ASH Oral History: Ernest Beutler

Q: I wonder if you can tell us something about your early childhood and early educational experience and how that might have played a role in your selection of scientific fields?

Beutler: I was born in Germany and my parents fled the Nazis with us, my brother and sister and myself. This was in 1935 when I was 7 years old. My parents were both physicians. I was always interested in science and I can't remember that there was ever much question in my mind that I wanted to go into medicine and/or science. That is, after I got over the ambition to be a baseball player. I was an avid fan of the Milwaukee Brewers, and for a while I dreamed that I would be a professional ball player. That went by the boards, probably by the time I was 10 or 11 years old. When I was 15 my parents enrolled me in the University of Chicago 4-year college program, as it was it called. It was a program that was started by Robert Maynard Hutchins. Basically it truncated high school education to two years. The last two years of high school became part of the university education. In that sense the four year college program represented a two year program, but the last two years of high school were really at the university level. One of the many unique things about this program was that it allowed every student to proceed at their own pace. Even at the age of 15, my age when I started that program, I was not required to attend class. As a matter of fact I was not even required to register for a course. I could obtain credit for the course merely by taking the six hour comprehensive examination that was given at the end of that course. I entered the University in 1944 and the United States was still in World War II. Of course at that time no one knew that the war would end within a year or two, so there was some real advantage to accelerating one's education. Accordingly, I registered for several comprehensive examinations in advance and I took more than the usual load of courses. As a result I completed the four year college program and another year or so of credits in a period of two years. By the time I was 17 I was ready to enter medical school.

Q: And you did so?

Beutler: And I did so. Yes, I actually applied to two medical schools. One was Harvard University. The other was University of Chicago. In those days it was very difficult to be admitted to medical school. I might say that it was particularly difficult for Jewish students to get into medical school because most medical schools actually had a Jewish quota. They limited the number of Jewish students that could enter.

The year that I entered the University of Chicago there were 3600 applicants for 60 places. When to my joy I received an acceptance, and was asked to make a decision, I never waited to find out how Harvard would respond. So I entered medical school in 1946. At that time the University of Chicago was really a very outstanding university. It is still an outstanding university, but at the time there was a real uniqueness to the university. There was the four year college program that I've already mentioned. But also it was really a hotbed of scholarship. Enrico Fermi was there, for example, and lectured to the undergraduate students. Under the West stands, which had been used for football games until the University of Chicago found that they no longer could or wanted to compete with the professional type of college football that was being played at that time, the atomic bomb was developed by Fermi and other leading physicists.

Q: Under Stagg Field?

Beutler: In the stands next to Stagg Field. That's right. And so it was a very stimulating environment in which to be. The medical school, too, is quite unique. In the forties most medical schools taught medical students by enlisting the help of the voluntary or clinical faculty and having a few full time faculty members who performed some research and organized the teaching program. The University of Chicago had a full time faculty. It had no clinical faculty except in the departments of obstetrics and gynecology. To the best of my recollection, at the time I was a medical student the University of Chicago had 50 or 60 full time faculty members in the Department of Medicine alone. Some of them very distinguished. And likewise in the Department of Surgery. An extraordinary number of graduates from the University of Chicago continued their careers in full time academic medicine as I have. Statistics that I read some years ago indicated that about 30 percent of them were in academic medicine, which greatly exceeded the number two school, which was Harvard. So my undergraduate training at the University of Chicago, which was extremely strong, and being able to go to a school of medicine with a very academic tradition and academic direction were factors that were very important in my future career.

Q: Were there any particular faculty that you thought at the time to be exemplary of the academic tradition?

Beutler: The one person, perhaps, who influenced me the most there was Leon Jacobson (deceased 1992). Leon Jacobson was the head of the hematology division. He later became chairman of the Department of Medicine and then Dean, and now he is retired, although I still see him from time to time. He was a fine role model. When we think about why somebody chooses a given field, or a given specialty within a field, more often than not, it's the people who are in that field at the place where they are being trained. I'm sure that was true for me at the University of Chicago. I liked hematology. I liked many of the other areas, too. But I was very impressed with the faculty of the hematology division. Not only Leon Jacobson, but also Matthew Block, William Bethard, and this is what motivated me to approach Jacobson and to ask him whether I could become a part of their division. The way that things were done--well, let me back up a little bit to quote from Richard III, "I run before my horse to market". I graduated from medical school in 1950. I was 21 and, as a matter of fact, I was first in my class. But interestingly enough, I was not accepted for the internships for which I applied. I applied at Beth Israel Hospital in Boston, and I was turned down. I applied at Johns Hopkins and I was turned down. I applied for an internship at the University of Michigan and I was turned down for that. But I was offered an internship at the University of Chicago and so I decided that that was the one that I would take.

Q: To what do you attribute that?

Beutler: Of course, I wondered about it at the time and I've wondered about it since. Actually I had personal interviews at each of these places and I think it's possible that the faculty that interviewed me felt that I wasn't sufficiently mature to be a physician. I was only 20 when I was being interviewed. In the case of Hopkins, for example, it was well known that there was a great deal of anti-Semitism and that would be very likely why they might not have considered me very seriously. Obviously, that wouldn't have been true at Beth Israel. But I thought afterwards, as things turned out, maybe they would have been glad to have me as an intern. But I wasn't unhappy with the University of Chicago as a choice. I might say in those days they had some kind of matching plan, so it was a matter of my not matching in the upper part of the offers that they were making. Maybe I was an alternate at one or another of those institutions, but I was not offered a slot and I was offered a definite slot at the University of Chicago. There were several different kinds of internships in those days and I took what was known as a mixed internship, which meant that I took six months of medicine, four months of surgery, and two months of obstetrics and gynecology. Nowadays, the trend is to have straight internships in which physicians who wish to become internists take just twelve months of medicine, surgeons take twelve months of surgery, and so forth. I think that's a mistake. After all, if the training program in internal medicine is to be four years, then I think having three and a half years of internal medicine and four months of surgery and two months of obstetrics and gynecology is really a pretty good mix. Much better than having no obstetrics and gynecology, no surgery. I believe that those experiences in surgery and obstetrics and gynecology are invaluable. The second year, that is the first year of residency, was a rotation through the in-patient services. Two months in each service. And I had two months of hematology, which I think was the first service I had, two months of gastroenterology, and so forth.

Q: Was that required for all residents?

Beutler: I'm not sure whether all residents rotated through all of the same services. I think that one could take six services, and there may have been eight so there may have been some who didn't get one or the other. But residents got most of the services. The following year, the second and third year of residency, were set up in such a way that one was attached to one or another division. And so it was at that point that it was appropriate for me to make a definitive choice about to what division was I going to be attached. Would I be attached to rheumatology, gastroenterology --? That's when my respect for the physicians in hematology motivated me to approach Leon Jacobson and ask him whether I could be in the hematology division. And he asked me only two questions. He said, "First of all, are you in trouble with anybody in the department?" I said, "No." And then he said, "Do you get along well with everybody in hematology?" I said, "Yes, I do." And the second question is the one that really stuck with me because, I think that Jacobson-really appreciated how important it was for people in unit to get along well with each other. I've always felt that I would much rather forego having a some very talented person in my unit if they were always at odds with others, than to have such a person and put up with squabbling.

Q: What was the structure of the hematology unit back then?

Beutler: There was the head of the unit: that was Leon Jacobson. Then there were two other faculty members. One was Matthew Block and the other was Bill Bethard.

Q: B-l-o-c-k?

Beutler: B-l-o-c-k. Matthew Block died about two or three years ago. He had moved on to the University to Colorado in the late fifties. He spent the remainder of his career there. And Bill Bethard (deceased 1997) actually moved to the Scripps clinic in about 1956. He remained at the Scripps Clinic for a few years and then worked with General Atomics in La Jolla and also was a consultant with the Salk Institute and in private practice. He retired about a year or two ago, and I still see him sometimes in La Jolla. Then there were residents who had, like myself, attached themselves to the department. One of them was Irwin Weinstein (deceased 2002) who later moved to UCLA and was probably the most prominent clinical hematologist in the Los Angeles area. My contemporary during the residence was Herman Klein who moved into practice in the Detroit area. The way that the division functioned is that, everyone had laboratory space and a research program, and the responsibility for the clinical service was rotated among the faculty. The residents would join rounds and listen to what was being said and participate in the discussions, but the primary responsibility would be with one of the faculty. They would make rounds with the students three mornings a week and the students would present new cases, and this would be a teaching exercise. The rounds were two or three hours in duration. An out-patient clinic operated every afternoon. I can't remember exactly how it was scheduled, but one would see patients there, again usually together with the students.

Q: It was a relatively small group?

Beutler: It was a small group. It was very small group. At that time there were perhaps two or three large hematology groups in the nation. The largest were probably William Dameshek's in Boston, Max Wintrobe's in Salt Lake, and Carl Moore's in St. Louis. Those departments turned out a great many hematologists, most of whom ended up in clinical practice, and a few of whom are prominent in hematology today. But Jacobson's program was a very small one. There were just a handful.

Q: Do you think there was a special value in the size of the department?

Beutler: Yes. Very much so. And as a matter of fact -- I find that in many ways that I've emulated what Jacobson has done and many of my attitudes about research and about organization, I can attribute to his philosophy. In fact, Jacobson was a very successful investigator. Very low key. Difficult to understand when he spoke. Not very articulate. But he made several important discoveries. His discoveries led to the whole area of bone marrow transplantation and he is the one who discovered that erythropoietin is made by the kidney. He was elected to the National Academy of Sciences, became chairman of his department and the dean. He was a very successful man. It was evident to me from the beginning that his philosophy was that you try to get good people, that you give them independence, and that if you charge them with some responsibility you don't second guess them, but just give them backing. And that you don't take a ride on other people's work. Those are all very important principles, and ones that I hope I've followed in my career. He also was not one of these people who built big collaborative teams, or joint projects -- something that has become very popular in science -- which I find to be very unproductive and unstimulating and the wrong way to do science.

Q: Why specifically?

Beutler: I would say that the bottom line is that it really doesn't work very well. The philosophy is that science is so complicated that you really can't do everything yourself, and so what you have to do is find a collaborator. If you want to do molecular biology, you find a molecular biologist and you send the material to him or her. If you want to do protein chemistry you send the samples to a protein chemist. I've seen some people who really don't do anything themselves, but just send samples to other people. Superficially this may seem like a good way to do science, but the problem is that if the molecular biologist is a good molecular biologist, he or she really wants to work on his or her own problem and your problem gets a very low priority. Moreover, there are nuances of the problem that he or she may not understand. Or there may be things that the molecular biologist observes that would be very important if somebody who understood the whole problem observed it. So I think that the best research is not done by networks of collaborators, but by an individual investigator with a small, dedicated, loyal team. Jake had -- that's what Jacobson's nickname was -- Jake had two technicians who had been with him forever, and this was, mind you, 40 years ago. Actually, when he came to The Academy meetings about two or three years ago he had one of those technicians with him as his guest. They had probably worked with him for a span of over 30 years. I have with me two technicians who have been with me for 22 years each and three technicians who have been with me over 10 years. That's the core of my research team. I have fellows. They contribute, of course, but they are there to learn more than to add productivity to the research program. When I decided 10 or 12 years ago that it was really for us to master the techniques of molecular biology to answer some of the questions that we hadn't been able to answer earlier, my approach was to bring molecular biology into our laboratory so that we would have the skills ourselves. As a result we now have a very strong molecular biology laboratory. The way that I accomplished this was first of all, to send one of my long term technicians to work with a colleague for a week to acquire some of the technology we wanted to learn then. Two years later I brought into my laboratory a very good young MD molecular biologist, Joseph Sorge, who worked with me for two or three years, and who taught all the people in my laboratory how to perform the techniques of molecular biology.

I myself performed hands on research until about 15 years ago or so. But I do relatively little now. Occasionally I will tilt a test tube or spot something on a piece of paper. Nonetheless, I'm very close to the laboratory. It's right out here as you saw, and I oversee everything that's being done. In my view that is the correct and productive way to do research. I believe, too, that there are some enormous benefits from having relied heavily on technical assistants as I do. One is that I can afford to take a chance on a project which may not pay off at all. One can't in good conscience do that with a postdoctoral fellow. The fellow's career is on the line. I have a responsibility for that career. If I give that fellow a "pie in the sky by-and-by" kind of project, and nothing comes of it, then he or she isn't going to be able to get a good post afterwards, because they won't have any publications. But if I want one of my technicians to perform a chancy project and that technician doesn't publish anything for 2 or 3 years, that doesn't really matter, you see. And there is the matter of continuity. I sent Wanda Kuhl, who's been with me for 22 years, to work with Y.W. Kan in his lab for week about 10 years ago. Subsequently she learned how to perform some of the other techniques from Joe Sorge. She's still here. If this knowledge was being passed on from fellow to fellow there would be a great deal lost. At the same time one has to realize that if one wants to have a long term impact on science, that one also has to train people, and for that reason I do have fellows in the laboratory. But I believe that it's important to realize that the fellows are young scientists who are in the laboratory to be trained, not people to be exploited so that I can write more papers. Of the publications that emanate from this laboratory about 80 percent really come from the work of myself and my technicians, and not from the fellows. The fellows contribute some work, too, but the core of the work at this laboratory is performed by technicians. That's very unusual in the United States these days, and even more unusual in Europe.

Q: And this is the tradition of the research ‑

Beutler: That I inherited maybe -- yes, from Leon Jacobson. Of course you never know for sure. Maybe I would have done things just the same. Maybe I would have had the wisdom to do it that way even if I'd never been exposed to him. But I doubt it. I think one tends to emulate one's chiefs. That's the way his program was and while I never consciously said to myself, "I want to do this the way that Jacobson did," that's the way it evolved. Now when I look back I realize that many of the things I'm doing are done the same way that Jacobson did them.

Q: Can you give us an example of how the organizational structure that you just pointed to was parleyed into a particular insight that came out of your laboratory? In other words, the benefits of training technicians, as opposed to collaborating with others?

