In Their Own Words:
I have had the good fortune of training 32 individuals who are leaders all over the country and, in fact, the world in the field of transplantation. And I think next to my family and my success with patients, the most important thing is having been an important influence in those people's lives and careers. And knowing that they'll go forward—as I said earlier, when I got into this, the frontier was entirely unexplored. There's still a big frontier out there and these are the kind of people that are going to explore it.
Dr. A. Benedict Cosimi is Chief Emeritus, Transplantation at the Massachusetts General Hospital (MGH). He was the 32nd
President of ASTS and President of the 2006 World Transplant Congress. Dr. Cosimi trained in transplantation with both Dr. Thomas Starzl at Colorado and Dr. Paul S. Russell at the MGH. He joined the staff of the MGH in 1972 as the Surgical Director of the Transplant Unit, where he established New England’s first liver transplant program in 1983; New England’s first pancreas transplant program in 1986; New England’s first intestine transplant program in 1991; and the world’s first successful tolerance induction program in 1998. Dr. Cosimi has had a special interest in highly selective suppression of transplant immunity, initially using antithymocyte globulin and then monoclonal antibodies. He was the first to demonstrate in 1980 the efficacy of OKT3 monoclonal antibody for treatment of allograft rejection.
Dr. Cosimi: I’m Ben Cosimi. I'm professor of surgery at Harvard Medical School and I've been Chief of Transplantation at the Massachusetts General Hospital now for over 30 years, but I have officially stepped down, so now I'm the Emeritus Chief for the last two years.
Interviewer: How and when did you become interested in transplant surgery? And remember the "when" is a year.
Dr. Cosimi: Well, I had either the luck or the destiny to be a transplant surgeon by being in medical school starting in 1960 where I was at the University of Colorado in Denver. And I'm sure that will ring a few bells for people of what happened at the University of Colorado in the early 1960s. Uh, I went to medical school knowing I wanted to be a surgeon and pretty convinced I wanted to be a neurosurgeon. As I was there in medical school, in the second year, Tom Starzl was hired as Chief of Surgery at the Veteran's Hospital across the street from the University of Colorado and immediately began the transplant program. I still was convinced I wanted to be a neurosurgeon, but I intermittently bumped into Tom Starzl on late night rounds; he was always in the hospital, midnight, 3:00 a.m., and I was a medical student with nothing to do but wander around and I constantly bumped into him and he invited me over to his labs and that's where it all began. So Tom was very influential in my getting into transplantation.
Bill Waddell, who was the Chief of Surgery there, was also involved with early transplants and put me into his laboratory, so I worked at both places.
Over the subsequent years, as many will recall, it wasn't a pleasant time for transplantation. There were many disappointments, many failures, and much criticism so that by the time I left the University of Colorado, now moving to the Mass General for my surgical training, I was pretty much thinking I was going back into neurosurgery. I had worked with Tom on the first liver transplant recipients, seeing sequentially one after another die of bleeding and other complications, and it just seemed that it was too hard for this field to move forward.
At the Mass General, interestingly, I bumped into yet another person, so again it's a matter of being at the right place at the right time, and it was Paul Russell, who was starting the transplant program there. And Paul convinced me along with Jerry Austin, who was by now the Chief of Surgery, that I should go into the lab again and start developing an interest in transplantation. And from there I went to antilymphocyte serum monoclonal antibodies, tolerance, xenotransplantation over the years, and here we are.
So the interesting thing to me was that when I first started, it was just the beginnings of transplantation. The frontier was out there to be explored and it just seemed no matter what direction you turned, there was something to be learned. The interesting thing is today, it's not too different. There are still many things to be learned and that's why we keep attracting, I think, the brightest and the most ambitious and the most productive of the young surgeons into our field.
Interviewer: Let's talk a little bit about the ASTS, your first impressions. You were a charter member, how that worked out, the beginning of the society as you remember it now.
Dr. Cosimi: Well, the ASTS obviously started as a fledgling little group of surgeons and uh, it was I believe the mid-1970s. At that time, the Transplant Society was the society that all of the professors belonged to. Particularly Fred Merkel and a few others decided that we should have an American Society of Transplant Surgeons and decided to start the ASTS. I was one of the charter members, which I think included only about 170 surgeons at that time. And interestingly, coming from Boston where there was a lot of transplantation going on, there was a lot of negativity about the ASTS, so I think amongst those charter members, the only individuals were myself, Tony Monaco, and perhaps Ray Levey; I don’t even remember if he was. But very few thought this society had anywhere to go, because the Transplant Society was satisfying our needs.
