Ultimately, it was de= termined that he had cytomegalovirus retinitis --CMV retinitis. That,= to the best of my recollection, was the first patient that I saw, who had = this sight-threatening problem, and ultimately had AIDS. That was a f= airly uncommon problem for ophthalmologists. I think I had seen proba= bly two patients before who had CMV retinitis. Its usually seen in pa= tients who are extremely ill or who are immuno-suppressed for a variety of = reasons, either because their disease itself causes an immunosuppression or= because of therapy that they receive, whether it be for transplantation pu= rposes or for other reasons. I had seen, as I said, two patients.&nbs= p; I remember one in particular, since he was a physician from the eastern = shore who had very bad CMV retinitis, Wegner's granulomatosis and was being= immunosuppressed for that problem. But this was an extraordinarily u= nusual disease, that could be reversed. If the immunosuppression stop= ped, then you would get rid of the CMV retinitis.
Harden: Now, this= patient came to you all from someone else who was treating the more genera= lized disease here?
Nussenblatt: That's correct. Indeed, we saw him throu= gh the consult service. We followed him and then, with time, this dis= ease or this problem became recognized as a uniform ailment. Then ult= imately, but not early on the term AIDS was applied to it. It was jus= t an immunodeficiency problem. This patient lost his vision because t= he CMV retinitis could not be treated at that time, then just marched acros= s his retina and unfortunately took his vision.
Rodrigues: When was this?
Nussenblatt: It was in the early 1980s. I can tell yo= u that it was during the time that [Dr.] David Bachman was with David Cogan= --Dr. Cogan. I think you're right. It was probably in 1981 or 1= 982, sometime then.
Harden: Which cas= e was this one? We had been talking about your earliest cases and I r= emember a reference to this. So, even though it's very hard to rememb= er how you were thinking at that time; could you tell us what you were seei= ng and how you evaluated what you were seeing in the whole patient?
Nussenblatt: It is difficult to give you the whole story.&n= bsp; Certainly this presentation was odd, in that he was clearly not being = immunosuppressed by physicians and he had other opportunistic infections.&n= bsp; I remember he had thrush. So, he was clearly ill for unknown rea= sons. The AIDS virus had not been discovered at that point. We = certainly suspected that he had an infectious process and it looked pretty = much like CMV retinitis, but we weren't absolutely sure. But it certa= inly seemed to fall into the category of the infectious process.
Rodrigues: I assume then that not too muc= h time passed before you began to see other cases.
Nussenblatt: Yes. Indeed.
Rodrigues: Were you directly involved wit= h some of the people in the Clinical Center who were admitting these patien= ts tests?
Nussenblatt: Our greatest and longest collaboration has bee= n with Dr. [Anthony] Fauci's group. With Cliff [Dr. Clifford] Lane, a= nd [Dr.] Henry Masur, as well. Henry, of course, is, perhaps strictly= speaking, not part of that group. But that was the group that really= we interacted with and we've continued to interact with them over the year= s. I had a working relationship with Dr. Fauci because of my interest= in inflammatory diseases and his great interest in immune-mediated disease= s. We had talked to each other when he was a lab chief, dealing with = questions of Wegner's granulomatosis. So, this was sort of a natural = continuation of that relationship. When it became obvious that more p= atients were going to be coming, we began to formalize the way in which we = were going to see these patients. On my side, the person who accepted= a very large part of the responsibility was [Dr.] Alan Palestine, who, unt= il recently, was here as a section chief in our laboratory. He's now = in private practice. Alan took the bull by the horns and helped estab= lish a uniform, logical way in which we were going to evaluate these patien= ts. Someone else who played an early role, again from our side, is [D= r.] Merlyn Rodrigues, who is an ocular pathologist. She's now at the = University of Maryland. Another person who was very instrumental earl= y on was [Dr.] Abe Macher who is a pathologist. He's no longer here a= t NIH. He's a pathologist and infectious disease expert as well. = ; He had an interest in ophthalmology because of his brother, who was an op= hthalmologist. We then began to see these patients on a fairly regula= r basis. One of the goals was to know what these conditions were in t= he eye. Was it all cytomegalic virus retinitis or was it something el= se? In one of the early projects that we had, we had the opportunity = to examine the eyes of an AIDS patient who died here at NIH. There wa= s a very large study that was published in the early 1980s, demonstrating t= hat the patients who had these ocular lesions had--almost all of them had C= MV retinitis and, that, in fact, we could correlate our clinical observatio= n to what was occurring pathologically. Another observation was that = those patients who had CMV retinitis had exceptionally low T-cell counts.&n= bsp; So, if the total T-cell number were below 100, we knew that they had a= very high possibility of developing CMV retinitis. Those were, perha= ps, the earliest observations, other than just the anecdotal one of this pa= tient, that I mentioned to you before.