Beutler: OK. Well, insights -- major insights usually don't come from technical personnel. They usually come from the investigator who has a broader and deeper understanding. But it's not enough to have an insight; you've got to develop the data. That's where the technicians are just invaluable. I'll give you one example. One of the topics that I've been concerned with for the longest period of time is glucose-6-phosphate dehydrogenase deficiency, and I'm probably better known for my work with that enzyme than anything else. That's work that I started when I was in the army and has been ongoing for about 35 years. By the late 70s that area was pretty well played out in terms of what one could do because the technology was really limiting. One of my colleagues, Lucio Luzzato, worked very hard and very effectively in the early 80s with a collaborator, a molecular biologist by the name of Graziella Persico, to clone the G6PD gene. Once that gene had been cloned and the sequence published, it was possible to begin to study mutations in G6PD at the DNA level. Now we're able to actually sequence the DNA to see where the mutations were. I actually started this work in our laboratory with a postdoc, with Dr. Akira Hirono, who had been sent to me by Shiro Miwa in Japan. I put him on the project of finding the mutation in the most common African deficient variant G6PD A-. He worked on this project for nearly two years. He didn't know any molecular biology to start with, but Wanda and the others in our laboratory were efficient and taught him the methods, and he found those mutations. After Hirono left, or shortly before, I put Wanda Kuhl on the project. Over the preceding 10 years or so we had accumulated, DNA from many patients with variants. Now the task was to find out what the mutation was in these individuals. I worked with Wanda for two years working out a simplified technology to find these mutations rapidly. Now we can find the mutation in a G6PD variant in a week; it took two years to find the first one. We have now basically opened up this entire field, shown where the mutations are in about 20 different variants, and developed some insights in that we now realize that many of the mutations that were thought to be different are really the same. For example, with respect to G6PD A-, which was thought to have been an African mutation, it turned out that that mutation is not uncommon in southern Europe but was thought to be different mutations under different names. But when we perform DNA analysis we find that they're the very same mutation. While these are not major insights that have changed the course of medicine and biology, they have been important in this area of the genetics of a very important blood disorder. And I couldn't have done it very well with a postdoctoral fellow. It took two years just to work out the technology and if a fellow worked out that technology in two years and then moved on and then tried to hand it over to somebody else, and somebody else tried to perform these studies, it wouldn't have worked out nearly as well. Moreover, after the first 10 or 15 mutants had been studied, perhaps a fellow wouldn't be interested in investigating any more. But I wanted to get more done because I'm interest in population genetics, and in working with a technician and particularly with a very excellent and loyal one, well, there's no problem. We just sit down and decide which ones we were going to study, and study them.

Q: So, this technology really has to do with sort of increasing the speed with which you can do hemoglobin analysis?

Beutler: This is an enzyme.

Q: Right. An enzyme.

Beutler: Yes. Right. And as a matter of fact, a really interesting example of how much better this system works is that just last week, using Reference Update I found that Lucio Luzzato had a paper -- that had just come out in Biochemical Journal, which is sort of the British equivalent of our Journal of Biological Chemistry in the United States. And this proposed a -- I could tell from the title and from the abstract -- a rapid technique for sequences of G6PD variants. They had done one variant. Their technique is not nearly as simple as ours. We have a paper in press in the Journal of Biological Chemistry and in that we did ten variants and presented a method which was really much better than theirs. That's the kind of work I can do with Wanda. The other thing about technical people like Wanda, or like Carol West, who's the other person who's been with me for a great length of time, is they themselves have really very good insights into what's happening. It's very common for them to come in to see me and to tell me that they've encountered a problem. Then they show me the problem and they wait respectfully for me to tell them what the solution is. I usually don't know. And then after giving me my opportunity to speak, they say, "Well, I think I know what it might be, Dr. Beutler." And then they tell me. And usually their answer's right. They really have very good insight into problems, particularly methodological problems; sometimes theoretical problems too. I'll give you another example, however. One of the most important genes to clone right now, or a very important one, is a gene for idiopathic hemochromatosis, iron storage disease. It's a very common disease. Not many people in molecular biology know about it. I know about it because I'm a physician and a hematologist, and patients with this disorder are usually taken care of by hematologists. I had a long shot idea of how to clone that gene. And with a long shot idea like that it probably won't work. But if it does, it'll be as important as cloning the cystic fibrosis gene, which as you know has gotten a tremendous amount of publicity recently. Well, I put Carol West on the project. Carol's been working on it for nearly a year. And actually I sent her to France for a week or so to learn some techniques that we needed and I have to say that we probably only have a 5 or 10 percent chance of cloning that gene using the approach I've chosen. But if we don't succeed, it won't be Carol's career or my career. It will be a disappointment but science is made up of a succession of disappointments and triumphs, I guess, and you have to take them as they come.

Q: So that's a really wonderful way of managing the risks.

Beutler: That's right. I have another fellow. She's a clinical fellow, really, who's spending a year in the laboratory, and she wants to do something in molecular biology to help her get a future job. I've given her a very circumscribed topic, that is going to give an answer one way or another. It has to do with linkage analysis of the G6PD A mutation. I was able to obtain the DNA from colleagues, and she's learned from one of my technicians how to perform the needed experiments. A paper will come out of that, and it will be an interesting one. But that kind of work is never going to be as important as cloning a-gene for an important disease. We can achieve a balance in our laboratory. There are some laboratories now that have 10 or even 20 fellows working in them. I don't understand how the head of that laboratory can give those people training or guidance or any of his or her time. You can do that with two or three fellows, but I don't think you can accomplish it with twenty. When you use fellows as technicians, as many investigators do, you're subverting the education process, and I don't think the outcome of the research is as good as either.

Q: Can you talk a little bit about the status of hematology when you first entered the field? The sorts of research problems that Dr. Jacobson was interested in, or the sorts of clinical reasons for pursuing hematology?

Beutler: Yes. Well, first off, when I entered hematology, it was a relatively small specialty. When I came to the City of Hope in 1959 to become chairman of the Department of Medicine there, there were probably a total of 6 or 8 hematologists in all of the Los Angeles area, and 5 of those were at UCLA. So, I knew everybody in hematology. Now there are probably 300 in the Los Angeles area. So first off, it was a much smaller field. The kind of problems that were being addressed then are really not all so different from the kind of problems that are being approached now but they're being approached at a different level. Jacobson had two major interests. First of all was protection against radiation damage. He tried very hard to isolate a humoral factor, which protected against radiation. It turned out that that humoral factor probably didn't exist, and that what he was really observing was the transplantation of cells. That is why I said earlier that his work really led quite directly to bone marrow transplantation. The second area in which he was interested was the regulation of red cell formation. He was one of the pioneers in the study of erythropoietin and there are still a large number of investigators studying erythropoietin. Only now they are studying the receptor for erythropoietin. They're studying the transduction of the signal that erythropoietin creates. They're studying the production of messenger RNA when cells are stimulated by erythropoietin and questions of that sort. My own interests in those days had to do with iron metabolism -- what regulated iron absorption. We didn't figure it out and there are still hematologists working on it today. I was working on defects in red cells that produce hemolytic anemia, and there are still hematologists working on that today, and sickle cell disease, and there's still many hematologists working on that today. So I would say that in the environment in which I worked, hematology was not that different from what it is now, except that technology has moved ahead. Investigators are looking at the same problems with different tools. For example, in the late 50s and early 60s, I conceived the idea that one could treat sickle cell disease by switching hemoglobin production from sickle hemoglobin to fetal hemoglobin. This involved switching production from the beta chain to the gamma chain. Well, we actually worked on this for-quite a while, but with the tools at hand we couldn't understand the switch and we couldn't influence it. People are working on it today and they can't understand it either, but they're getting closer because now they can study at the DNA and messenger RNA. I believe that within a few years they'll get there. But the problems are the same. If I looked back at the generation of hematologists before mine, who were still senior at that time, there were some like William A. Castle, who was very physiologically oriented and he was doing the same kind of work. He worked on iron. He worked on what turned out be vitamin B12. But there were also a large number of hematologists whose orientation was very largely morphological.

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Beutler: -- And it's still true today that there are those who were trained by the previous generation of hematologists who believe that morphology is the beginning and end of hematologic diagnosis. They were trained to believe that you have to look personally at every blood film of every patient that you see. And I don't think they do it, but they feel guilty about not doing so. I don't personally study each blood film and I don't feel guilty about it. So I believe that at that time, perhaps, the strong morphologic roots of hematology were more heavily represented in research. But in the environment in which I was, that wasn't really nearly as true. We were studying physiology and biochemistry, and the main change has been that one can now extend this by investigating the biochemistry of the DNA and the RNA, which we couldn't do earlier because the technology hadn't been developed.

Q: One of the things I asked you to do with your curriculum vitae was to highlight what you felt were the most important research contributions, and one of the things you did, you highlighted a series of articles on primaquine, if that's the correct pronunciation, and I was wondering why you chose to highlight those and how that fits into the themes that you're talking about now.

Beutler: Primaquine sensitivity was a phenomenon in which certain individuals, usually black, sometimes of Mediterranean origin, develop severe anemia every time they took the drug primaquine. Our work showed that this was due to a hereditary enzyme deficiency, glucose 6 phosphate dehydrogenase deficiency. There are about 200 million people in the world who have this deficiency. So it's pretty important, and basically my studies were instrumental in leading to that discovery.

Q: What was that drug used primarily for?

Beutler: For malaria. It was actually developed during World War II when the supply of quinine was cut off from Southeast Asia, and it was an analogue of a drug that was used earlier, actually introduced in the 1920s. It was called pamaquinine or plasmoquin. And pamaquinine or plasmoquin had fairly favorable anti-malarial properties, but it produced severe and even fatal anemia in some susceptible individuals. When primaquine was developed as an analogue of plasmoquin, it had the same properties. It was a good anti-malarial --probably better than plasmoquin but it also caused hemolytic anemia. When I entered the army in 1953 after my second year of residency at the University of Chicago, I was assigned to the Army Malaria Research Project in Joliet. This was not a coincidence, because that project was run by the University of Chicago, I'd been a resident at the University of Chicago in hematology, and one of the problems in which they were interested was this kind of anemia. And so, my major projects during my year there was to investigate the cause of that anemia. It was those investigations led to the discovery that the defect was in the enzyme glucose 6 phosphate dehydrogenase. That's why I consider those articles to be important.

Q: How were those studies constructed? In other words I notice that many of them were published in the Journal for Laboratory and Clinical-Medicine

Beutler: That's right.

Q: And then you published a summary somewhere, some years later in Blood. I'm wondering about your co-authors. How those studies were put together, how the clinical studies were actually -‑

Beutler: The senior person in charge of those studies was Alf Alving. Alf Alving was not a hematologist. He was a nephrologist and quite frankly he really didn't understand very much about the studies. His name appears in the all the papers and it did use to wound us a little bit in our younger days when the studies were referred to "That fine work that Alving did", because Alving really hadn't done any of it. There were basically two people who did the work. One was Raymond J. Dern (deceased 2001) and the other myself. Ray Dern was also assigned to Joliet as a military officer. He had been a resident also at the University of Chicago. But he was some years senior to me and also had a Ph.D. in physiology, from the University of Rochester. Ray Dern has retired recently. He lives in Redondo Beach. He and I utilized what was then a quite new technique of chromium-51 survival of red cells. We took red cells from primaquine sensitive individuals, labeled them with chromium-51, transfused them into non-sensitive individuals, and then showed that those cells were destroyed when primaquine was given to non-sensitive individuals.

Q: Could you describe that technology?

Beutler: Yes. It's a technique that's still used today. What you do is you take blood, you add chromium-51, radioactive chromium, wash the red cells and then you inject those red cells into the recipient. One can perform such studies with a person's own cells or one can with those of somebody else. Nowadays with concern about AIDS we wouldn't use another person's cells, but in those days there was no AIDS and while were concerned about hepatitis it was not that much of a problem. And so we were able to perform those studies on volunteers. Blood samples are taken every two days or so, and their radioactivity measured. Normally the radioactivity declines very slowly, maybe two percent or so a day. But if the red cells are being destroyed rapidly because they're abnormal or they're being challenged by primaquine, then there's a drop off of radioactivity. So if you start out by asking the question, "Are individuals who are sensitive to the hemolytic effect of primaquine sensitive because their red cells are different, or do they metabolize the drug in some different fashion?", one can obtain an answer by performing this kind of cross transfusion experiment. If the defect resides with the red cells then red cells from a primaquine sensitive person will still be sensitive in the circulation of a non-sensitive person. Coversely, if you take red cells from a non-sensitive person and transfuse them into a sensitive person, even when that sensitive person has hemolysis, the radioactivity of the transfused cells will remain unchanged because non-sensitive cells will not be destroyed. Those studies, by the way, were done by Raymond Dern and Irwin Weinstein. In this way it was established that primaquine sensitivity was due to a defect of the, red blood cells. Over the next year I performed many studies trying to determine what was wrong with those red blood cells. One of the measurements that I made, for reasons that probably are not worth going into now, was the content of glutathione in red blood cells. And that turned out to be low. Then I showed that not only was the content of glutathione low, but the glutathione stability was low. That finding led my colleague Paul Carson to measure the enzymes that maintained glutathione in the reduced state and he found that the defect was in glucose-6-phosphate dehydrogenase. Thus, primaquine was the drug that opened the door to the finding this defect. Now the defect itself could be identified without administering primaquine or performing red cell survival studies. One could measure the activity of the enzyme. One could measure the properties of the enzyme. To leap frog to where we are now with this defect, it was shown over the subsequent 20 or 25 years that glucose-6-phosphate dehydrogenase deficiency was common all over the world, but the properties of the residual enzyme in the deficient subjects differ from population to population. Among Africans, for example, the enzyme moved fast and therefore it was called "A minus" because its mobility was faster and it was deficient. In the Mediterranean areas the defect was much more severe than it was in Africa. There was much less residual enzyme and the properties of the enzyme were different. There was a bi-modal pH optimum curve and the affinity for substrates was different. This enzyme was called G6PD Mediterranean. In the Orient there were different variants, yet. Eventually a list of more than 400 different variants emerged. What we've been able to do just in the last 2 or 3 years is to examine many of these variants and find out that many of them that were assigned different names are actually the same. So there aren't 400 variants. Probably there are one hundred, or 80 or a number in that range. We don't know. We'll never know for sure, because some of them we'll never be able to examine again. But we found out, for example, that in the Mediterranean area, where many different variants had been described and claimed to be different from one another, many are actually the same. They have mutations in nucleotide 563. Another interesting feature about these variants is that they also have a nucleotide substitution in a different place, nucleotide 1311, which does not produce a coding change. Very recently we found that the 1311 mutation occurs in about 10 or 20 percent of the population at large in the Mediterranean region, not just in those with G6PD deficiency. But in the G6PD deficient subjects almost all of them had this mutation. What that means is that G6PD deficiency in the Mediterranean area probably arose in one individual and that the millions of people who have it now are descendants of that one individual: he happened to have that 1311 mutation. We found the same Mediterranean mutation in India. We've now examined three such subjects from India and they don't have the 1311 mutation. What that implies is that this mutation arose independently in India, so that we have the same mutation at 563, rose in one guy in the Mediterranean area, one guy in the Indian subcontinent, and now there are millions of people who have inherited that chromosome, presumably because they had some kind of survival advantage, probably defense against malaria. And the same thing is true of G6PDA-. There's a nearby polymorphism, and all the subjects who have G6PDA- have that polymorphism.

So G6PDA- probably arose only once too. And the individuals in Europe, too, who have the A- mutation, all carry the additional polymorphism. Well, I find these discoveries very interesting. It's one of the things that I enjoy about doing science -- We can answer questions that we didn't even dare ask, let's say 10 or 15 years ago, because there just wouldn't have been any way to explore the problem. How would one even have approached the question of whether all the G6PD deficient people in Europe arose from one founder, or rather they were all a bunch of different mutations that occurred repeatedly?

