In their own words:
I think we’re [transplantation] heading down the road toward a better understand of how to achieve tolerance through the T-regulatory system and I think we’ll have more studies like the ones recently published in the New England General from Mass General where patients are not required to take immunosuppression forever. I think we’re getting close to that in the liver, or closer in the liver than we are the kidney. I am very excited about the role that progenitor cells might have in replacement of injured kidney or liver cells. I think that there is a lot of interesting things that are coming down the pike, not the least of which is stem cell transplantation.
G. Melville Williams, MD, was a founding member of the ASTS and served as its 9th President in 1982-83. After medical school at Harvard and general surgical training at Massachusetts General Hospital, Dr. Williams joined the Medical College of Virginia as Director of Surgical Research, being appointed by Dr. David Hume. During that time, early efforts at kidney transplantation as well as active involvement in surgical research led to lifetime interest in transplantation and vascular surgery. Moving to Johns Hopkins as Chief of Transplantation and Vascular Surgery, Dr. Williams took on leadership roles in the Southeastern Organ Procurement Foundation and the United Network for Organ Sharing, serving each organization as President. After retiring from active clinical practice, Dr. Williams has continued with interest in surgical research and teaching both surgical residents and young faculty.
Melville Williams: I’m Mel Williams and I got interested in transplantation surgery in 1963, just as I was completing my residency time at the National Hospital. I was predominantly interested in vascular surgery and when transplants came along, I saw the opportunity to do something on the scientific frontier as well as use the technical skills that I had gained doing vascular surgery with Robert Linton.
So when John Mannick was leaving Richmond, this provided an opportunity for me to go down as his replacement because I knew John and John was two years ahead of me in the residency. So I wrote a letter to Hume and said I was really interested in this as a career and didn’t hear and didn’t hear. And all of a sudden I got a telephone call from Dr. Hume saying he wanted me down in Richmond in two days, that they were quite interested in me and could I please get on an airplane and come on down.
Well not having heard from him, I had arranged to get a special grant to go to Australia for a year to study with Gus Nossal and Sir McFarland Burnett, the Nobel Prize winner, to learn some immunology. So I was in a little bit of a tough spot, but I went down there anyway. And Dr. Hume needed somebody right away to replace John Mannick, so there was a little bit of tension going on here until finally I met with him at 6:00 am before the last day I was there. He said, “Are you still intent to go to Australia?” And I said, “Yeah.” And he said, “Well I don’t know about that. I have never heard of anybody starting a career with a sabbatical.” And I said, “Well it’s a good way to do it because if I go, you’ll have somebody to argue with and I think you need that.” He said, “My God, you go to Australia. But before you go, you come to us and spend a month learning some of the clinical foibles so then you will have a little more pertinence to the stuff you do in Australia.” And so I did.
And it was great to come back to Richmond after this year working in a basic science lab. He put me quickly in charge of the surgical research lab. I worked closely with Jim Wolf and Myron Kaplan at the time and it was really quite a team. H. M. of course had stayed on and he was the main engine in the surgical care of these patients and I learned a tremendous amount from H. M.
Now Dr. Hume had recruited quite a team and my best friend, other than H.M., was Dick Lauer. And Dick had been recruited from Dr. Shumway’s laboratory in Stanford and had established a very real investigative program in heart transplantation in dogs. Dick as a fellow had invented or discovered the technique that was used throughout the world when heart transplants were done in humans. And so he had dogs that were a year on Imuran and prednisone with a donor heart and he would exercise them regularly and people at the NIH were all interested in studying how the heart worked that was not innervated and so on.
The first time I really was brought upright by his work was his plea to take out a heart after we had taken out both kidneys and the heart had stopped, of course before we took out the kidneys, to see if he could resuscitate a human heart and get it going on the bench in a Langendorff preparation. Well we all though, well that’s hopeless because we wouldn’t be operating on this patient; he’s not dead if he can start the heart again. This is kind of stupid. But low and behold, there was the occasion where after about 40 minutes of not breathing, the heart stopped. I took out the kidneys but probably took about half an hour, after which Dick took out the heart, dumped it in some salt water, cold with ice, took it over to the lab and started it up.