Harden: I have a = question about CMV. Is CMV a virus that is so common, that normally i= t's around and one fights it off immunologically, or is it a more rare kind= of a virus?
Nussenblatt: CMV is ubiquitous, and certainly anyone who's = in a hospital environment is infected with the virus. As long as you = are immunocompetent, nothing happens. You have to be extraordinarily = immunocompromised in order to develop problems with it, so it's really a ub= iquitous organism.
Harden: Opportuni= stic infection.
Nussenblatt: It is indeed. Other disorders that we sa= w--and this has seemed to have changed now, maybe because of the kinds of p= atients seen at NIH, was Kaposi's sarcoma. We saw Kaposi's on the eye= , around the eye, and made some of the early observations dealing with that= . We also dealt with the problems of how to treat it, what to do.&nbs= p; Other conditions include ocular toxoplasmosis, which is fairly rare in A= IDS patients. We really don't know the reason for that. It's mu= ch more common in the central nervous system, in the brain, than it is in t= he eye. As time progressed, other things were observed, but the predo= minant disorder that we saw in these patients, and the one that was sight-t= hreatening, was CMV retinitis.
Rodrigues: This is sort of an aside, but = are there ocular manifestations before the patient actually progresses to t= he AIDS, like people who are infected with HIV [Human Immunodeficiency Viru= s], such as ARC [AIDS Related Complex] patients, or do you see ocular compl= ications later in this state?
Nussenblatt: There are early changes within the retina; how= ever, they're much more common in patients who have AIDS. They are co= tton wool spots--microinfarctions of the retina that appear to be fluffy wh= ite. When one looks at the back of the eye, there's a fluffy white na= ture to them. There's also a vasculopathy--vascular changes that can = occur in patients who are HIV positive. Sometimes it's difficult to d= ifferentiate those changes from that of CMV retinitis. In fact, only = time can tell, that is, if it begins to expand, we feel pretty secure that = it's CMV retinitis. Those are much less common, however, in patients = who have ARC as opposed to those who have AIDS.
Rodrigues: One of the things that I'm cur= ious about is the process by which different institutes dealt with this pro= blem. Everybody at that time, during the early 1980s, had a pretty fu= ll plate of activities and there weren't excess resources sitting around wa= iting to be utilized. When a new problem came up, decisions had to be= made about shifting personnel and resources. Is there something you = can say as to how decisions were made? For instance, you just indicat= ed that a number of people were now having to deal with these patients.&nbs= p; Presumably, they let go of other responsibilities that they had prior to= that. Who made these decisions?
Nussenblatt: In all frankness, I'm not even sure that a con= scious decision was made, at least within our institute, to drop other prio= rities. One of the interesting parts about working at NIH is that peo= ple are really devoted to looking at interesting questions. What happ= ened, in all honesty, was that people just worked longer and included it in= to their schedules so that they didn't have to let go of other projects.&nb= sp; I do not remember off-hand, at least with the people who were close to = me, anybody dropping other projects in order to become involved in AIDS.&nb= sp; They simply worked longer. When it came time to do animal work, f= or animal experiments, they were simply put off until after clinic hours.&n= bsp; If they had to come in on the weekends, they did that. The eyes = were accessed whenever we could get them, and that would be in the wee hour= s of the morning or late at night or whenever the case may be. So, pe= ople just make time and they really don't work the eight to five or eight-t= hirty to five shift. They simply are here as long as it takes to get = these interesting projects going. In terms of a decision--one of the = other interesting aspects, from my point of view, and one of the reasons wh= y I think this is a unique a place that has to be nurtured and kept, is tha= t the decision to become involved in this was made very early. It was= purely scientific and medical. It had nothing to do with politics; n= othing to do with making someone happy. It was a scientific decision = that this was an interesting area, it was an important, and that it was cle= arly going to be an important area because it was an unknown. The eme= rgence of a fairly rare infectious entity inside the eye, which suddenly be= comes so much more common, clearly told us something very profound about th= e way the body deals with the eye. That decision then was made by the= people who were involved in the work itself. It was not imposed upon= us in any way. That's been really the attitude all along through the= years.
Harden: We have h= eard what you said and we have spoken to some other people who said that it= was an interesting problem. I'm sure you have read a number of the p= opular books about AIDS. Government scientists, in particular, but sc= ientists, in general, have been criticized for stepping back and saying it'= s an interesting problem. AIDS activists are saying one needs more de= dication, than that you were talking about in the beginning on going into m= edicine requiring dedication. Perhaps you would comment on how these = two things scare research physicians.