Q: At what point in your work did you begin to ask questions about the relationships between G6PD and these larger questions about population genetics?

Beutler: Probably about 3-4 years ago, because that's when it first became possible for us to do it. I may have wondered about it before, but I never gave it very much the time of day. This type of work has been pioneered very effectively by Y.W. Kan with the mutations in hemoglobin. So basically what we're doing is to exploit the ideas and the technology that he developed in the late seventies with the sickle cell and thalassemia genes. And we're doing the same thing with another enzyme defect, and that's the defect of Gaucher's disease, which is a very common Jewish mutation. Here, again, it turns out that 75 percent of the Gaucher disease alleles are the same, and they all are originated in one person. They all have the same haplotype. They're in the same DNA pattern.

Q: You said earlier that specializing in hematology was much more a decision based on your fitting in with a group of hematologists. What particularly about hematology and how it fit into questions of medical research or function of the hospital appealed to you after wards?

Beutler: I'm not sure that I can say as a clinical specialty that I find hematology more appealing than I would have found endocrinology, rheumatology, or other medical specialties. One of the attributes of hematology that's appealing is that there are some hematological diseases for which we can offer a spectacular cure. The two examples that come to my mind immediately are, of course, pernicious anemia and iron deficiency anemia. You have a patient who is very ill and you give him a simple remedy and they're perfectly well. You can't get around the fact that that is very gratifying for a physician to be able to do. But the down side is that you also have patients with leukemias and lymphomas that don't do very well. I will say that in the leukemias and lymphomas there have been spectacular advances in the time that I've been in hematology. That's gratifying and actually I take pride in the fact that I've personally participated in some of those advances. But I can't say that that is what attracted me to the field. There is something else that's very attractive about hematology to somebody who is a scientist, and that is that the tissue in question is very easily sampled. You can get a blood sample from almost anybody at frequent intervals, count the cells. You can study the cells. That's much harder to do if you are a liver specialist or a small bowel specialist or a brain specialist. So from the point of view of doing clinical science hematology is really quite ideal.

Q: I was looking at an article of yours in which you used the phrase "iconoclastic" to describe the relationship between the classifications that hematologists have made that have proven to be very successful in terms of really coming to an understanding of disease. And then you expressed some skepticism about contemporary classification, looking at lymphomas and so on.

Beutler: Yes. Actually, that's sort of an interesting article. I think I am somewhat iconoclastic about some of these matters. Hematologists are not much better than other physicians in accepting what they're taught without asking many really good questions. I find that the quality of clinical practice is impaired by the acceptance of what are basically really nothing much more than superstitions. In that article, which I published at the end of the seventies, and which by the way was turned down by Blood, I thought I might as well get on paper what I think about some of these matters. If you showed that article to people now, with respect to several points that I raised, people would say, "Well, that's obvious." But in those days it wasn't obvious. It was so unobvious that the journal wouldn't accept even my expression of my personal opinions.

Q: And in that article you sort of argue that some of the way of characterizing specific diseases syndrome today, might at some point in the future seem as sort of

Beutler: -- Like the Chinese classification of animals.

Q: Right. As archaic and

Beutler: Yes. And I think that's already emerging. In my view some of the weakest science in hematology has come from those who classified lymphomas. They are getting better and they probably will get better in the future, but it's so extraordinary to me that the fellows in training accept this stuff as gospel, and I think it's mostly not correct.

Q: What sorts of ideas do they accept as gospel?

Beutler: Well, they accept as gospel that you can accurately predict the outcome of a lymphoma by its morphologic picture that you can accurately design therapeutic approaches based on morphology.

Q: Is it the morphology and the morphological orientation that you think of a problematic as opposed to one looking more at cell physiology, cell metabolism and that sort of thing?

Beutler: Yes. That's right. And even the clinical course. I'm much more impressed in my appraisal of the patient with what the history of the tumor is than what the tumor looks like when one fixes it in formalin and cuts and slices and stains it with a dye.

Q: By the same token, are you also skeptical of molecular biological approaches to classification of blood disorders, or do you find that to have --

Beutler: -- Well, that I think comes much closer to the truth. I'll try to give you an example. When physicians tried to practice medicine in the nineteenth century and they had a patient with a boil, they might try to classify that boil in terms of being hard or soft or big or a lot of red color on it or not, and so forth. Those properties might have some weak relationship to prognosis -- but when the science of bacteriology developed so one could take fluid from that boil and say, "This boil is due to a staphylococcus," "This boil is due to tuberculosis," "This boil is due to a fungus," or "This boil is due to a streptococcus." Now when you have agents that have a therapeutic effect on each of these causative organisms, then you begin to see how weak it was to say, "Well, this is a very big boil which is not painful and this is a small boil which moves a little bit" and other such descriptions. It's probably true that when one classifies by morphology, that one does differentiate in broad overlapping groups between various etiologic mechanisms, but it's not the same as finding out what the etiology is. When one starts looking at diseases in the molecular biologic sense, where one sees, let's say, what chromosomal translocation there is, what receptors are present or not present, then one is getting much closer to differentiating these disease states from one another. There's nothing wrong to do what one can with what one has when the technology isn't available. So, you know, I don't want to come across as totally debunking morphologic assessment of lymphomas, but I just think it needs to be looked at in the proper perspective. That's what I tried to say in that article because what I was finding is that our trainees thought that this was really the gospel, that people had discovered that these were entirely different tumors, and they seemed unaware of the fact that if you send the same section to ten pathologists that you get 11 different diagnoses. I can't remember what all of the issues that I approached there were. Another one may have been platelet transfusion. Here a whole generation of physicians has been deluded into thinking that if a patient has a platelet count of less than 20,000 that they should get a platelet transfusion. That is not only wrong but it's dangerous. And it's based on no real facts. Indeed, we and others have developed facts that are quite contrary.

Q: To the layperson it seems that there are various ways that hematologists fit into the medical establishment. One is to look at the relationship between blood and diagnosis, prognosis, therapy, how blood and the interpretations of blood can inform medical practice. And there's the other aspect of looking at genetic disorders, coming to terms with population questions, the distribution of particular kinds of deficiencies. That's maybe a schematic picture of the various options. How do you see yourself? I mean, you've clearly done all of those things. How difficult has that been and do you think of that it as an accurate sort of schema of the ways in which hematological work can go?

Beutler: I think the first one is a little too broad and the second one is perhaps a little narrow. I look at hematology as the study of blood and blood forming organs. Not so much as it reflects what's happening elsewhere in the body. In other words, your first definition would suggest that if one measure increased thyroxine level in the blood, that that made it a blood disorder, but it really isn't. It's a thyroid disorder. So it's hard to draw the lines. I would say that the study of genetics as hematologic disorders is something that has particularly interested me but there are those in hematology who perform very good research in physiologic mechanisms who don't really think genetically and probably don't need to think genetically in a lot of their projects, at least not as one thinks of genetics in terms of heredity rather than control of cell function. And so there are those people who deal, for example, with coagulation, and who are very interested in the cascade of reactions, which are stimulated by a wound which ends by the formation of fibrin. For them genetic disorders are a very important tool in the understanding, but they're not really interested in genetics itself. Coagulation is one very broad area and when you talk to Dr. [Samuel I.] Rapaport, I think you'll probably get a very good vista of that area. Then physiologic control mechanisms, the cytokines. All of these subjects have some clinical concomitants, and one of the trends which has developed in all biomedical science is that clinicians and scientists tend to polarize their interest, either in the laboratory or in the clinic. And they justify, rationalize, this by saying that it's just too hard to do research to be able to spend time doing clinical work, just too hard to do clinical work to be able to do research. I don't really agree. My belief is that the best investigators who are physicians will do some of both. It isn't easy. But it's very rewarding. First of all, I think the patient contact itself is rewarding. But then it also gives one a perspective, it gives one ideas, it gives one ideas of the importance of various subjects. I have to say that virtually everything that I've worked at has been related to some clinical topic and usually in relationship to some patient I'm taking care of. That is true, in a sense, with the primaquine sensitivity problem when I was investigating anemia. It was true in the sickle cell problem where I was taking care of some patients with sickle cell disease and became interested how one might try to modify the disease. It was true when I worked with the glycolipid storage diseases, where I had a very lovely patient with Gaucher disease, that got me interested in this group of diseases, and it was true with my interest in iron metabolism because of patients with iron deficiency that I saw. My research career would have developed very differently if either I had not been an MD or even if I'd been an MD but I had decided after my internship, as many of my colleagues did, that they just didn't want to do clinical work.

Q: Can you talk a little bit about your relationship with ASH, the American Society of Hematology? When did you come to be personally involved with them?

Beutler: I recall that my first involvement was that after it was formed I received a letter from one of the founders saying that my application had been acted on favorably and that I was asked to send in my dues. I was a little amused by that because first of all I hadn't applied, and in the second place I had submitted an abstract to the first meeting and it had been rejected. Nonetheless I was asked to join that year or the next. I do many different things in science. I do genetics. I do biochemistry, microbiology and nutrition. So I come in contact with many different professional groups, but I have to say that I feel my real roots are in hematology. So I've always felt very close to ASH and in the 1960s I was invited to be or elected to be a member of the executive commitee. I had a four year term on that and I found it interesting. Rather frustrating, too. I remember in particular one meeting. It's strange how these things kind of pop out of your mind. This one was in Puerto Rico. The ASH meeting was there that year. Bill Dameshek, Max Wintrobe, and Lou Wassermann were there, and there were all kinds of hidden agendas that I didn't understand. The topic in question was that the by-laws stated that there had to be a certain number of Canadians on the executive committee. I objected to that because I object to quota systems of all sorts. I said, "They could all be Canadians, or some could be Canadians. Whoever was the most qualified." That didn't go very far. I remember Ralph Wallerstein - - have you interviewed him?

Q: I will be seeing him in San Francisco.

Beutler: Ralph was sitting next to me. He turned to me and he said, "Ernie, never piss into the wind."

TAPE MACHINE TURNED OFF

Q: I think we were talking about your early experiences in ASH.

Beutler: Well, it probably did like most hidden agendas: they were probably so unimportant that I don't remember what they were. I think that that changed over the years. There were a lot of antipathies between some of these older senior hematologists. Later when I was president of the Society I really didn't feel that kind of spirit no longer existed and that people really worked together very well. In 1960 ASH met in Los Angeles and I think I was chairman of the Housing Committee and I was asked by Joe Ross who I think may have been the president at that time to make sure that the people that were considered to be VIPs were well-treated by the hotel. So that may have been my first responsibility with the Society. In those days we didn't have Slack or another service that took care of the meeting, so basically the local hematologists had to arrange everything. And of course the meetings were much smaller. Then later in the 60s I became a member of the Executive Committee. Then in 1974 I was asked to give a first Stratton lecture. And then a year or so after that I was asked whether I would stand for election as vice-president. And, especially when I found out there was no other candidates, I felt pretty comfortable about doing that. I felt very close to the Society and I felt privileged that my colleagues had thought that I could be the president, because the vice-presidents leads automatically to the president-elect position. To be selected as vice-president basically means election to the presidency. After I stepped down as president I became chairman of the Advisory Council, which is what normally happens. Then after that I was a member of the Advisory Council for another 2 or 3 years and after that, nothing more. I think that it's been pretty much customary for the Society to, let's say, not involve their ex-presidents in running the Society and that's fine. So I have to say that in the last 10 years or so I've really not been very active in the Society, except that I always go to meetings and I'm glad to see my colleagues there, but I'm really not an active participant except occasionally I may chair a session, or give a lecture.

Q: And what were your responsibilities and your goals as president and subsequently as member of the Advisory Council?

Beutler: Well, I think that my principal responsibilities were to see that first of all the annual meeting was held and was run in a way that was acceptable to the members. Since the presidency itself lasts for only one year, there are really no major programs involving the Society that a president can initiate and carry through. There are certain activities that are underway that he has some role in guiding as his term develops. Now there were some problems having to do for example with a slide bank which was run by Jim McArthur. It was a question of how much authority the publications committee should have over the slide bank. I just don't consider these major issues. There were two major issues in those days that I tried to address the best I could during my presidency, but they were both long term issues that one can't really fix up or influence very much in a very short period of time. One of these has to do with the relationship between hematology and oncology. And the second has to do with the role of the practicing hematologist in the Society. And with respect to the first of these issues, I felt that it was important for us to recognize that hematology and oncology were really one and that people should not feel that they needed to choose between these specialties.

Q: Was there a pressure on practicing hematologists to choose?

Beutler: There were, in the sense that the American Society for Clinical Oncology had been formed. In medical schools hematology and oncology divisions were being split into oncology and hematology divisions and then physicians did then have to choose. Oncology actually grew out of hematology. When I was in my early training as a clinician, all the oncology was done by hematologists. I saw the division between hematology and oncology unfortunate from several different points of view. But one of the most important was that the very life-blood, so to speak of clinical practice of hematology is care of patients with lymphomas and leukemias. And these, it turned out, are really the only neoplasms that respond very well to treatment. So those who specialized in oncology wanted to have control of patients with those diseases. And very often when hematology and oncology divisions are split at a university, the oncology division would take those patients with them and the hematology division would be left taking care of a few consultation patients-with coagulation problems and anemia. And that really emasculated the specialty. This was an issue that I think has not been resolved to this day. I felt, for example, that our journal -- and I was also on the editorial board of the journal for many years -- should sometimes carry articles about solid tumors too. I thought that we should recognize that physicians who were hematologists also saw solid tumor patients and should be allowed to at least read reviews in the journal. I might say this was not a popular view. It was I think -- it sort of was unimplemented after I'd --

Q: Can I ask, to what do you attribute to the sort of a surge in oncology claims to these sort of traditional hematological patients?

Beutler: The issue is that these are neoplasms, and the oncologist say, "Well, we're experts in the treatment of cancer and leukemia is nothing but blood cancer and therefore we should take care of leukemia patients."

Q: This was happening in the 50s?

Beutler: In the 50s there were no oncologists. And in the 60s, in the late 60s the division began to emerge and in the 70s it got to be a big problem. And what happened is that oncologist made claims which were often somewhat extravagant about what they could do for cancer patients and there were not very many physicians who were very interested in taking care of cancer patients. It also became a fact that a good deal of revenue was generated by hospitalizing cancer patients and giving them expensive chemotherapy even if it didn't help the patient very much. This gave oncologists a position of power in many medical schools, where administrators said, "We need more oncology." And then when the oncologists became very strong, having patients and revenue, they were able to wrest the leukemias and lymphomas from the hematologists, claiming that these patients are really in our specialty and not in your specialty. But that left the hematologist with almost nothing. And as a matter of fact, as things evolved, pure hematology, even with the leukemia and lymphomas, has become very much of a hospital-based, or let's say large multi-specialty group based specialty. It's not feasible now for a young person to go out into practice in a community and say, "I take care of only patients with blood disease. I will not take care of patients with breast cancer, colon cancer or other solid tumors." I felt when I was president that that was a fact of life, and that we needed to recognize that physicians who considered themselves hematologists but also practiced oncology should not be made to feel that they didn't get the full breadth of their professional interests covered by their society, even though I felt that our main focus should still be on blood diseases. The other issue which I think is tangential to the first is that the Society was started, more or less, by academic hematologists. But if we look at the Society membership today, most of the members are physicians in practice. And therefore I felt that it was very important for the journal, the annual program of the Society, and the activities of the Society, to reflect to a large extent the needs of the practitioner.

