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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.
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.
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.
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.
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