The early days of the ASTS were remarkably interesting. We all met at the Drake Hotel in Chicago. There were maybe 15 or 20 papers presented out of maybe 50 abstracts that had been submitted. The attendance was in the hundreds, but everyone knew everyone. There was tremendous collegiality and I think that contributed a lot to the progress.
Contrast that with the World Transplant Congress, which I was fortunate to lead in 2006, where we had 6,500 delegates, over 1,200 presentations, and people from all over the world attending, so there's been a remarkable growth in the field of transplantation. The ASTS was there at the beginning and remains as the leader in our field. I've had the good fortune of being president of the ASTS, again in 2006 where I happened to be chairing the congress as well.
And I think every president has provided major contributions not only to the Society, but to the field of transplantation by utilizing the talents and the strengths of all of the members, the committee structure, to move whatever needs to be moved forward. And one could start citing all the things that have been done by the ASTS, but they are well chronicled in the history of the ASTS that Oscar Salvatierra produced some 15 years ago and keeps being updated.
Interviewer: So as you were in your residency and learning the nuts and bolts of clinical transplantation, where did you think transplantation was going to go then?
Dr. Cosimi: Well, I always thought transplantation had a tremendous future. It wasn't clear to me how it was going to get there, but it just seemed that if it could be done in an individual, it could be done in many individuals. And it had been shown by the time I got into it that it could be done in a few individuals, only a handful of course. When I encountered Paul Russell, transplantation was kind of at its low for that early period. There had been terrible results from heart, liver, lung transplantation and kidney survival was perhaps 50% at one year.
At about that time, in the mid to later 1960s, Sir Peter Medawar and Ray Levey and others had developed this antilymphocyte serum that seemed to be perhaps a major breakthrough. And I think Paul Russell hired me primarily because he considered me a cowboy from Colorado, and therefore I'd be good for harnessing horses and infusing them with lymphocytes and obtaining their sera and I'm convinced to this day that was the major qualification I had. So in fact, he asked me to start producing antilymphocyte serum for human administration while I was still a resident. And I went out and bought a couple of horses, stabled them right in East Boston; at that time, you could keep horses essentially in your house. It wasn't my house, but it was someone I rented from. And I immunized them, bled them, and produced antilymphocyte serum. It was antithymocyte because we were using thymocytes for immunization. The amazing thing was we purified it, we gave it to patients; very little regulation, as long as you didn't cross state lines, it didn't come under federal regulations and so you could give it to patients. So every center that was interested in the field was producing their own for their patients. And it became a standard of care. So immediately, it became evident to me this was the key, that one had to develop some kind of a more specific immunosuppression than what we were using at that time, which was Imuran and prednisone, which were borrowed from cancer therapy. So they're cytotoxic, they're nonspecific, they affect any cell that's metabolizing. It was clear that the future of transplantation required more specific immunosuppression and that's therefore where I devoted my efforts, going from polyclonal antibodies to monoclonal antibodies, and ultimately the tolerance induction, the most specific type of suppression one might develop.
Interviewer: Actually, you did grow up on a ranch, didn't you?
Dr. Cosimi: I did. I grew up in Colorado on a farm, yes.
Interviewer: Let’s talk a little bit about your presidency of the ASTS and the interaction of the ASTS at that time with our colleagues in the government. I know that you spent the subsequent two or three years as our representative to UNOS and gave us reports about the OPTN. I want to go down the road to explore your sentiments about the regulatory aspects of transplantation, particularly in recent years when you had boots on the ground.
Dr. Cosimi: Well, the field of transplantation has always been the most highly regulated and monitored of the specialties, probably because it's the newest field. We're monitored and regulated by now three agencies: JCAHO, UNOS, and CMS. When I became president in 2006 of the ASTS, one of the major problems facing the transplant centers is that the bureaucracy behind the OPTN and UNOS had developed such an extensive requirement for centers returning data points on patients that the centers were bogged down just trying to become compliant with these regulations. There were over 3,000 data points required at that time for every patient being followed that had to be submitted to UNOS and if they weren't submitted, the center became noncompliant and could even be decertified. Very few were, but there was constantly that threat. One of my major goals during that year and subsequent years therefore was to try to bring this under better control.