Q: When you say "practice," do you mean general practice or hematological practice?

Beutler: Hematological practice. Hem/Onc practice in reality. I don't know what the exact break-down is, but if there are let's say 4,000 members of the Society now, maybe 2500 when I was president, of those 20 percent might be hematologists like myself who are full time hematologists at major institutions. But most of the members are physicians who have training at such institutions and then join some medical group like Kaiser-Permanente, or Beverly Hills Professional Corporation, or whatever, and they're doing hem/onc out in the community. If you welcome these people into your Society, as we always have, then it seems to me that you can't ignore them when you decide what to include in your journal, or what to include in your annual meetings. You have to provide them with something that makes them feel like it's their Society.

Q: Some sort of outlet for their concerns.

Beutler: That's right. And some representation in the planning of activities. It shouldn't be run by a clique of high-powered academics and these other guys can come at their own pace.

Q: What is the work structure of someone in hem/onc practice?

Beutler: Well, it varies. Many of the physicians probably end up doing a certain amount of general internal medicine but when a patient has anemia or leukemia, their colleagues tend to refer them. But in many instances there probably aren't enough such referrals to keep somebody's appointment book completely full.

END SIDE 2 TAPE 1; BEGIN SIDE 1 TAPE 2

Beutler: If there is a fairly large group, a large multi-specialty group of some sort, then they may spend all their time doing hematology/oncology but scarcely any of them do just hematology. And I would guess that on the average they would probably end up doing about 75 percent oncology. So, they give chemotherapy for breast cancer patients, ovarian cancer patients or prostatic cancer patients and so forth. Then some of their time, they spend with problems such as anemia and hemostasis.

Q: You were saying just before the tape went off -- I just want to get that.

Beutler: Yes.

Q: That generally people in hem/onc practice don't have the sort of patient population that would allow them to constantly deal with hematologic problems.

Beutler: That's right. I think that practicing pure hematology is something that only a few dozen people in the whole country probably do, and those are working at academic centers. Now I practice only hematology, but you have to realize that I spend only about ten to fifteen percent of my time doing clinical work. Even in my circumstance it might be difficult for me to be kept really busy if I worked clinically full time and saw nothing but hematologic problems. Possibly I could. But you know there are just not very many physicians who would have that many referrals of that sort.

Q: Has the percentage changed over the course of your career? The percentage of time that you've spent looking at clinical -‑

Beutler: Yes it decreased somewhat. When I first came to Scripps about eleven years ago, I came not only as chairman of this research department in the Research Institute, but also as head of the hematology/oncology division of the medical group. And I was actually head of that division for eight years. During that time clinical activities, some of them administrative, took up more of my time than they do now. I have been trying, actually, to cut back on my clinical activities. Hematology, especially when you include in it patients with leukemia and myelodysplastic syndrome can be a very acute specialty. And I don't think it's right to take on responsibility for somebody and to see them when they are doing well and when they critically ill to say that you don't do that kind of practice and turn it over to a resident or a fellow. So basically, once I take a patient as my patient I feel responsibility to follow them, even when things happen in the middle of the night that are particularly intense. The only way that I can see of getting around this problem is to see patients, as a one time consultation.

Q: If you like we can break here.

Beutler: O.K.

Q: And then resume tomorrow. There are a few things I'm very much interested in pursuing some more. One is your earlier comment about your relationship with patients and how looking at particular diseases had influenced the sort of questions that you've chosen to ask, in hematology, and I'd like to talk about that.

Beutler: O.K.

END OF SESSION #1

November 7, 1990

Q: This is part two of the interview with Dr. Ernest Beutler at the Scripps Clinic and Research Foundation. The date is November 7 and my name is Keith Wailoo. Yesterday you mentioned that your work with G6PD was perhaps what you are best known for and I wondered if you could talk about your initial involvement with that and how that played a role in your career.

Beutler: When I was a second year resident at the University of Chicago in about 1952, I had already committed myself to a career in hematology, at least to the extent of asking Leon Jacobson if I could work in that division and having a laboratory there in which to initiate a research program. At that time we were in the midst of the Korean War and I'd not been in the army because I'd been too young for World War Two. But I was about the right age for the Korean War, and it was apparent to me that I would have to serve in the military sooner or later. The University of Chicago, through Dr. Alf Alving, operated a malaria research project at the state penitentiary in Joliet, Illinois, which was some 40 miles distant from the University in the small town of Joliet. That unit was ordinarily staffed by University of Chicago physicians who used it as a way of fulfilling their military obligation. And although I didn't know Dr. Alving -- I hadn't been on his service when he was making rounds -- my friend and colleague Bill Bethard suggested to Alving that I would be a good choice as the next person to serve in that facility. Dr. Raymond Dern was already there. He had been a resident in renovascular diseases, and the two main lines of work that were to be carried out were, first of all, the study of the anti-malarial effect of drugs such as primaquine, chloroquine and daraprim, and secondly, the study of the toxicity of these drugs, in particular, the hemolytic anemia that occurred in some individuals when they were given primaquine. At the time that I joined the project, Dr. Dern and Irwin Weinstein had already started some of the chromium-51 studies that showed that the defect was one of the red blood cells, and during the next year I worked on identifying the nature of the red cell defect. I moved my family to Joliet. My family then consisted of my wife and my oldest son, Steven, who was then perhaps one year of age. I went to work each day at the penitentiary. I went through the guard house, had a body search, was locked into the hospital unit where the inmates were, and worked there with a staff which consisted almost entirely of inmates. Most of my efforts were devoted to trying to understand what was different about the red cells of primaquine sensitive individuals. After I'd been there for some 6 months, the army decided they could no longer assign army officers to civilian research projects, and so I was told that I would have to be transferred to another position. Actually I looked at two other positions in the army. I didn't realize until then that one could sort of shop around for jobs in the army, that one wasn't just sent somewhere. One of those positions was with William Crosby at Walter Reed, and the other one was in Puerto Rico under Joseph Smadell, who was head of infectious disease at Walter Reed. Both were research positions and both suited me very well, but there was some question about whether I could take my family to Puerto Rico, and I greatly respected Bill Crosby and I arranged to go to Walter Reed. However, when my orders came through they weren't for Walter Reed and they weren't for Puerto Rico. They were actually for Fort Dietrick, or Camp Dietrick, as it was then known, in Frederick, Maryland. It turned out that there was a high priority research project having to do with biological warfare that Smadell, who was an advisor to this project had recommended me for, and that's where I was sent. But I continued to work at the state penitentiary for a total of about 13 months before I moved to Fort Dietrick, and during that time I was able to reproduce the abnormality of primaquine sensitive cells in vitro by incubating them with various drugs and showing that the pattern of Heinz body formation was different in these cells than in normal cells. I also showed that they were deficient in reduced glutathione. Then I spent a year at Fort Dietrick and while I was there I began to work on a major review, the one that you alluded to that you had seen in Blood 1959. I collected the material at the post library, which was not a bad library since it was a research facility. I used to work there in the evenings and get those data together. During that time, too, I went to a meeting -- I think it was either in Memphis or Nashville, with Dr. Dern to present our data to a tropical medicine meeting. I mention this because we were required to submit a manuscript to be published in their journal and so I pulled together much of the data that I had collected at the library at Camp Dietrich and many of our unpublished studies, and submitted the paper to them. Ironically they declined to publish it. They declined to publish it because they said there was nothing new in it. That was really rather extraordinary because it turned out to be a very important subject and it would have been the first major review of the subject that had been published. Then, while I was at Camp Dietrick, Leon Jacobson invited me to come back to the University as an instructor, that is, as a junior faculty member. And so I did return to the University in 1955 having completed my military obligation and I continued to work on the question of primaquine sensitivity.

Q: Can I interject a question -- how did the state penitentiary setting or the Fort Dietrick setting compare to the traditional research station? What kind of work could you do? Were there certain limitations?

Beutler: Both of them provided laboratory facilities that were adequate for what I wanted to do. What certainly was not provided at the prison setting was the kind of intellectual exchange between many colleagues that one is used to in a university. I might say that another one of my iconoclastic views is that I don't place much value on that. That may not be because I don't need the interchange, but I get the interchange because in science one travels so much, one meets so many people that one has ample opportunity to exchange ideas. The concept that one can only perform good work in the setting in which one is surrounded by colleagues who are doing similar and related work is is one that I don't accept. My experience at the prison really proves it, because when I look back on it the amount of work that I was able to accomplish there was really quite remarkable. We took this problem from the point where we had no idea what was wrong with these red cells to showing that they were deficient in reduced glutathione, and I did that essentially myself with a couple of prisoners helping me as technicians. But they weren't bad technicians. You know, they worked long hours. They never went on holiday [irony] and they were really quite devoted to their work. I have to say they were very good technical assistants.

Q: There's also a stable patient population.

Beutler: That's right.

Q: Did that figure at all in the -‑

Beutler: Yes, it made it much easier. In fact I can tell you an interesting anecdote afterwards about what happened after I left. You're quite on target that being able to say to my secretary there, who was also a prisoner, that I'd like to get [omitted]. But he also was primaquine sensitive, you see, and anytime that I wanted to get him to give me a blood sample I could call him up and he would provide the blood sample. When I went back to The University it was not nearly that easy and I'll tell you a little bit about that. I returned to the University in 1955 and at that time I started to work on the same problem again. This created some friction between Alving and myself because Alving felt, and I think quite inappropriately, that this was his problem, although the fact is that he really hadn't done any of the work. It had really all been done by Ray Dern and myself. But he felt very proprietary about it. At about that time William Dameshek, who was the first editor of the journal Blood, wrote to me and invited me to write a review of primaquine sensitivity for what was already then the leading hematologic journal. I had in hand the review that I had written for the American Journal of Tropical Medicine and Hygiene, which by that time was a year or two old, but which had a very good historical introduction. So I went to Alving and I showed him the invitation and told him that I would like to write this article and that I would be very glad to have him and whomever else he wanted to participate in the review as co-authors. Alving, refused somewhat angrily, and said he thought it was inappropriate to write a review at this time. I went to my chief Leon Jacobson and I said I have this invitation. This is what Alving had said and Jacobson, who I think was a peacemaker by nature, suggested that we have a meeting between the departmental chairman, Wright Adams himself, Alving, and myself, and see if we could sort it out. Alving refused to participate in such a meeting. I decided that if he didn't want to participate in the review I would write it myself and I did and I published it. It was a very successful review, and the following year I wrote an equally extensive review for the Metabolic Basis of Inherited Disease. It was a first edition of that book and it was a classic in its field. Those two reviews, I think, helped to establish my position in the field of glucose-6-phosphate dehydrogenase deficiency.

When I returned to the University of Chicago, I knew that the primaquine-sensitive red cells were deficient in glutathione, but I knew little else about what the defeat was. I didn't know why they were deficient in glutathione. And I then faced the problem, to which you just alluded, and that is how do I now get primaquine sensitive subjects? Well, there was a man by the name of [omitted] who had been one of our G6PD deficient individuals at Stateville, and he had been released from prison, he was without a job, and was very happy to come in to donate blood for me. I can't remember what I paid him, but it may have been $5 a donation, which in 1955 would have been a pretty princely sum. So [omitted] came in and I got his blood and I did a number of tests on it, and I conceived the idea that if one would incubate this blood with something like a drug that caused hemolytic anemia, that maybe something would happen to the glutathione. So I incubated this blood with acetylphenylhydrazine to my delight I found that the glutathione disappeared, while if I incubated normal blood with acetylphenylhydrazine there was no effect on the glutathione. This made it possible for the first time to clearly distinguish, in vitro, normal blood from primaquine sensitive blood. It led Paul Carson, who had then replaced me at the prison, to study some of the enzymes involved in reducing glutathione and this led directly to the discovery that the basic deficiency was one in the enzyme G6PD. Mr. [omitted] would come in and give me blood whenever I asked him and one day he was in a very happy mood because he had gotten a job, and he said what he needed for this job was a suit of clothes. He needed $20 and he wondered if I could pay him for the next four donations, which I did with slight misgivings because I knew his background. That's where I'd met him. Well, I gave him the $20 and I've never seen him since. It was very difficult for me to find people who were actually G6PD deficient.

Q: How prevalent is that deficiency now?

Beutler: It's present in about 11 percent of black American males. And there are some population isolates where over 50 percent of males are involved, but that's, for example, among Kurdish Jews, which is a very small population.

Q: And how did this manifest itself?

Beutler: The way that it manifested itself when we first discovered it was that it made people susceptible to hemolytic anemia when they took primaquine. But then working with Ray Dern at the prison, we found that it was not only primaquine, but certain sulphonamides and certain other compounds that also produced hemolytic anemia. Later it was realized that these individuals were also susceptible to hemolytic anemia merely when they got infections and that in the form of the disease which is found in Mediterranean and Oriental populations, which is a much more severe deficiency, there's also a jaundice of the newborn, which actually can be fatal. So those are some of the principal manifestations. And in the Oriental and the Mediterranean populations it also produces hemolytic anemia on exposure to fava beans. That's another manifestation of the disease.

Q: So the coincidence of the consumption of certain drugs along with this deficiency is in fact a very useful -- has been a very useful coincidence for you in studying genetic -‑

Beutler: That's right. And I think that brings us to what was perhaps the most important discovery that I made probably the most important one of my whole career. This gene was sex linked. That was discovered by a group at Johns Hopkins. A medical student by the name of Exall Kimbro came to my laboratory and learned how to do the testing. They already had a considerable group of black families where all the family members were available and they tested them and they found that in most cases the transmission was from mother to a son which tended to show that it was sex linked. So the defect then was localized to the x chromosome. But what was very peculiar was that while males, as one would expect in a sex linked defect, were either normal or severely deficient. The female carriers were sometimes severely deficient, sometimes entirely normal. And that puzzled me. I was invited to Edinburgh, Scotland in 1960 to speak at the International Congress of Clinical Chemistry, and I presented a review of G6PD deficiency as I was frequently invited to do in those days. One of the other speakers was a well known geneticist, Harry Harris, and he raised a question that had never occurred to me before. And when I say it never occurred to me before, I think the reason it hasn't occurred to me before is that you have to realize that I'm not trained as a geneticist. I'm really trained as a hematologist. I'm a physician, but I've learned other things along the way as people do in scientific careers. And so Harris asked me, "Well, since women have two x chromosomes and men have only one, why don't women have twice as much G6PD as men?" And this puzzled me, and as a matter of fact it was not an original question in the sense that this phenomenon had been described for many years and written about, although I didn't know that, in Drosophila -- as a concept of dosage compensation. Under dosage compensation even though there are two doses of the gene in females and one in the male, the gene product was always the same. I had just moved then to the City of Hope to become chairman of the Department of Medicine there. I did that in December of 1959 and a few months after moving to the City of Hope I'd been at a meeting with my friend and colleague Arno Motulsky, who'd been at a meeting in New York that dealt with drug induced blood dyscrasias. We were on a committee which had been organized by Max Wintrobe and Motulsky and I.

