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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: Yes. So I told you what Ralph Wallerstein said to me.
Q: You mentioned hidden agendas and I wonder if those became subsequently clear at all.
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 --
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