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't do 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 Hematolgy", 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: What are the -- briefly, what are the conclusions about the possibility of treating sickle cell disease with bone marrow transplantation?
Beutler: Well, first of all, it's been obvious from the beginning that one can cure sickle diseases by doing transplantation. And the issue has been whether the risk justifies the ends. And what has made this a really much more pregnant issue now is that gradually, not by leaps, but gradually bone marrow transplantation technology has improved so that now mortality is probably down to about 10 percent. And the issue that has emerged as the principal issue of this meeting is that everybody would be willing to offer bone marrow transplantation to patients who have sickle disease, who have bad disease. But there are some people who have sickle cell disease who have rather mild disease, and we would hate to treat those. And yet you have to make your decision early. What was interesting to me is that not only the bone marrow transplanters, who represent about half of the meeting participants, but the people who ran sickle cell centers and who were the frontline people taking care of sickle patients, were all rather positively disposed toward transplantation, including one physician from Africa who actually has a child with sickle disease. He is very active in the sickle field. Probably there's enough of a consensus so that if people want to start transplanting some children with sickle cell disease it would not be considered to be too much out of line. What they really would like to do is be able to pick out the unfortunate child who is fated to get a stroke, which is the most devastating manifestation of sickle disease, and to transplant that child and to prevent the stroke, but not to transplant the child that's going to have a few aches and pains and feel a little unwell sometimes, which is the other end of the spectrum.
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: 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 Hematolgy", 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: What are the -- briefly, what are the conclusions about the possibility of treating sickle cell disease with bone marrow transplantation?
Beutler: Well, first of all, it's been obvious from the beginning that one can cure sickle diseases by doing transplantation. And the issue has been whether the risk justifies the ends. And what has made this a really much more pregnant issue now is that gradually, not by leaps, but gradually bone marrow transplantation technology has improved so that now mortality is probably down to about 10 percent. And the issue that has emerged as the principal issue of this meeting is that everybody would be willing to offer bone marrow transplantation to patients who have sickle disease, who have bad disease. But there are some people who have sickle cell disease who have rather mild disease, and we would hate to treat those. And yet you have to make your decision early. What was interesting to me is that not only the bone marrow transplanters, who represent about half of the meeting participants, but the people who ran sickle cell centers and who were the frontline people taking care of sickle patients, were all rather positively disposed toward transplantation, including one physician from Africa who actually has a child with sickle disease. He is very active in the sickle field. Probably there's enough of a consensus so that if people want to start transplanting some children with sickle cell disease it would not be considered to be too much out of line. What they really would like to do is be able to pick out the unfortunate child who is fated to get a stroke, which is the most devastating manifestation of sickle disease, and to transplant that child and to prevent the stroke, but not to transplant the child that's going to have a few aches and pains and feel a little unwell sometimes, which is the other end of the spectrum.
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.
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