Q: What do you mean "blood dyscrasias?"

Beutler: Any blood disorder. And by blood dyscrasia one means, for example, low white count, or low platelet count, or low hemoglobin. Those are all blood dyscrasias Wintrobe had become interested in organizing this committee because there'd been a sort of tragedy involving the drug chloramphenicol. We now realize that chloramphenicol (or chloromycetin) is a dangerous drug which can produce fatal aplastic anemia. It turned out that there'd been a fair number of cases of aplastic anemia associated with chloramphenicol before the cause-and-effect relationship was recognized, simply perhaps because people hadn't communicated with each other. It's a rare event, so if somebody had one case and somebody else had another case, and unless they talked about it they wouldn't realize that there was an association. He felt that if some kind of registry were established that this kind of situation might be avoided in the future. So he organized a committee on blood dyscrasias under the auspices of the AMA. Arno Motulsky and I were on that committee and Arno told me about a very bright young geneticist at the City of Hope by the name of Susumo Ohno. Now, I'd only been there for a few months and I thought I'd heard the name but I'd really hadn't met him, though there were quite a few people I hadn't met there. I didn't really meet Ohno until I attended the International Congress of Hematology in Tokyo, Japan in August-September 1960.

Q: In other words you were working in the same -‑

Beutler: -- Institute but we met in Japan. We may have met briefly at the City of Hope, but there we had a chance to visit a little bit. But more important I had a chance to hear him give a lecture about what he was doing. He had done studies in rodents in which he had shown that the two X chromosomes of the female were morphologically different. One was tightly condensed and the other one looked like the other chromosomes. And this gave me the idea that the two X chromosomes might not both be active in females, that only one might be active. It led me to formulate the X-inactivation hypotheses. The same hypothesis, based also on Ohno's work, was proposed by Mary Lyon and it turned out as events unfolded that she published her work before I published mine, although I presented mine earlier. She's very often credited with what's called lyonization, which I prefer to call the X-inactivation hypothesis. Basically that proved to be a rather fundamental discovery in biology and genetics and although Mary Lyon ended up getting a very large share of credit for this, I don't think it escaped the scientific community that I made this contribution also. It played a role in my later election to the National Academy of Science, because I think some of my colleagues have recognized that I also had the same insight.

Q: Was she a hematologist?

Beutler: No. She was a mouse geneticist. Well, you know, in retrospect, many great ideas are obvious and that one is and she had a couple of major advantages over me and one was that being a geneticist, perhaps she was a little closer to the whole situation. But basically what she did is this. She knew that there were mutant genes in mice that effected coat color and so she reasoned that Motulsky only one or the other x was active in each cell that mice who were heterozygous for these coat colored genes would have a doppled, patchwork appearance. And they did. And that was her evidence. I didn't know about these genes. As a matter of fact I asked our geneticist at the City of Hope about such genes but he didn't know about them either because he was a drosophila geneticist. And this phenomenon doesn't occur in drosophila. So my approach was quite characteristically hematologic. I reasoned that if only one X was active in each cell and different cells had different X's active, that if we examined a heterozygote for G6PD deficiency, that she should have one population of normal cells and one population of deficient cells, rather than what had been thought heretofore as just an intermediate population. It was much harder to measure the activity in individual red cells than it was to observe the coat color of a mouse. And actually it was very difficult for me to solve that problem. I solved it in I think what was a reasonably elegant way, but it took me more than a year to solve it.

Q: How did you solve that problem of distinguishing two different --?

Beutler: Well, the way that I tried to solve it initially was to see whether there was some way in which I could histochemically measure individual red cell enzyme activity. But I failed doing that. And then one day I got the idea that I could approach the problem by measuring glutathione stability. As I mentioned earlier if when one incubates deficient cells with acetylphenylhydrazine the glutathione disappears. If one measures it in normal cells, it's stable. It suddenly occurred to me that if one had a mixture of normal cells and mutant cells, that one would observe a rapid fall as the glutathione disappeared from the deficient cells, but then, after that, the remaining glutathione being in normal cells would be stable. If, on the other hand, the enzyme activity were intermediate, then one might have a fall in concentration, but it would be intermediate in severity between being mutant and being normal. And one could test this model by taking blood from a person who was G6PD deficient, a male, and mixing it with blood from a male who was not deficient, seeing how the glutathione disappeared. Indeed it disappeared in components, and then studying a female, it disappeared exactly.

Q: I see. So there are certain kinds of interesting costs and benefits to looking at the blood level as opposed to the mouse coat.

Beutler: That's right.

Q: -- As an indicator of -‑

Beutler: Well, you know, if I'd known about that mouse mutation that would have been very easy. I would have gotten a mouse. I would have looked at the heterozygotes and I could have published the same paper that Mary Lyon did. As it was I worked for a year or more trying to work out a technique -- trying to think of a technique in which I could demonstrate there were two populations and that took time. You know, when I took the chairmanship of the Department of Medicine at the City of Hope, people assumed that I was giving up research. That was the end of my research career. Even then people considered chairmanships to be so demanding that somebody really couldn't continue to do research when they were chairman. I moved to the City of Hope at the very end of '59, so basically I started at 1960 and I did this work at the end of '60, the beginning of '61. So actually not only was it a somewhat a difficult problem, but also I was in a new place. I had a lot of responsibilities that slowed me up a little bit. And then, another thing that slowed me up is that I didn't want to publish something that was wrong and even though I had the data quite a bit earlier, I was hesitant to make a fool of myself, and I re-repeated the work numerous times. So the sum and substance of it was that her paper came out a little bit before mine did.

But I continued to work on the genetics of G6PD deficiency. It became evident that this was a heterogeneous disorder. When we first studied it we studied it mostly among black American males. When I had worked out the methods for detecting this defect in red cells, investigators in different parts of the world began to look for this defect, too, and it was found I think almost simultaneously in Israel by Chaim Sheba and Ari Szeinberg and by Sansone in Italy. At first we thought that G6PD deficiency was the same wherever it was found. But then it became apparent that that the G6PD deficiency in the Mediterranean area was much more severe than the African kind of G6PD deficiency and that the residual enzyme, the little bit that there was, was really very different in its properties. Then I participated in standardizing methods which would have allowed people all over the world to study enzymes and to compare the enzymes. The result of this as I told you yesterday was that over 400 variants have been described. In the last few years we've been able to study these at the DNA level and we find that there aren't really that many different variants. But there are still quite a few. And that's basically the thread that has run through my G6PD work.

Q: Now you mentioned yesterday that by the late 70s the technology had become limiting for exploring for that area of research. Can you talk a little bit more about that and particularly about what the technology had been?

Beutler: All one could do until this last decade is to purify the enzyme from red cells and determine its characteristics. One couldn't even determine its structure because one couldn't obtain enough enzyme to sequence it, except from normal blood; with these deficient mutants one simply couldn't get enough. There wasn't really very much one could do except to study additional cases, to characterize them, and then to publish a paper about them. Really what I think it was, from a point of view of acquiring Knowledge, it was really kind of spinning wheels. That was really true through most of the 70s. Most of the excitement went out of G6PD deficiency for me after the 60s, and actually it led me into other areas that were perhaps equally fruitful.

One of these was the study of galactosemia which is a hereditary defect that is relatively uncommon but extremely important to diagnose early because if one detects galactosemia at the time of birth or within a few days thereafter, a lactose free diet will salvage that child. But if one doesn't detect it the child will usually die, or if one detects it before it dies, the child will be severely damaged in terms of blindness, mental retardation and so forth. I'd learned quite a lot about the metabolism of red cells in my work with G6PD and so I decided to see whether one could use red cells to screen for galactosemia. There was a complex assay that one could carry out, but could one do a simple test on every newborn? And to make a long story short we developed such a test and that test is still being performed all over the world and many millions of infants have been tested with it. And this also got us interested in matters such as the frequency of galactosemia. We found that there was another very common mutation that caused lowering of transferase, which is the enzyme which is defective in glactosemia; lowering of transferase activity, but not a clinical disease. We worked on galactosemia for some 10 years or so, but then I moved on to other areas. One of the areas that we moved into was red cell storage, because I thought that one of the really practical applications of understanding red cell metabolism was in the storage of blood and blood banking. That's an area in which we've worked intermittently probably for the last 25 years and we're still working on it to some extent. We've been involved in developing better blood preservatives. Another major area that we have been studying for quite a long time is in the glycolipid storage diseases. I became interested in the glycolipid storage diseases through a patient whom I first saw in about 1965 or 66 with very severe Gaucher's disease. She was a girl of 17 or so at that time. As it happened 10 years previously when I was taking care of patients with sickle cell disease, I felt very frustrated by the idea that here is a disease that we actually understood to some extent, but we really couldn't do anything about. And it was about that time that the enzyme defect that caused Gaucher's disease had been discovered and I began to wonder whether there was something that I could do to correct the enzyme deficiency. I've worked on Gaucher's disease intermittently now for about 25 years and actually a treatment is just beginning to emerge from some of this work, and there may be better treatments in the future. But we also studied two other diseases in that general group. One is called Fabry disease. It's a rather rare disease. And the other one, more common, is Tay Sachs disease. There we were quite successful in actually determining the structure of the enzyme that is deficient in the disease. We showed that it was made up of two different kinds of subunits. We showed that one of these subunits was missing in Tay Sachs disease and the other subunit was missing in a disease called Sandhoff's disease, which is very similar to Tay Sachs disease. So we worked in that area as well.

Q: Did you think that your later work then has shifted from studying deficiencies, the mechanism for deficiencies to studying diseases and possible therapies based on your knowledge of the deficiencies?

Beutler: I don't think it's really been a shift. In every case I've been interested in the deficiency from a clinical point of view. I've been interested in the possibility of doing something about it and I've been interested in understanding the fundamental mechanism. When all we could do is to do protein structure then I was interested in the mechanism from the point of view of protein structure. Now that we can look at DNA structure much more easily, we examine DNA structure.

Q: Getting back for one moment to the G6PD work. I noticed that you were involved in several groups. The WHO group on hemoglobinopathy in the late 60s and the early 70s, the National Research Council Committee on sickle cell disease, CDC hemoglobinopathy task force. Can you explain something about the importance of those committees, or those organizations, and for you at the time? Why did they appear when they did. What kinds of work did you do?

Beutler: The WHO committee was really one that had to do with standardization and perhaps working on methods to bring technology to developing countries -- there was just one meeting. I learned a lot about the hemoglobins I didn't really know. I was the lucky person who was appointed the recorder so I had to write the report. I got to meet some people, some of whom have been lifelong friends. But that was sort of a one shot type of thing. I think the most important of those bodies probably was the NRC committee on sickle cell disease. It was probably in the late 60s when sickle cell disease became very politically prominent, there was a great move to screen everybody for sickling. And I might say that I was opposed to that from the beginning. As a matter of fact I organized a letter that was written for The New England Journal of Medicine, opposing that in the early 70s. I felt that it would do much more harm than good to identify people with sickle trait because there was such a tremendous amount of misunderstanding and also a lack of information about what the trait really meant in terms of a person's health. Here you're dealing with something that nine percent of black people have. Obviously it can't be very bad, but now you have stories of people who developed splenic infarcts at high altitude flights, people who developed blood in their urine, and perhaps most important, people who died suddenly during severe exercise. And then the issue became, "Well, if you identify people with the sickle trait and particularly in the military, which was the organization that sponsored the commission, the NRC study, what do you do with that?" What do you let them do and what don't you let them do? If a young black man wants to be a marine and he has sickle trait, do you exclude him? Or do you let him be a marine? And if you let him be a marine, well what are the chances that he's going to die suddenly when he's exercising in the heat one day? Well, these are very hard questions. Do you let a person with sickle trait be a pilot? Do you let him be a diver? All those kinds of questions. The committee that I was on tried to grapple with those questions and we made recommendations that we thought were reasonable with the state of knowledge at that time, but we strongly recommended that a study be done, which really determined what the risks were. That study was never really done, although fragments of the information have come out since through some partial studies. Our recommendations, as I remember at the time, were that with the uncertainty of what might happen to a pilot, particularly a pilot who was piloting an aircraft that had other people aboard, that one couldn't really let a person with sickle trait be a pilot. But that in terms of any other activities, we just didn't see that there was enough evidence to preclude people from following a career which might be rewarding to them because of sickle trait.

Q: What were -

Beutler: Well, that's just what I was going to say, I think that was really sort of the extent of my involvement in that issue.

Q: What other fields were represented on that committee?

Beutler: Well, the committee as I recall had a few people from the humanities, you know, a professor of philosophy, who I think didn't show up for the meeting. That sort of thing. Then there were several prominent hematologists. I think Clem Finch was on the committee -‑

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Beutler: My memory might not serve me well on this but I think Lou [Louis] Sullivan was on the committee, too, and as you know he's Secretary of Health, Education and Welfare now. But there were participants from hematology, from genetics, from the humanities, and those were really basically the issues that we dealt with.

Q: Is that still the -- the question of the importance of the sickle cell trait, the possible effects that the sickle cell trait at high altitudes is still a problem that -‑

Beutler: Well, I don't hear as much about it anymore. There was a study published two or three years ago in which a large survey was made in the military, which is something that we recommended many years before, that indicated that there was an increase in the incidence of sudden death of people with sickle trait. But the incidence was so low that I'm not sure that one really should be making decisions on that basis. There are too many people, not only on this matter but I think in all matters affecting humankind, who expect absolute answers. That yes it's OK or no it's not OK. So suppose you have a situation -- and here I don't think I stray far from the truth -- let's say that a black recruit with sickle trait has two chances in a million of dying while he's running on the parade ground in the hot sun. But there are also probably 20 chances in a million that people will die from various other misadventures healthwise and probably a thousand in a million that they're going to be run over by a truck or some other accident happening. To what extent do you set policy in terms of such rare risks? You get into a position where you can't say there is no risk and yet if you take the risk and that one thing happens, then you're in the soup. If you're in the army there's a congressional investigation, a lawsuit from the family and so forth. "You should have known, you see there's this paper." These are tough problems. Tougher than sequencing than DNA, I'll tell you.

Q: What was the importance of establishing a hemoglobin standard in this country. I notice also that you were a member of the National Academy of Science, special committee on hemoglobin standards.

Beutler: Can I see what that is? I can't remember what we did [laughter].

Q: I have it written down here.

Beutler: I can't really tell you. It might have had to do with the standardization of hemoglobinopathy, but I really don't know. I just don't remember.

