Interview with Joseph E. Murray by Sten Orrenius at the meeting of Nobel Laureates in Lindau, Germany, June 2000.
Joseph Murray talks about what led him into research; developing transplantation medicine (2:38); and whether breakthroughs in clinical research are often ignored by the Nobel Prize Committee (13:10).
I have the pleasure of sitting here with professor Joseph Murray, who won the Nobel Prize in 1990 for his work on organ transplantation. If I can start this little talk and say that from studying and from learning to know you it is quite clear that medicine was always a primary choice and that it was clear that you would become a physician from very early on. My first question is really when was it clear that you would be a researcher as well, what stimulated the early interest in research in you?
Joseph E. Murray: I think at Medical School the professors were doing interesting work. I remember one professor of pathology, he was really an instructor in pathology, was studying inflammation. I would look in the microscope with him and see different cells under different circumstances. I remember the trichina had ear centrefolds around it and an infection would have polymorphs. I wondered how the body attracted one, rather than another, and of course this is caused by xylocaine. We know now but this was back in 1941 and there was no knowledge of intercellular reactions. That interested me and then it was reinforced in my World War II experiences when we used skin from dead persons to cover burns in patients. We knew that the skin would last, survive, for maybe three weeks or four weeks but eventually it would melt away, whereas if his own skin had been used, the skin would have grown and then permanently survived and actually grown. I wondered how the body could be so smart as to distinguish between a piece of skin which to you and me would look the same, would treat one differently from another. Those were the two biological observations that were in the back of my mind.
You came to the Valley Forge [Valley Forge General Hospital] shortly after you graduated from Harvard, I suppose, and got a lot of clinical experience I would say immediately.
Joseph E. Murray: Yes, we had battle casualties from all theatres, the European, African and the Pacific. We also cared for German prisoners of war, Italian and Italian prisoners of war as well in the same hospital and they received the exact same treatment.
Problems associated with transplantation, the first one of those that you saw was the burns treatment and the difficulty in transplanting skin from unrelated individuals. I suppose a few years earlier there had been skin transplantation between identical twins.
Joseph E. Murray: Yes. that was 1934 or -35. A plastic surgeon in St Louis treating burns found that if skin came from relatives, it would survive longer than if it came from an unrelated person. He quite reasonably felt that if a related person has better survival, maybe an identical twin would have better survival and he found a pair of identical twins and cross skin grafted them and he got permanent survival. That was the only type of survival that we knew in the 1930s.
What was the process between the burns treatment in the Valley Forge and the kidney transplantation? How did you focus on kidney and kidney transplantation?
Joseph E. Murray: It was quite logical. When I finally got out of the army and I finished my residency in the late 1940s I joined the kidney transplant team at the Brigham. It was already in operation. I joined them and rather than transplanting skin, it was more fun to transplant kidneys because you had the vascular anastomosis to do the ureter plantation and you could tell when the kidneys start functioning. It was a natural transition to use a kidney as a biological indicator rather than a piece of skin, but our research used both skin and kidneys throughout.
Was the animal experimentation, the transplantation in dogs, was that going on already when you arrived?
Joseph E. Murray: No, but I started a large series of dog transplants, also with mice, rabbits, all sorts of animals.
Based on that you performed the first transplantation between the identical twins.
Joseph E. Murray: Yes, in the course of operating on dogs, I figured if we didn’t have a good operation that would work in genetically similar persons, it would be no use and so I developed a surgical technique in dogs that was reproducible and could function normally. I had a whole group of dogs surviving on one transplanted kidney back to himself. It was an isogenic transplant but there was no genetic barrier.
Then of course a big jump or the major development was going from the identical twins to genetically unrelated people.
Joseph E. Murray: Yes, but before that we had to show that in man, the identical twin transplant would work.
Joseph E. Murray: We happened to get a set of identical twins, one of whom was dying of kidney disease, the other healthy. That took about two years to work it out against the ethics and the morals and the acceptance of the community. We went to doctors at other hospitals, we consulted clergymen of all denominations, we went to corporate executives to try to get a feeling for what the general public would feel about it because we were weak. We knew we were doing something experimental and we just wanted to inform as wide a variety of society as possible.
During these early days you investigated various methods of immune suppression including ionising radiation.
Joseph E. Murray: Absolute, yes.
When was the breakthrough coming, would you say, with immune suppression that would …
Joseph E. Murray: The real break came with the development of drug immunosuppression. However, we had had some success both in animals and in humans with total body radiation and we had one set of brothers with a permanent kidney survival with an allogeneic kidney, treated with x-ray therapy. We started to do a series of 12 humans and one did very well, several did well for a while but then they would, after five or six weeks, would reject the kidney. We needed something more predictable and fortunately at that time the drug 6-mercaptopurine and it’s derivative as the azathioprine came along. That was synthesised, as you know, by doctors Hitchings and Elion from Burroughs Wellcome and they were very helpful to us. They sat in with us, educated us about biochemistry, they saw our patients, they knew our dogs by names, and soon we had long term surviving dog kidneys /- – -/.