Nussenblatt: In terms of the complaints that have surfaced,= I can't really answer them, because I think that they swirled about at a v= ery different level than what I am interested in. When I say it's an = interesting problem, that in no way suggests that, that is a cold, uncaring= point of view. If anything, it was an interesting problem for us bec= ause it potentially could give us information to help people. In the = end, that's really, the goal--to develop new ways that we can help people.&= nbsp; However, one does try to take advantage of nature's quirks and certai= nly from a research point of view, one wants to be on the look-out for thes= e observations and to take advantage of them. In some ways, the role = of a researcher is somewhat different from the role of somebody who's going= to be treating a patient in a local hospital. Their roles are differ= ent, and I can fully understand the frustration of the lay community, when = they say that more money and time should be spent. But sometimes we d= on't have the ideas and that's a simple reality. Sometimes we're wait= ing for nature to give an answer to us and sometimes she doesn't want to do= that. So, it can be very frustrating at times for us, as well.
Rodrigues: Picking up on that--has AIDS t= aught us something profoundly new? Beyond what we've learned about HI= V and the advances that we made on that particular problem, do you feel tha= t AIDS has expanded our understanding beyond its own immediate sphere?
Nussenblatt: The answer is "Yes" in perhaps at least two ar= eas that come to mind. One is that it has enhanced our understanding = of viral diseases of the eye and how, in fact, some of these mechanisms may= come about, not only in the AIDS patient but in others. It was our a= wareness and suspicion that virus may play a role in even immune-noncomprom= ised individuals-- patients who do not have immunologic problems. The= other area that is important is the better understanding of the way in whi= ch the HIV enters into a cell. There are certain concepts that have d= eveloped concerning our ability now to alter cells in a positive sense--to = use this very nefarious methodology of molecular biologic techniques, for t= he benefit of individuals. So, from a very specific ocular point of v= iew, it's been very helpful, and also in terms of developing new ways in wh= ich we can treat certain diseases.
Rodrigues: One of the things we've also b= een looking at is the different activities that were going on preceding the= emergence of HIV, that were particularly helpful in being able to quickly = come to grips with this new viral entity? Were there any efforts that= you were working on, or that you were aware of, that played a big part in = your ability to understand what the nature of this disease was?
Nussenblatt: Well, I think I would, say that somewhat diffe= rently. I don't know if it was so much the area that we were working = on as opposed to the ability to interact very rapidly with a variety of ind= ividuals. By that I mean, there was a very close-knit group that came= from very different specialties that were able to work together, and I thi= nk that dramatically helped our ability to come to an understanding of what= was going on, as opposed to a specific area of research. I can tell = you, however, much later on, there were unusual entities within the eye tha= t sometimes occur in AIDS patients and new surgical technologies helped us = identify that. In fact, this entity is a bacterial infection that can= be cured with simple antibiotics. So, the new technology helped us i= mmensely in our ability to make the diagnosis and then treat a patient.
Harden: Could you= talk a little more about the bacteria and the technology?
Nussenblatt: Well, yes, though it should be put in perspect= ive that we have been really discussing very early aspects of AIDS history,= or ocular AIDS history, and this is something that happened more recently,= only a few years ago. We saw patients and we've reported this in the= American Journal of Ophthalmology. There are patients who came to us= with a very unusual entity inside the eye. At least in our minds, it= didn't look like the more common disorders that we see, such as CMV retini= tis or toxoplasmosis, though the initial patient had been treated for those= and he did progress. He had the problem in both eyes, but one eye wa= s not doing well at all. We elected then, to do a retinal biopsy.&nbs= p; We were able to take a small piece of his retina, with the eye remaining= intact. We didn't have to remove the eye. The very small piece= of retina gave us an enormous amount of information. It was a very s= mall piece of retina, perhaps one by two millimeters, two by two millimeter= s, with which we were able to obtain evidence to show that it was a gram-po= sitive bacteria. Ultimately he was treated with a standard antibiotic= and he was cured of his problem in his other eye. In fact, he probab= ly had this systemically, because he felt much better after therapy. = We were then able to recognize the same entity in one of his sexual partner= s, and we were able to treat him as well. So, that technology helped = us immensely in identifying the problem and, ultimately, in treating it.&nb= sp;
Rodrigues: Were there particularly unique= problems in dealing with those AIDS patients?
Nussenblatt: I think there was. I think that there wa= s a fear, of how problematic dealing with the AIDS virus was going to be.&n= bsp; We ultimately reported from here that, we can find the AIDS viru= s in tears as well as in the cornea. We did that with Dr. Gallo's gro= up and [Dr.] Zaki Salahuddin. So, we had a real concern about whether= , the AIDS virus could be spread through touching the eye. There was = also the need for greater sensitivity, I think, on all of our parts, in ter= ms of interacting with many of the patients. The patients that = came to us were frightened, and needed tremendous amount of support. = I think that's changed dramatically over the years, at least here, where I = think, we have an extremely good rapport with our patients. I think, = and hope in any event, that at least from the eye point of view that, the c= ommunity of individuals who are at high risk from getting this kind of prob= lem, know that they will be treated in a correct and ethical manner. = It was an evolutionary process as we learned about their needs. = For me, I think that that was the most important, because the area of ocul= ar inflammatory disease is such that these are generally chronic problems.&= nbsp; Unlike some of the other areas of ophthalmology where you might inter= vene with a surgical procedure, and never see the patient again. Pati= ents with uveitis come back again and again. One of the things that w= e have to do is to develop a good rapport with the patient. Their inp= ut is certainly as important as ours. The same was true for the AIDS = patients who had CMV retinitis. They clearly have to know what the pr= oblems are and have to trust us as we have to trust them. It took tim= e to develop that trust.