Q: That whole problem of the standardization of hemoglobinopathy, you were referring to it as a question of technologies in developing countries?

Beutler: Yes, well, that's what the WHO meeting dealt with quite a lot. Some of the -- well, there are a whole gamut of issues. For example, there is a rather simple method to screen for hemoglobinopathies which is -- to screen for sickle hemoglobin, which depends on hemoglobin turbidity. This method was actually invented by Harvey Itano many years ago. Later Murayama and Nalbandian sort of reinvented it and tried to popularize it. This method detects sickle hemoglobin, but it doesn't detect hemoglobin C and it doesn't detect beta-thalassemia and the interaction between hemoglobin C and beta-thalassemia and the sickle cell gene is such that you can have sickle cell disease without any two parents with sickle cell trait. So if you just screen people for sickle cell trait and you say Mr. Jones, Mrs. Jones, only one of you has sickle trait so not to worry, you are misinforming them. They have a chance of having a child with sickle disease because the one who doesn't have the sickle gene may have the beta-thalassemia or the hemoglobin C trait. So then the question is how do you go about looking at a population? If you're going to study a population what methods do you use? Or if you perform just electrophoresis and hemoglobin moves like S, it isn't necessarily S. One needs to confirm that, and one can do that with a solubility test for example. I think some of those are the issues that pertain both to our society and also to developing countries where they were talking about doing various kinds of screening for the sickle trait.

Q: So each of those tests have an implication? It has a certain way of fitting into the society and certain kinds of implications? Do you ask questions of the parents or do you ask questions of perspective patients? Is this the kind of question you were -‑

Beutler: Well, no. Perhaps that's all part of it, but basically if you're setting up a screening program in Alabama and you want to screen all blacks for sickle cell disease and you want to give counseling, what do you screen for? What test do you use? And a part of the question it is what do you do with it when you get the information? Then you could ask a parallel question. Suppose that you're doing the same thing in Zaire, or suppose you're doing it in Saudi Arabia where sickle is very common, too. What kind of tests do you do? What kind of questions do you ask? Those are some of the considerations.

Q: I was interested in going back a little. Yesterday you talked about Dr. Jacobson's particular work style and the sorts of things that you picked up in his hematology unit. And you, I suppose, implied a contrast with other hematology units elsewhere at that time. And I was wondering if you could talk about what the structure of other units were.

Beutler: Well, it's a little hard for me to be very precise about that because I wasn't in these other units, but I think that one of the major differences was size and perhaps another difference was the extent to which the leader gave autonomy to his people. This is a question really for science as a whole, rather than just hematology. Some leaders have a strong agenda, and when they recruit somebody to be a fellow or an assistant professor in their unit, they say basically: "this is the part of the job on which I want you to work. You find out about the alpha sub unit of the xyz receptor," if that's what they're interested in. "And you find out about the gamma sub unit," "and your job is to do the blood levels," and so forth. To do that you need many people, and I'm not sure it is the way really to develop people's scientific style and personality. And this was true in hematology at that time to some extent, too. Hematologists like Bill Dameshek, who had many fellows probably put them on various projects and they orchestrated matters in a little bit more autocratic fashion.

Q: I was reading the transcripts of Dr. Cronkite's oral history and he focused on Dameshek's very autocratic style, not specifically in his hematology unit, but his running of ASH in its early years. And he seemed to think that this was not for the short term benefit of the Society.

Beutler: Yes. Well, I'm sure that's true. And I think the same thing was true, even more so perhaps for Wintrobe. He had a large program. Many people from all over the world went there to train and I'm sure that he told them how and what to do. When Jacobson invited me to come back to the University of Chicago he asked me what I would like to work on. I was interested in continuing some of my work with primaquine sensitivity, in working on iron metabolism, which is another area, by the way, in which I've done a lot of work, and I was interested in working with erythropoietin. And he said -- he wrote to me -- that he would prefer if I did not work on erythropoietin because he had two students, Lou Plzak and Walter Fried, who were working on erythropoietin and he didn't want to discourage them by having a more senior person coming in and take on that, problem. It turned out of course that he made a major contribution to the problem with his students. Basically he wanted to avoid conflicts within his unit and I think it was very appropriate for him to say, don't work on something somebody else is working on. But he certainly didn't say that "I think that your problem should be such and such," and I don't think that that's what would have happened if I had gone to work for Wintrobe. Wintrobe would have had a project for me. Maybe he would have given me a choice of one or two. I don't know.

Q: What were their interests? People like Wintrobe and Dameshek at the time?

Beutler: Dameshek was interested mostly in immunohematology, in other words, in autoimmune hemolytic anemia. I remember that when I first accepted the job at City of Hope, I attended the Central Society meeting at the Drake Hotel in, Chicago in 1959. It was just before I left, and I was already looking for bright people to take with me and I met Bob Schwartz, who is now head of hematology at Tufts, where Dameshek was. At that time Bob was a fellow in Dameshek's lab and he had done some work that was really very exciting. And I remember he drew it out for me. We were sitting having a cup of coffee and he showed me what he'd done. It really looked very good. Then he said to me that after he had done all of this work he took it in to Dr. Dameshek and showed it to him and Dameshek said, "That's very nice Bob. I think I'd like to be an author on that." So Bob said to me, "What could I say." I said, "Thank you Dr. Dameshek." [laughter] You see, that never would have happened with Leon Jacobson. And as a matter of fact, when I did some work, I offered him authorship and he said, "I didn'tdo anything. It's your work." In this way he was very unlike Alving who insisted on putting his name on the work and getting credit for things that he'd never done. Of course Wintrobe's early work had to do with the morphology of red cells. There are some very nice memoirs, biographical memoirs for the Academy written by [William] Valentine about Wintrobe that were just published. And he later worked together with George Cartwright on iron and copper metabolism, the anemia of chronic inflammation. I think anemia was the main area that he worked with.

Q: He was at Utah?

Beutler: Right. Now there's one other area which I think I've been is active in hematology -- maybe more than one, but one other one worth mentioning, and that is, as I discussed yesterday, the life blood of the hematologist really is leukemias and lymphomas. I've been interested in the treatment of leukemia for quite a long time and there are two things that I've done in which I take considerable satisfaction. One of them actually resulted in my decision to leave the City of Hope, which I'll tell you about. In the early 1970s I began to realize that the conventional wisdom about bone marrow transplantation was not correct. Everybody said, "Well, you know, Don [E. Donald] Thomas is doing this but most of his patients die, look what he puts them through and it's very costly, and it's really not very good." That's what everybody said. But I knew Don Thomas and I knew that he was meticulously honest. When I looked at his results and I saw that basically he was salvaging about twenty percent of patients with acute leukemia who would never survive because they had relapsed leukemia. And while most people looked at these data and said, "Well look, 80 percent of his patients died." I looked at it a little differently. I saw that 20 percent survived. At that time, in about 1974, the City of Hope had decided, after some agonizing, to discontinue their cardiac surgery program, which had been very unsuccessful, and they asked me to consider what other kinds of programs should be brought to take its place. I decided that bone marrow transplantation would be an appropriate program. I recruited one of my former fellows, Karl Blume, to head the program. We started transplanting in 1975. And we were actually the first to transplant patients with acute leukemia who were in complete remission. I felt comfortable about doing that because I knew at that time that the outlook for those patients was virtually 100 percent relapse, and we actually were able to cure more than 50 percent of those patients. I was actually the first to report that at the Association of American Physicians meeting about 1977 or so. Even before Don Thomas announced -‑

Q: Was your role in that mostly organizational or --?

Beutler: I was actually involved in the care of patients as well, but the primary responsibility for the day-to-day running of the program was Karl Blume's. I played mostly an organizational role, but I did take call. I did go and see the patients and take care of the patients and I helped to select the patients. And I set the direction of the program. I'm the one who really basically decided that we should be transplanting patients before they relapse and we should do this right from the beginning.

Q: Just one question, a quick question. What were the problems with the cardiac surgery you mentioned that --?

Beutler: Well, I think their results were not very good. The people they had were not the best. Then I think they had recruited one very good surgeon and he tragically died and the other people they had just weren't up to, I think, doing very well. I can't remember all the details.

Now, the marrow transplantation program was very successful. Today, as a matter of fact, the City of Hope often has commercials in which they point out the pioneering role they, played in bone marrow transplantation. What they don't tell you is that in 1977; two years after I started the program, they voted to discontinue it. And they voted to discontinue it, I think, because they were listening to a lot of people who were just kind of spewing out conventional wisdom which was the same stuff that one heard in the early 70s. I decided that it was time for me to move. I'd been there for about 18 years. I was almost 50 years old. I decided that if I didn't move then, that I never would. And I thought that the decision Taking process that had arrived at such a manifestly wrong decision didn't bode well for what was going to happen at that institution. And so when they made that decision I told them I would leave. Then after about 3 or 4 months they came to me and said that they'd rescinded the decision and that they would continue the program. I said that was a good decision, but I was going to leave anyway. And so then I looked around for what might be a suitable place for me and I found this position at Scripps which has been very rewarding. I moved here together with my group in '78-'79. Actually it took about year to move because we were all only about 120 miles away and some of my people went ahead and I commuted back and forth.

Q: Was that mostly technicians or --?

Beutler: Mostly technicians, secretaries, I think one staff person, a couple of fellows. Two of the technicians are still with me now. One of the secretaries retired at age 80. She was already over 70 when we moved. And, yeah, so although like any institution, this institution has problems, too, they're not of the magnitude of problems of City of Hope. As a matter of fact the City of Hope has had increasing problems since I left, and, I believe it's because of flaws in its organization. I felt that since they were not willing to correct those flaws, they were in for tough times, and there have been tough times.

Q: Have you mostly left your interest in bone marrow transplants behind you?

Beutler: No. Actually, when I came here I thought this was an excellent place to start a bone marrow transplantation program and I started one here. I was fortunate to have Dr. Robert McMillan as a member of our staff here. He's a very excellent clinical hematologist whose laboratory interest is in immunohematology. But this research institute, as you may know, is noted for its work in immunology and most of the problems in bone marrow transplantation are immunologic problems. And so I started a bone marrow transplantation program here in 1979-1980 and it's a very successful program. Actually, I'm much less active in this program than in the one at the City of Hope. I did participate to some extent in the early days of this program. But I don't really anymore. And McMillan's really done a fine job in running it. I'm still involved in this area to some extent. I find myself being called on, as it were, as an elder statesman to chair various meetings and things of that sort. Actually, I was at a meeting in Seattle about two months ago on a very interesting topic which represents an intersection of two of my old interests, the question is whether to treat sickle cell disease by transplantation. It was a one day meeting on that topic and I was asked to summarize the meeting, which I did. The proceedings will be published in the "Seminars on Hematology", probably early next year. Just now, as a matter of fact, I've been asked to chair an NIH committee that's looking at the marrow donor, the National Marrow Donor Program, so I still have some presence in that area, but that presence is not a bedside presence any more.

Q: Can you distinguish these children?

Beutler: It's impossible. There are methods now that, perhaps, separate them a little but there's still a lot of overlap. That's the issue. There are some DNA techniques. You see the sickle mutation has arisen at least four times, and that each time it's arisen in a context of a different genetic background in that chromosome. That distinction can be made and one type is called the Central African Republic type and that seems to be associated with rather severe disease. And then there's another one called the Senegalese type which is a milder disease. But I'm sure there are patients who are homozygous with the Central African Republic type who have much milder disease than some patients who have the Senegalese type and so I think that can help a little bit with the decision making but there is no really good way of telling. As I said earlier, there are some questions for which we just don't have any clear cut answers and that's one of them.

Q: For how long a period of time has it been established that bone marrow transplantation can be efficacious for sickle cell disease?

Beutler: Well, I could have told you that in 1960. It's obvious from the science that when you do a bone marrow transplantation you replace all of the cells that make sickle cells. The first time this was actually done was when a patient with sickle cell disease was transplanted because he had acute leukemia and of course the sickle cell disease went away. Unfortunately the leukemia came back, but you know, that was proof. Then there is a group in Belgium that has transplanted about 12 children with sickle cell disease for reasons that are really not very compelling. They really should not have done it. But they've all survived, so they were lucky. So there is some background, but nobody has really gone into this in a big way. I think you can see it's a tough question when you do deal with some real mortality.

Q: Yesterday you mentioned that -- well, it kind of leads out of the question of the issues which you were just dealing with, which are for reasons for treating patients with bone marrow transplants and the fact that some reasons are fairly poor. And yesterday you mentioned that your relationships with patients had been very important in structuring the question. I wonder if you could talk a little bit about that and the sort of responsibilities to patients and how that relates to the work you do.

Beutler: Well, through my whole career I made myself the physician of some patients. In other words, I'm their doctor. Obviously I can't do that with very many patients and be sitting here and talking to you, or running the department or the laboratory. But I do it with some. And I guess I would have to say that I find that having people depend upon me and my being able to give them what they need is very gratifying. At the same time, the work that I've become involved in often is derivative, and I can give you several examples right off hand. Primaquine sensitivity is perhaps not a good example because those weren't patients of mine. In fact I might tell you that when my children were very small and they asked "Daddy what do you do?" and I would say I'm a physician, and what a physician ordinarily tells his children is that I make sick people well. I would have to say I make well people sick because I was giving malaria to people. I was giving primaquine to them and giving them hemolytic anemia. So these were not patients I was making well. These were subjects in some very important clinical investigations. But there have been groups of patients that I've been very interested in. One problem that I worked on in the fifties that I haven't even mentioned is that I became interested in women who were very fatigued and who had either no anemia or very mild anemia and who were written off as being psycho-neurotic. I discovered that when I did bone marrow examinations on them, that some of those women had no iron in their marrow. They were iron deficient. I reached the conclusion that iron deficiency could produce symptoms without producing anemia, an idea which was very radical at that time and quite generally dismissed, but which now I think is quite well accepted. For a number of years I worked on iron metabolism, particularly with this question and I worked on experiment with animals. I made them iron deficient and studied their enzymes and I looked at their performance.

Q: When you say they were "written off" as psycho-neurotic do you mean the conventional tools for distinguishing an iron deficiency of some kind did not reveal --?

Beutler: Well, the conventional tools that were used then. Serum ferritin had not been invented. Plasma iron was considered to be a very esoteric test that wasn't usually done. People looked at their blood, they applied the Wintrobe indices and standards for normal blood counts and they were normal and they said, "Well, they're normal."

Q: So it was a kind of iron deficiency that did not really reveal itself --?

Beutler: That's right. So that was one group of patients that led me into an area of research. Now, a second group would be the patients with acute leukemia.