We were fortunate at the time that Frank Delmonico, my colleague, was president of UNOS and, working together, we were able to cut by about 40% the data requirements that were currently being sent into UNOS. I think that has been one of the major contributions, trying to control this degree of regulation and monitoring that we had, much of which was purely the whim of some committee chair. If someone decided it was important to know if the deceased donor of a kidney transplant had ever chewed gum, that might be listed as something that was required to be sent in. So we went through point by point and our current president, Mike Abecassis, was very, very important in this bringing UNOS and SRTR and the government to accept that we could not continue on this route. And I think we made a major difference there.
The other issue that came up during my presidency was whether we, the ASTS, should be more involved with how organs are allocated, whether we should be involved with things like use of organs from prisoners who had been executed in China. A number of ethical issues arose and we addressed a number of these and felt that some of them were in our purview and some of them belonged on a different stage. And I think again, at the World Transplant Congress in Boston in 2006, I can remember now the Falun Gong protestors out in front of the convention center claiming that we had not fulfilled our responsibilities in preventing the Chinese government from utilizing prisoners' organs. And we did in fact send a number of memos and recommendations and subsequently, not through only our efforts but through the efforts of all of the transplant community, have persuaded them to change their actions as far as the utilization of these organs.
Interviewer: Let's reflect a little bit on the lighter side of professional life. Surely, with the many hundreds, maybe thousands, of transplant operations you've been involved in, there's been a mishap or an occurrence in the operating room that's memorable. Wes Alexander told us about the kidney that got spit out when the patient woke up because of anesthesia error and so on. Anything either in the operating room or in the clinics that stands out?
Dr. Cosimi: Well, one of the things that stands out in my memory is when we first began using monoclonal antibodies, which was in late 1970s, early 1980s, I had come upon the OK series of antibodies, Ortho Kung antibodies, and OKT3 was of particular interest to me. Unfortunately, it couldn't be tested in non-human primates because it doesn't cross react with any except chimpanzees, so we hadn't tested it in non-human primates although we had tested its OKT4 and OKT8 siblings and found them to be nontoxic. So the very first patient that we decided to treat was a young woman who had severe rejection of a kidney allograft. And we brought the antibody up, got the appropriate consents, and told her this had never been done before and we were giving her this preparation. And we kind of were sitting there, myself, Paul Russell who was the administrative chief at that time, Patrick Kung who had actually developed the antibody, and Gideon Goldstein, who was the head of their scientific program. We sat at her bedside and we injected it and chatted with her and everything seemed to be going fine, when all of a sudden the bed starts shaking, she starts shaking, she starts screaming that she was having headaches and we thought sure this was the end, not only of our careers, but probably we'd be going to jail. Fortunately, it all went away and subsequently we defined very carefully and very clearly that there is this cytokine response. But I'm sure I would've lived ten years longer than I'm destined to live if that episode hadn't occurred because I know my heart must've stopped for a period of time.
But it's an example of the kinds of things that progress resulted from that can't happen today. You wouldn't be very easily able to give a drug like that today without multiple regulations preventing it and I think progress has been stymied by this. But it was frightening and we were able to come through it.
Another time, John Whelchel was my first fellow. When I finished my residency training at the Mass General, it was in 1970 and at that time the Vietnam War was still on and I was destined to go to Da Nang. And at that point Nixon declared a stand down or a stand still, whatever it was, and we didn't go, so I got sent to Wilford Hall and met John Whelchel, who was the chief resident in surgery, and convinced him to come back to the Mass General as my first fellow. Well, when we got back there, they were only doing kidney transplants and we were kind of bored, so I decided we'd start doing bone marrow transplants, which seemed pretty simple. And we did a few bone marrow transplants and in fact achieved some long-term successes, but one patient developed severe graft-versus-host disease and was about to die; it was clear that he was terminal and in fact, to this day I have the permission for his postmortem in my office that his mother had already signed because it appeared he was going to die. Well, John and I were sitting there thinking what could we do, and we had all these ATG and ALS preparations that we had been studying in animals. We put them all together into one bottle and infused it into this kid and he had the most violent reaction, like a cytokine reaction, but he lived for another 20 years. The graft-versus-host disease was reversed. And again, John and I were pretty worried, what we had done, but in fact we made progress because we were able to do these kinds of things.
Interviewer: You and I share the good fortune of having married the right person. Talk a little bit about how transplantation has affected your family and personal life, maybe the bad and maybe the good.