Harden: It must b= e one of the most terrifying things to encounter, when you already have a g= eneralized disease, to realize that you may not be able to see. I thi= nk that you must have to intervene at a critical time.
Nussenblatt: It's horrible. I think we do, and I thin= k that it took time to fully appreciate this reality and for us to maturate= in our minds. You know, as an individual with AIDS becomes more debi= litated and more bedridden, the only thing for them to do is turn then to r= eading or watching television, whatever the case may be. And then wit= h the idea that they may become blind on top of that, it seems like the ult= imate horror that can happen to them. They risk losing their ability = to become self-sufficient, even in terms of taking medication, and so forth= . We've learned to take better care of individuals who have AIDS, and= their life span has been extended. There is a very strong possibilit= y that between ten to twenty-five percent of the individuals with AIDS will= get CMV retinitis. So, the answer is "yes".
Rodrigues: So, if I understand this corre= ctly, one way of looking at it is that although we've been able to extend t= he life of these patients, our ability to protect them from different types= of complications, such as CMV retinitis, is not on a par with some of the = other problems. In other words, although they may be living longer, t= hey're still going to be susceptible to a variety of other problems that ar= e going to make life very difficult.
Nussenblatt: Well, yes. If I rephrase that in another= way--what we knew was a complication before, still is. What may have= been in somebody who only lived three months, a peripheral problem, becaus= e of their increased life span now becomes a serious one.
Harden: And there= is no therapy for CMV?
Nussenblatt: Yes there is. We can halt it. We w= ere the first to report it in a study. That was in the American Journ= al of Ophthalmology some years ago. That was again, I unfortunately c= an't tell you the patient's name, but this was in conjunction with Cliff La= ne, Henry Masur and Dr. Fauci's group, in which we began using DHPG, or Gan= ciclovir as it's called now. We had never seen a reversal of CM= V retinitis. We had tried a variety of methods. The CMV retinit= is marches through the retina causing a necrotic lesion, which has a front = which moves as in a wave. Indeed you can see this border of very acti= ve disease. We tried to put down a border of laser and did a va= riety of other things. It just didn't work. I remember very viv= idly when we first used it. Alan Palestine was in the clinic and he c= alled me and he said, "You've got to see this." The CMV lesion = in the eye had disappeared. In fact, it was an extraordinary experien= ce because that had never been seen before, at least here. Initially,= we weren't even sure we could believe it. But, in fact, higher dosag= es of Ganciclovir arrested the problem very nicely. However, in an underlyi= ng immunosuppressive problem, if you stop the medication, it will come back= and, unfortunately, if you reduce the dosage, which one has to do because = of the problems of side effects, a very large percentage, and some might ar= gue that in even all of the individuals, the disease relapses. We hav= e a second medication and that's Foscarnet. We've just finished the f= irst randomized massed study to be done in CMV retinitis with Foscarnat.&nb= sp; So, we can stem it, but we can't cure it.
Rodrigues: You mentioned earlier about so= me of the political fire storms that were raging about AIDS. I think = you said at one point that that was at a different level and didn't really = concern you. Looking at the institute in general, and the way the pro= gram revolved, did you think the level of political concern about the disea= se has been helpful or has it harmed the effort?
Nussenblatt: My answer really is a very localized one. = ; It's dealing with our level. I can't speak for other areas. I= don't think it's necessarily harmed. I don't really perceive as bein= g harmful to us the awareness of the problem, whether that's translated int= o the ability to recruit patients or in monies. I think that by being= in the Eye Institute in some ways, we were protected from the main thrust = of many of these problems, since we weren't really considered to be particu= larly relevant at that time. We were a small institute; we were on th= e periphery of things. Perhaps the problem of CMV retinitis wasn't ab= solutely recognized at that time. We now recognize that CMV retinitis= is an excellent way to evaluate new drugs, because we can visualize whethe= r the medication is having an effect. It's much more difficult to do = that in other areas of medicine. But, at least then, I don't think th= at we were in the mainstream of what was going on. So, we were protec= ted, from a large part of that.
Harden: We certai= nly appreciate your taking the time.
Nussenblatt: My pleasure. It's an interesting experie= nce.
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