[tape interruption]

Beutler: When I first started in hematology acute leukemia really was 100 percent inexorably fatal in adults. And this has changed a great deal of research. To be able to give a patient like this a chemo-therapeutic regimen and see that their blood returned entirely to normal was really very exciting to me. This is what led me into bone marrow transplantation as a way of extending this response and really curing some of these patients. I've mentioned to you that my interest in Gaucher's disease, again began with a patient. She was actually the first patient that we tried to treat with enzyme replacement. She died, nonetheless, and now, unfortunately, I see that the reason was that we just weren't able to make enough enzyme. Now that a firm is making it commercially, patients are responding to the enzyme but in 1977 when I gave [omitted] -- that was her name -- enzyme, it just didn't do enough for her. She died. Most recently the other clinical aspect which I was going to mention is a drug that's been developed in this department, 2-chloro-deoxy-adenosine. This drug was synthesized, really designed and synthesized by a young man in the department, Dr. Dennis Carson, who is really a very outstanding young scientist. He came to me in about 1980 with his laboratory findings and he wanted to know whether he could test this drug on people. He had already written to the FDA and they had told him that he would have to submit all kinds of information which he couldn't possibly get together. I pointed out to him that the FDA had no jurisdiction over this drug because we made it in California and we used it in California. And so I wrote to the FDA. I established that they did not have authority and we started giving it to patients here. And that I might say is quite unique, that this drug was not made by a pharmaceutical firm. It was not made by some research institute somewhere else and sent out for testing. It was made in this department right across the corridor and we tested it on our patients.

Q: Now when you say the FDA had no jurisdiction is it because the California laws -‑

Beutler: Because the FDA is a federal agency and it only has powers in interstate commerce and at that time there was no California law. There is a California law now, and actually we proceeded to get approval from the FDA about five years ago, but that was much easier for us to do because we'd already given it to one hundred patients and we had the needed data. And this drug has been tested now in a number of lymphoid malignancies and it's rather effective in some of them, but it's spectacularly effective in hairy cell leukemia, where it produces complete remissions in about 80 percent of the patients. The first patient we treated is four and a half years out and he's not relapsed. No patient has relapsed. And so I played a major role in the development of this drug and again, it is really based on my clinical interest. In the first three or four years when I gave it to patients, basically I could only really give it my own patients because I couldn't get the other staff interested in enough to give it to their patients. So if I hadn't have been seeing patients myself, there wouldn't have been anybody who'd gotten it. Then one of our fellows, a young man by the name of Larry Piro, became interested in the drug. And he's a very outgoing guy, and he got other people sort of interested and he's been doing a lot of the testing with the drug now. But basically this is an area in which I've been very active in over the last six years or so since this drug has proven to be as good as it is. In fact, we're having an international meeting here next week, where collaborators from other countries to whom we've sent the drug are going to report their results and the following week I'm going to the FDA with representatives from Johnson and Johnson, which is the pharmaceutical company which is now going to make the drug for us. And I think that within a year or so the drug will be licensed.

Q: How do you go about getting jurisdiction over a patient? Is that a point of tension at all, or--

Beutler: Well, not for me. Why don't you rephrase the question, so that I understand what you really mean?

Q: I guess what I mean is I'm not quite sure how a person who devotes a significant amount of time to research -- what is the relationship on one hand with the clinical staff?

Beutler: Well, for eight years I was in charge of the clinical staff. That's what my relationship was. But I feel that being in charge of a clinical staff, just like being in charge of a research staff, is really an obligation which one discharges, not by telling people how to take care of their patients, but by facilitating the overall process. So if, for example, Dr. [Joan] Kroener, who is one of the hematologist oncologist, who trained with me as a matter of fact, has a patient and she wants to give that patient drug z, I'm not going to tell her that that patient should have drug x. In many departments it would be different, you know, where I would simply say, well, if you want to stay here, you give this experimental drug to all of your patients with chronic lymphocytic leukemia, or -- you know," My way or the highway", I guess. But I just don't feel comfortable about dealing with professionals in that way. As long as she's doing a good job taking care of patients, I don't feel that I can press her to participate in my research program. So she doesn't. But if a patient is referred to me, and I see that patient, with a fellow let's say --and I always have a fellow see the patient -- when I'm the staff physician, then there's really nobody between me and the patient. But if it's Dr. Kroener, or Dr. [Bill] Miller, or Dr. [Robert] MacMillan, who are staff physicians, then it's their patient. Now, if I had wanted to when I was head of the division I could have forced them to do it, but I just didn't want to do it.

Q: What are some of the special responsibilities that go along with as you said making, in the research context, well people sick?

Beutler: Well, I think the overriding moral, consideration is that you are not subjecting people to unreasonable risks for what can be gained by society on the one hand and the patient on the other hand. There are two very different kinds of situation. When I gave malaria to inmates at State Penitentiary I wasn't giving them malaria to make them healthier, but I was giving them malaria so that we could learn how better to treat malaria and then we would do a lot of good for society. And of course they were volunteers and they went into this fully understanding what the risks were, and they were quite willing to do it for various reasons. They had some personal gain in that they were paid a very small amount of money. They were able to stay in the hospital, which was nicer than staying in their cell. There were some who felt they were repaying society, and some felt that perhaps when they went up for parole that the parole board might take this into account in deciding whether or not release them. So those were their motivations. So that's one kind of situation. Another kind of situation is when you do a bone marrow transplant on a patient early in the course of developing transplantation as a treatment. And there I think that you have to decide, is this patient likely to benefit, and is that benefit enough to justify the risk of going through it? Now, what's grown up in the last two decades is a complex web of consent forms, committee approvals and so forth that we have to go through, which I think hampers clinical research. But it all comes down to the same thing. I must say that I don't have trouble getting consent for the kinds of things I want to do because I think that I want to, generally, are things that are pretty darn reasonable. Some of the studies we're doing now are treating patients with Gaucher's disease with enzymes. There is no other treatment they can be given. The treatment seems to be very safe and the tests we're doing are very reasonable to check to see whether they're getting better. When it comes to giving 2CDA in a patient, the first few patients we treated were patients who had end stage leukemia. They've all died, but they had very little to lose and it was a chance for them to get well, although a very small one. And nobody lied to them and told them, "You take this and you'll get well." I'm sure that what I said to them is "You take this and we hope that it'll make you better." But it's up to you.

Q: How do you think that this, whole web of consent forms hampers the function of clinical research?

Beutler: Well, it just consumes an enormous amount of time effort and paper and it -- you know, it really becomes kind of absurd. Let me give you an example. The type of research that we do here is that of a general clinical research center. The general clinical research center has an advisory board and I appoint that advisory board because I'm the principal investigator of the general research center. We also have what's called an IRB, Institutional Review Board. Every research proposal has to be reviewed by the IRB. Then it has to be reviewed by the research committee and very often it has to be reviewed by an outside agency as well. In fact, it always does as a matter of fact. So there are three separate bodies, and then they make different suggestions. And then you have to sent it back because let's say that the General Clinical Research Center committee said that you didn't mention such and such in your consent form. Fine, I'll put it in. But that consent form has to be approved by the IRB, which had already approved the previous one, you see? Now the NIH has just passed a rule where we have to indicate what is being done to involve people of different sexes, ages, and ethnic groups in any project. It's almost a Catch-22, you know? [omitted] So, I mean, everybody's always trying to achieve some kind of different balance. What it all ends up as really is just filling out more forms. So it holds up the work in just generating a tremendous amount of paperwork, which I have to generate, then my colleagues have to review. And everything takes longer. And it also means that if I want to do something very simple that really doesn't subject anybody to any particular risk, that I'm likely not to do it. Suppose, for example, that I want to measure the levels of some particular compound of somebody who smokes a cigarette. He's a smoker. I can't just say to that person, "Look, next time that you have a smoke, come on over and let me take a blood sample." "Sure Doc, I'll be glad to do it," and I take the blood. I can't do that. What I have to do is I have to write a protocol. I have to take it to the committee. I have to get the consent form. I have to have him sign a consent form. So I say, "Well, I really don't care about the blood sample of that smoker." It's just not worth the -‑

Q: There's no sharties walking around --

END SIDE 1, TAPE 3; BEGIN SIDE 2, TAPE 3

Beutler: You know, I'm quite cognizant of the fact that these practices have all arisen because of some abuse and the way that administrators and lawyers try to fix up abuses is to make rules and those rules never get rescinded, they just get piled on each other.

Q: Pretty soon it's part of a larger and larger bureaucracy.

Beutler: Yea. And then there are some very anomalous things that happen. For example, one of the things that I established here in the General Clinical Research Center when I first came, was a program for screening blood -- blood donors. This was done so that when blood is drawn from normal people to be used in a laboratory, it isn't just drawn from somebody who happens to be passing in a corridor, which is how things were being done when I came, but rather is taken from somebody who has a blood count, so you know you're not taking blood from person who is anemic. You know they don't have hepatitis. And then a few years ago we started checking it for AIDS as well. We can't check every sample every time it's given for AIDS, so what we do is we check all of our donors once a year for AIDS, and we also put them through the kind of questionnaire that is used in blood banks so that if they're homosexual they're not supposed to give blood. Well, about a month ago one of our donors screened positive for AIDS. He was called in and it turned out he was a homosexual. [Omitted] really did have AIDS, but he hadn't been tested for a year, so during that year he'd given about six donations and they'd been sent to various laboratories and we had a record of them. We could not tell them "you received a blood donation from John Jones on May 3rd and if you still have the blood you should destroy it because it could be contaminated with HIV." The law in California does not allow us to disclose, even to the people who are at risk, what that donor's name is. And the way that we got around this is to tell them that during the week of May 1st you got a sample from somebody who has subsequently tested positive for AIDS. If you have any blood left from that week from anyone you'd better destroy it. There are strange things that happen in our society.

Q: Which brings me to one of the questions that ASH is interested in, which are questions on the increasing role of the NIH in clinical research and in your work in particular.

Beutler: Well, first, the NIH is what has made everything possible. As a result we've all grown extremely dependent on NIH. This research institute derives, I would say, probably about 88 percent of its support from NIH. When I say 88 percent I include even my salary and the salary everybody else here. I'm not talking about faculty being here and being supported by the institution and 88 percent of their research being NIH supported. I'm talking about 88 percent of everything. So when there is a cut in funding it puts us really very very much at risk. On the other hand, I don't believe that the answer to our problems with research funding are to put another billion into the pot. Putting another billion into the pot will certainly take care of the problem right now. But then there would be another problem two years from now. In other words speaking as a clinical researcher I would have to say we'll never be satisfied. What I think the best we can hope for is gradually increasing even support and support for training programs, which is geared to the availability of funding. What I consider very unfortunate is rapid growth followed by a drought. Then you get people who go to graduate school, from undergraduate school. They think they're going to have a career in the field and then suddenly it isn't there. And that's not fair. So I think that we should try to make training funds available to the extent that we're able to provide career opportunities. The other aspect of what is happening at NIH that I consider unfortunate, and this has always been somewhat of problem, is the politically inspired goals of research. Suddenly somebody gets excited about something from a political point of view and a large amount of money gets put into that. I don't think this advances the field. I think it tends to retard it, actually, and it's hard on everybody else in research. The most recent example is AIDS, but there have been others.

Q: What others?

Beutler: Well, sickle cell. I have a theory of diminishing returns of research. In fact, I call it, to borrow a term from biochemistry. "substrate inhibition". If you have a field like sickle cell disease and there are good people who are working in it as have been right from the fifties, then you make good progress in that field. Now if you put a huge amount of money into that field, what you do is you draw all the unsuccessful people from other areas into the field and what they do is they create noise, you know, in the communications sense. They create data that aren't correct and they actually then retard the field. So you see, if you put a large amount of money into an area, whether it's AIDS, or sickling, or aging, or whatever it is, the scientists that you're going to draw in the field, aren't generally those who are highly successful in what they're doing. You're not even going to draw on those who are really motivated to do something about that field. You're going to draw on scientist who say, "Gee, I didn't get funded on my thyroid project, so I think I'll work on AIDS". But the reason they didn't get funded on their thyroid project might be that it wasn't a very good project. So, I think that it's fine to target areas of importance, and I think AIDS is an important area and I think sickle cell disease is an important area. And I think these areas deserve support at a good level. But I don't think that the political process should suddenly jump the amount of support from these areas three or fourfold. And then very likely some years later, when it's not quite as popular anymore, suddenly drop it, to a low level. Cancer exemplifies the same problem, with all these cancer centers. Apart from not helping the field that the politicians are trying to help, they harm the others, because they do take away money. Right now two problem areas are the genome project and AIDS. They are eating up a lot of money that could be going for very good research which might actually help those projects. So that's where I think the NIH could perhaps try to improve a little bit.

Q: You also mentioned the way in which clinical researchers need to respond to NIH requirements for patient control groups and that sort of thing. Any reflections on that?

Beutler: Oh, I think that's just a minor irritant. That's one that came across my desk last week, you know. I mean, there's another one that came across my desk the week before and that is that apparently every institution has to have a course for their research fellows on research ethics. Well, I think research ethics are extremely important. I don't think you teach it to people by giving them a course. I think you teach it to them by being ethical and if they are trying to cut a corner you say, now wait a minute we don't do that here. That's the way people learn. Not by setting up a course where they have to attend six hours and we have to certify that these people are trained in ethics -- but that's a part of the administrative political process.

Q: Yesterday you said something about oncology making more and more claims on leukemia patients. Patients who had been traditionally the life blood of hematology. Do you have any reflections on, or any ideas about how that's going, and what it means for hematology and the field for the long run?

Beutler: My feeling is that the situation is getting better and that there is a tendency now for hematology and oncology divisions to come back together. I have always resisted splitting hematology and oncology divisions because I think it's easier not to break a plate or a vase, then it is to glue it back together. I think that's sort of passed through its heyday. Oncology was a new specialty, I think they so wanted to feel their oats and I get less of that feeling now.

Q: What time period is this in which oncology became a new type of field.

Beutler: I think it started happening in the late sixties, early seventies. They very aggressively took over quite a lot.

Q: That probably had something to do with increased funding -‑

Beutler: Yes, probably so. And then you see because of the increased funding and because of the patient revenues, they became political powers in university medical schools. And they very commonly were able to get deans to say -- or chairmen to say, "Well, we need a separate oncology division." And then some guy who is number two or three in the hematology-oncology division became number one in the oncology division, which eclipsed the hematology division. That's happened a lot of times. But I don't think that's as much of a problem anymore, but maybe it's just that I'm not as aware anymore. I'm not sure. I'm not very close to that situation.

Q: It sounds like one of the pictures you're painting of the liberal structure of medical research today is quite different from the one in which you were trained in. That might seem a general question.

Beutler: Well, I think in some ways that's true. And I think that that's true in medical practice, too. There are things that I hear here and that I don't like and I think probably people hear them everywhere. That is that the top administrators, who themselves are MDs, are talking about "market share", about "product line". I was taught that medicine was a profession, an art, and not a commercial enterprise. But the people who lead major institutions now, even academic institutions, I think believe that they are at the cutting edge if they talk like they're corporation executives. I like to think they're not.

Q: One question that I've been interested in is do you think that your particular set of interests during the course of your career, hematology, hemo-genetics, nutrition, is that unusual for a hematologist in this country?

Beutler: Well, in this time or in my time?

Q: In your time.