Dr. Cosimi: Well, transplantation has always been my life, and it isn't clear to my wife whether it's number one or number two priority versus the family, but it has affected us tremendously. My wife and I first met when I was a fellow in transplantation in 1968 at the Massachusetts General Hospital; she was the head nurse in the emergency ward and I'll never forget our first meeting. I was the triage officer down and a patient came in with laryngeal obstruction from some viral infection and was asphyxiating right in front of me and I called for a scalpel to do an emergency tracheotomy right there in front of the firemen and everyone else and she handed me the scalpel. Without looking, I made my dramatic flourish across the man's neck and saw a small scratch appear because there was no blade on it. So it was rather embarrassing, but we were able to do the tracheotomy and he did survive and I did end up marrying her, but I've never let her forget how she almost destroyed me in front of everyone. We were married in December, and we went on a honeymoon down here to Florida and we got back to the Mass General on New Year's Eve and they were doing a kidney transplant and of course I went in for it.
And when I left, Paul Russell gave me a bottle of champagne and said, “Go home and celebrate with your new wife.” I was home for about two hours when I got a call that the patient was having problems and I had to go back on New Year's Eve. And that was our first New Year's Eve together, with me at the hospital and her at home, drinking the champagne.
Over the years, that's happened many times. She's always reminded me that our children grew up with one parent in the family; they didn’t know who their father was until they reached the age of reason and I was not around much. But we did have a wonderful life, and being in the role of some of the leadership positions in transplantation has allowed me to be invited to a number of very interesting and exotic places and I usually take Pat, my wife, with me and sometimes even take the children with me. So it's been a rewarding and an exciting time for us as well as a difficult time. The bottom line is I wouldn’t change it in retrospect one iota. I think it has worked out well for everyone. I have three wonderful children and five grandchildren, all of whom are perfect as best I can tell. Of course, I'm not biased. As best I can tell, they haven't suffered from growing up in a one-parent family.
Interviewer: Let's give you the reins here. Is there something you want to mention that I have not talked about?
Dr. Cosimi: Well, one of the things that has been most important to me in my career has been the opportunity to train young people and try to form the minds of the leaders of the future, and I think that's one of our most important objectives in addition to giving the best possible care for patients, which is of course our first priority.
Our second has to be to train the physicians of the future, and I think the ASTS has been particularly knowledgeable and responsible in that area. I think John Najarian started the very first fellowship accreditation when he was president, and we became accredited early on and I have had the good fortune of training 32 individuals who are leaders all over the country and, in fact, the world in the field of transplantation. And I think next to my family and my success with patients, the most important thing is having been an important influence in those people's lives and careers. And knowing that they'll go forward—as I said earlier, when I got into this, the frontier was entirely unexplored. There's still a big frontier out there and these are the kind of people that are going to explore it.
Interviewer: Where are we going to be in ten years, 15 years on the clinical side of transplantation? Can you speculate about that?
Dr. Cosimi: Yeah, I'd like to. I think transplantation has been a series of milestones over the past 50 years. We all perhaps identify different ones, but we all kind of come down to the same things. When I first got into transplantation of kidneys, it was even difficult to dialyze patients. There was not adequate access available, and then along came Scribner shunts and then fistulas and that was a big change. And then we got into a few kidney transplants and there was nothing else going on, because the success was so poor, and along came antibodies and calcineurin inhibitors and all of a sudden, the field opens up again. Preservation solutions became a very important thing. So going forward, what are the problems? Well, the problems still are we don't have enough donors and the immunosuppressive modalities are still too non-specific.
So I think in ten years, we'll have probably identified a new donor source. It won't be human, at least it won't be human whole organs. It's either going to be some kind of stem cell technology or xenotransplantation is going to solve the organ donor crisis. Paying for donors, taking prisoners, taking extended criteria donors, is never going to solve the problem. So I think in ten years, we'll have solved that problem with one of these two technologies. The problem then is how are we going to pay for it? If we went to the government today and said next year we could do 50,000 heart transplants because we have 50,000 organs available, we'd break the bank. So that's going to be the next problem to solve, but I have confidence that we will. So I think that's one of the things. The second is, I think, tolerance induction, which we've started to produce clinically, will become more widespread and patients won't be on immunosuppression for the rest of their lives after they receive a transplant. That's going to be a major breakthrough and I think it's going to happen in the next ten years.
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