It’s very interesting to hear because I’ve learned from you that you had regular visits, I think, by Medawar early and then you were long standing collaboration with Hitchings and Elion. My question is did you have to stimulate our colleagues, our immunology colleagues to come or was it obvious, did you have to recruit them so to say?
Joseph E. Murray: That’s a wonderful question because our local immunologists were not interested. They tolerated our interest they’d say: Joe you can’t do it, why don’t you wait until we solve the problem, but they did not attempt to discourage me, they just said, It won’t work. It wasn’t until Peter Medawar, who visited frequently, come to our lab, he would see some of our patients in the hospital and he was /- – -/ that a group of clinicians especially surgeons were interested in the biological problem. I think that he came to Harvard Medical School to give a series of lectures and he spent quite a bit of time in our lab and the immunologist wondered why.
Joseph E. Murray: A prophet is without honour in his own country. Once we got going and showed some good laboratory results our own immunology department became supportive. But an important thing was, we had the support of our chiefs of the clinical service. The chief of medicine was really behind it, Dr Thorn and Dr Moore achieved the surgery, supported us in every way including finances and so we developed a nice fine team.
Coming back to the theme of today’s panel discussion which was extremely interesting, I would like to ask you, as we know that some people objected to the development of medicine and surgery at the time, did you experience much opposition, like people came up and told you that one shouldn’t do such things as transplant organs between different individuals?
Joseph E. Murray: Both yes and no. Some of my closest friends at the medical school faculty – I was young then just got out of the army – advised me not to get involved because they said it would ruin my career, but others were supportive and the ones that gave some warning didn’t forcefully stop me, they warned me in a friendly way.
I guess, as you have said, it was very important that the first operation was successful.
Joseph E. Murray: Absolutely. We had done the operation in dogs many times successfully, but when the twins came, it had to work. We didn’t know whether the exact anatomy of the human was going to be receptive to a transplant kidney, so we went to the pathology department during a post mortem exam about a week or so before the operation and transplanted a kidney in the anatomy lab. All the way through from the beginning to the end, we wanted to be sure the blood vessels would work well, the ureter would fit into the bladder and so we prepared as well as we could.
Your own career shows the importance very clearly in terms of the collaboration between clinical research and pre-clinical research and the fact that we can work together. I know that you have been a prophet for that ever since. I think a problem that exists in many medical universities and medical schools is to get enough collaboration between the pre-clinical scientists and the clinical scientists.
Joseph E. Murray: For today’s panel we had a breakfast meeting a few days ago and one of the persons in the panel, I won’t mention who, very fine person, said that a physician can never be a scientist. I didn’t say anything, but I don’t know how they define scientist unless it’s somebody who doesn’t work with patients. I hear that all the time and I have been a prophet of clinical investigation because people ask me why did we keep on when there were so many failures. It was the patients who were dying and most of them were young in their early twenties. The families knew that we were experimenting and even though they didn’t expect success, they said, It may not help us but it may help someone in the future. It gave me an indication of the wonderful generosity of human nature.
That is really wonderful. Staying for a moment with pre-clinical and clinical medicine I would ask you something that relates to the Nobel Prize and some discussion which comes out now and then and which was obvious in some of the journeys last year. That is a question of pre-clinical prizes or prizes to basic science vs prizes to clinical science and to clinical medicine. I think that many of us have a feeling that it would be very nice to be able to give more prizes to clinical medicine. Do you think that clinical medicine is sometimes neglected in this respect?
Joseph E. Murray: Yes, I definitely do. I think Pasteur has a wonderful quotation that there is only one science, basic science and clinical, and they are locked together like the trunk of a tree to the branches. All forms of seeking knowledge, and I think that when a person feels that he or she must be in the laboratory to make scientific progress is stultifying their vision. I feel very strongly that we in the clinical side have certain advantages because we see patients, who have problems that need solving, that the bench scientist is never going to see. I feel very strongly that it would be a great loss to society if clinicians were not also research minded.
Thank you very much. I think that is a very nice conclusion of our talk, unless there is something that you feel that I have missed or not remembered or which you would like to add.
Joseph E. Murray: Yes, you asked a question about are there subjects that might have been missed by the Nobel Committee. I feel very strongly that cardiac surgery has developed tremendously in the past 30 or 40 years. It has saved hundreds of thousands of lives and I think that the pioneers in cardiac surgery, mostly surgeons, are physiologically oriented and I have nominated several of them and obviously there are good reasons why they were not selected, but I think that the Nobel Committee should at least search out for clinical investigators whether it’s respiratory, physiology, gastro-intestinal or endrocin – there are many areas that could be recognised.
Thank you. I think with this advice, we conclude this interview. Thank you very much.
Joseph E. Murray: Thank you for the opportunity.
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