Beutler: In my time. Well, I think there have been a few other people who have had similar kinds of interests. I think Arno Motulsky, whom I mentioned earlier, started out as a hematologist, then became one the most prominent geneticists. The person who just took over after his retirement, George Stamatoyannopoulos is also in the same vein. No, I think it's not that unusual. Another one is David Weatherall. He is now Knight of the Realm and the Nuffield professor of physic at Oxford University. And he's a hematologist who works in the basic aspects of Thalassemia. Y.W. Kan started out as a hematologist. You'll probably interview him. He's thecurrent President. No, I think there is a small group of people like that. What is changing almost inexorably, I would say, is the extent to which these people are clinically involved. That as I see the younger people, they tend to have less and less clinical involvement. There is much more polarization and the rationale for it is that science is just becoming too complicated to allow you to do clinical work as well. I don't think that's true. Like all older people I think the younger generation just does not work hard. That's all. That's what I tell my kids. I think that there is a distinct reward, both personal reward but also professionally in terms of research and to continue to see patients. I have three children who are physicians and one who is in the computer business with me, and one of my children is a --the oldest boy is a clinician who specializes in infectious disease, and does it very well. My younger boy is a MD also, but he is really a full time researcher and I continually try to encourage him to see patients; but he really doesn't want any part of it. I think he's wrong.

Q: I have one final question and that's about -- you mentioned the reference manager. I wonder if you could reflect a little bit on the origins of -

Beutler: Yes. In the middle 60s I was being asked to write many reviews about G6PD glutathione iron deficiency and so forth and I've always liked to document what I write very well and it became quite a chore to always try to find the references that I needed, particularly with the medical literature growing as fast as it did. And so two years after I arrived at the City of Hope I decided to use marginal punchcards to hold all my references, and then I could sort the cards and make a bibliography. I thought it was a great idea. The secretaries always hated it, and it worked reasonably well, but once I got up to about 10,000 cards, trying to sort those with a needle and I don't know -- you're probably too young probably to know what these marginal punchcards are like. Do you know what I'm talking about?

Q: No.

Beutler: They're like file cards but they have holes all around outside. And you can code them by punching out the outside, and then if you use a needle and put it through a hole in a stack of them, the ones that have been punched out, they drop out, you see? So it's sort of a primitive mechanical computer. In 1972 or so, '73, our clinical laboratory at City of Hope purchased a PDP 11/40 computer, which was a mini-computer, state of the art at the time. And one day I was having lunch with Art Schneider who was the person in charge of the department of pathology, and he and I were talking about bibliographic retrieval and he had a programmer, had a computer, and he had space on the computer and we decided to write a program that would take care of my work. And so the programmer worked for me for a period of six months or a year and he wrote an assembly language program for the PDP 11/40, which I used then for the next 10 years or so. By the time I came to Scripps, the program had grown and I had accumulated about 8,000 references. It really didn't fit on the discs, the machine -- no more than that fit on the disc -- the machine had three disk drives, and worst of all, I had to bring the computer with me because the program wasn't transportable. So I bought the computer from City of Hope and brought it here. In the meantime my son, Earl, had graduated with a Master's degree in computer science from UCSF, and was working for a publishing firm, and he and I decided to form a company and rewrite this program so that it'll run on a micro-computer. In this way it could be used by others.

I really needed a new program because this computer was costing me $8,000 just to maintain my bibliographical retrieval material. And so the plan was that we'd incorporate a company in California called Research Information Systems with $65,000 in capital, $40,000 which came from me and $25,000 in the form of a note. Came from him [laughter]. He's not dumb. And then he was to write the program. And months went by and he didn't write it. And then about Christmas eve in 1982 I said, "Earl, I need that program. When are you going to start writing it?" "Well," he said "Dad, I'm really all burned out with programming. Why don't you write it?" Well, actually this was not a preposterous suggestion because I'd been programming since the 60s and I'm actually quite a good programmer. In fact I like programming so well that once I get into programming I do very little else. Eight hours goes by just like that and I'm just sitting at the computer. But against my better judgment I started writing the program and I wrote the whole program. It took me about a year and a half to get the program to a point where we could market it. We showed it first at a clinical meeting in Washington. My wife and I, and also one employee from here whom we hired for this purpose, went out together with Earl also. The program was very well received. It started selling very well and a year or two went by and I spent a lot of my time improving the program, modifying it, changing it for the more advanced computers that became available and so forth. Sales were very good. But it really was eating into my time and of course once you sell software you have to provide service to your customers, you have to answer phone calls, you have to ship, you have to bill, all that sort of thing. So we talked to my son about the possibility of his giving up his job, with the publishing firm and taking over the program. We hadn't wanted him to do that initially because he had good job, a very good job, and we didn't know whether our endeavor would be a success or a flop, but now it was clearly a success. So in about -- I think it was probably February '86 I would guess, he took over the program and he rented a small office and the agreement was that he would do everything himself. That he wouldn't hire a bunch of people, but that as things went on he could hire some people. To make a long story short, we now have 35 employees and an 8,000 square foot office facility in Carlsbad which is about 15 miles north of here. And we have several additional products, one of which is called Reference Update, which is very strong competition for "Current Contents", an old service. We now have 5 programmers and we've just come out with new versions of several programs one for the Macintosh. It's a business venture that has given me a lot of satisfaction. It's entirely different from what I do normally, but I use the programs in my work, of course, and I really enjoy working with my son, and I enjoy seeing the business being profitable. As a matter of fact one of the things that we've been doing for the last few years involves ASH. This year we make a meeting edition which we send anybody in the Society a disc, which has all the papers from the meeting on it. And they put the disc in their computer and they run the program. They type in whatever their areas of interest are and it creates an itinerary for them with all the papers that touch on those topics. We're doing that for ASH this December. So those are the company products, Reference Manager and Reference Update.

Q: And it's generally used by researchers to maintain their own bibliography?

Beutler: Oh yes. Our sales of Reference Manager I would estimate, are running about 350 copies a month and we probably have over 20,000 programs out there and our Reference Update Service has many thousands of subscribers. In spite of the fact that we're supporting 35 employees and my son and his family we're very profitable.

Q: What's the name of the company?

Beutler: Research Information Systems. We're just going to test a new version of a grant accounting program. Our target audience or market so to speak is biomedical scientists. And I think the reason that we've been very successful is that I'm a biomedical scientist. I wrote the original program the way a biomedical scientist would want it, not the way a programmer thinks he wants it or the way a librarian thinks he should want it. And so our products hit a very responsive chord with our audience because they're people like me. One of the good traits that my son has is that he's quite willing to listen to others and to create products that they want. If he sends me something that he's done and I don't like it and I say "Look, Earl it needs to have this and that done." He doesn't always and do exactly what I' tell him, you know he is my kid. But on the hand he's not stubborn about it. He listens and if what I tell him makes sense or if he asks some others and they agree he'll change it. So our products have really been very much tailored to the community to which I belong.

Q: And what role did programming play in your work as early as the 1960s?

Beutler: Until very recently I wrote almost all my own programs, and the earliest programs I wrote were on a desktop computer, the Olivetti 101, which was the first desktop computer ever made. I wrote programs that allowed my laboratory staff to compute the results of routine laboratory studies that we'd do, enzyme studies for example. They would enter the raw data and it would automatically calculate for them. Then I wrote some standard statistical routines, regression equations and standard deviations. And later I did that with other computers. Then when I did some population genetic analyses I wrote programs to analyze that. For example, when I was trying to calculate gene frequencies for galactosemia I wrote programs that would handle the thousands of assays that we have done and analyze those. I wrote those programs in Fortran for an IBM computer. One of my other avocations is the financial markets, particularly the stock market. So I wrote programs to keep my personal stock records and transactions. And I've written programs, for example, that examine all the G6PD variants, to show you one example right now. Nobody would write -- well, I could hire a programmer to do it. [Computer turned on.] OK suppose, for example, I wanted to see what the characteristics are of G6PD for Marion. Here are the characteristics, this is the electrophoretic mobility. This is the activity as a percent of normal. This is the Km of G6PD. So it has all of these data. Now, suppose I want to see what other variant a G6PD variant is most closely related. These are weighting values I can change if I want to. I don't particularly want to. There are 291 variants. Now it's comparing about 12 characteristics for each of these variants other variants, picking the one which is closest, according to an algorithm designed. It finds that the most closely related is GASTONIA, which by the way is very interesting. I didn't know it would come out this way because now we've got DNA analysis that shows that these are, in fact, identical.

Q: So, in other words, your computer program is in fact very closely -- it's actually predicting the effect you found.

Beutler: That's right. To some extent. Sometimes the predictions are not as one would think and then that gives one something to think about.

Q: So has this been a way for stimulating questions --?

Beutler: Yes. Actually, one can -- what I've done with this, for example, is to compare every variant with every other variant and calculate distances and there are 43,000 such comparisons, which this computer program does in about 15 minutes. And then I've written a little routine that dumps the results into another file and which then I put into another program which plots out the distribution of the data. And then I can see where different comparisons fit on this distribution. So there are a lot of things that I do that call for a computer.

Q: How would you say that other people in your field are as computer literate or use computers as frequently?

Beutler: Yes. I think that I'm into computers much more than they are.

Q: OK. I think that's about all the time we have.

END OF INTERVIEW

Addendum

16 years have passed since this interview, and during this time there been many changes in the world, in the field of hematology, and in my career as a hematologist.

Few would argue that the world has not become a more dangerous place since 1991. In my view the principal factor in bringing about this lamentable state of affairs has been religion, particularly extremist religion. However, the line between what we might designate "extremism" in religion and "mainline" is difficult to establish, and it is distressing to me to note how candidates in the current campaign for the Presidency of the United States pander to the religious right, and how each candidate seems to vie with the others in trying to establish their own closeness to God.

Hematology itself, like every field of science has suffered from changes in the world scene. Funding has become a major problem, even though the NIH budget has grown enormously in the past 16 years. In the 1991 interview I pointed out that spurts of funding followed by times in which funding did not grow was bound to create major problems, and this is, indeed, what has happened. It is increasingly difficult for young medical scientists to launch an independent career. The average age at which an M.D. scientist obtains his or her first RO1 grant is 43. No wonder that our young scientists become discouraged about a career in medical science. In the 1991 interview I pointed out that politically driven focus on certain areas such as AIDS or sickle cell disease had a serious negative consequences. Not surprisingly, this trend has continued. Often it is driven by talented and persuasive members of our own scientific community who "hype" their own areas of interest. The leadership of the NIH can apparently be convinced that areas that have dubious scientific merit are at the vanguard of science and need massive infusions of funds. Unfortunately, total funding is not increased, and these funds come at the expense of meritorious investigator-initiated research. An example is the current interest and massive funding for "personalized medicine" based upon genetic polymorphisms. My view is that while some small advances will result from this approach, they will not justify the diversion of resources that is taking place. The reason is a fundamental statistical one. When a large number of polymorphisms is examined the binomial distribution dictates that there will be many polymorphisms in which the frequency differs in the disease population when compared with the normal population. This can be taken into account by correcting for multiple comparisons, and when the number of comparisons is very large -- and the number will be between 100,000 and 500,000 in the case of whole genome scanning -- most true differences will be lost in the forest of random variation. The only ones that will survive scrutiny are the ones that are very large differences; these are the only ones that will be detected by gene scanning techniques. This major consideration does not even take into account the perturbing affect of population stratification, and efforts to correct for such stratification decrease the statistical power further.

My own interest in this area of research has developed from our own studies in which we have tried to better understand the variation in the phenotypes of patients with "single gene" diseases. As we have performed these studies I have become increasingly aware of the difficulties in identifying modifying genes, and have increasingly come to the belief that the effect of the genome as a whole on the phenotype is considerably less than I had assumed two decades ago. Instead, I believe that epigenetic modification probably plays a much larger role in determining disease phenotypes than has been generally recognized.

In my 1991 interview I pointed out that the involvement of past presidents of ASH with the society tended to be minor as new leadership emerged. This seemed quite appropriate to me, but somewhat unexpectedly my involvement with our society has increased in the past decade. I became a member of the Committee on Investments and Audit some years ago and some five years ago was asked to serve as its chairman. As a chairman of a standing committee I was privileged to become more active in the affairs of ASH and to attend the annual retreat. This allowed me to become better acquainted with the current generation of leaders of our society. The society itself has grown enormously and has been very successful. One major change in ASH has been the increased participation of foreign members. At the time that I was active in the leadership of our society for membership was deliberately restricted to eminent hematologists from other continents. Subsequently, the leadership of the society decided that there should be no barrier to hematologists from abroad joining our society. In effect this has transformed ASH into an International Society; there are now more participants from abroad in the annual meeting than from the US, Canada, and Mexico. While a large society may be a stronger society, size also has the disadvantage that it is more difficult to encounter colleagues from one's own hematologic community in a meeting with 20,000 attendees. In recent years the society has generously recognized the research work of my group by asking me to present the Don Thomas lecture in 2003 and by awarding me the inaugural Coulter award for Lifetime Achievement in Hematology this year.

In my 1991 interview I stressed the value of combining hands-on clinical activities with laboratory research. I still hold that view, but I also believe that the responsibility inherent in delivering health care is so great that there is an age at which one should probably no longer take on this burden, both from the point of view of the patient and the physician. I kept postponing my own decision in this regard, but finally decided that after I reached the age of 70 I should no longer see patients. My laboratory studies, however, have continued to the present time. They have taken an interesting turn, in that the major topic of my research is one that occupied me 50 years ago, viz. iron metabolism. There seems to me to be definite advantages to working in an area of science, leaving that area either because of a lack of innovative ideas or because the techniques that are needed to push ahead with the science are not available. Our work with the regulation of iron homeostasis is a good example of this principle. In the late 1950s and early 1960s we attempted to understand how the body regulated its iron content, but it became clear that the system was too complex for us to unravel with the tools at hand, and I abandoned this area of research for some 40 years. The development of molecular techniques that allowed one to clone positionally gene producing diseases made it seem to me that the time had arrived at which it might be possible to find the gene that caused hereditary hemochromatosis. We therefore embarked on an unsuccessful attempt to find this gene. But others were more successful and so the gene for hereditary hemochromatosis, designated HFE was identified. This has opened the way for us to carry out extensive epidemiologic studies, which overturned the conventional wisdom that hemochromatosis, as a disease, was very common. The disease is actually quite rare; it is the genotype that is common. This is one of several projects which, as noted above, have stimulated my interest in the dissociation between genotype and phenotype, and which is taught me that it is unlikely that a major portion of the variation of phenotype is, in point of fact, due to variation in other parts of the genome. There is a distinct advantage to returning to the field in which one has worked previously. The older literature, almost completely ignored by an unknown to my younger colleagues in the area research contains many valid pearls that can and should influence our interpretation of the more modern data. Although our ability to search the literature has been greatly expanded by computerization, and the some of the older literature has come "online", the pearls are often difficult to find, and I've found that my earlier experience in the field has sometimes been invaluable.

©2008 Columbia University

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