After I finished the transplant, it was sort of late at night and I came back to the lab to see what was going on. And I was totally spooked because here was this heart in a Langendorff prep, which is the heart being the pump. There was a little oxygenator and a little CREB solution or something like that as the perfusate and here was this heart illuminated with a gooseneck lamp just whacking away there on the bench in the lab. And I though, “Oh my goodness gracious, this is really something.” You know to see a human heart, out of the body working like this. And in my mind, it really did sort of settle the kind of argument, “Is brain dead really dead?” because this heart was just nothing you know until it was resuscitated. So I could look at it more as a muscle rather than the seat of the soul after that experience.
Now Dick did this several other times and so we realized that the heart had a fair amount of reserve. But Dr. Hume wasn’t satisfied. He said, “Before this goes clinical, we need to make sure that it can support the blood pressure and do a bunch of things. And why don’t you put a heart into a baboon?” Can you imagine out animal review committees now or the human investigation committees seeing a proposal to do what Dr. Lauer called a reverse-Hardy procedure, because Jim Hardy had done a transplant from a Baboon to a human in a heart, so we were always kidding Dick about his reverse-Hardy? And so he did.
And the first baboon we did, the heart was too big and we couldn’t close the sternum. But it started right up and supported the blood pressure as long as we were there to watch it. And Dick did not remember for some reason when I last talked to him which was about three months ago, that he had done a second one. But I remember it vividly because I was the guy responsible for giving immunosuppression in a banana to the baboon which was unsuccessful because the banana was peeled, the banana ingested and the pill spat out. So here was this baboon you know and a human heart, spitting out the pills and being quite happy in his cage for about three-and-a-half days before the heart was rejected. So that kind of settled all arguments.
And then I think certainly not widely known, Christian Barnard was visiting our laboratory and Dick tried to teach him how to do heart transplants in dogs and I don’t think one ever got off the table. And it is a hard operation, because the pulmonary artery is sort of unforgiving.
Well we agreed that we would do a human heart transplant if there was a patient that we could not separate from cardiopulmonary bypass and we had a donor at the same time. Now what are the chances of this? Now I had a chance to go in and visit Lauer in the operating room and would see him sweating away and I’d say, “You need a heart?” you know just sort of kidding him. Well one day we did have a donor, it was sort of 1:00 in the afternoon and I came into the operating room and I said, “Do you need a heart?” And Dick stopped what he was doing and he said, “Are you kidding or are you serious?” I said, “I’m serious. We have a donor, we’re about to take across the hall.” Well he went, “Carry on, guys” and he broke out of the operating room.
This was something that needed Dr. Hume’s touch, so we all met in Dr. Hume’s office, H.M., Dick Lauer, Dr. Hume and myself. The notion was, you know should we go ahead? And H.M. had the donor’s chart with him and there was an ABO mismatch so that by rule as if this were a kidney, you would not do the transplant. I had never thought to check to see whether the heart carried ABO blood groups or whether this was necessary for heart transplantation and so we didn’t know what would happen. And Dr. Hume was along the lines of, “Well I think we ought to go for it because you know that patient that can’t be separated from the heart-lung machine is going to die anyway and this gives him a crack and I think, what have we got to lose?”
And H.M. and I were on the fence and Dr. Hume looked at Lauer and said, “Bud Dick, it’s your call.” And Dick said, “You know, I’d love to do it but the first one has to be done right” and that was just the kind of guy he was, as solid as the day is long. Well Chris Barnard saw how close we were and it was several months later when he did his heart transplant in Johannesburg. So Dick loses credit but in my mind, he has bigger credit.
Dr. Hume is a legend. That man was unbelievable. He would be invited to give these distinguished lectures. He was invited to give the Harvey Lecture, which is a physiology lecture on kidney transplantation. And he said he needed about 50 pages, so how about some data, guys. And he sent H.M. do to this and me off to do that and Jim Wolf to do that and Myron Kaplan to do that and collected all of this stuff. And I remember sitting at his desk, papers everywhere, but then he got them all arranged according to charts and graphs and stuff like that. He picked up his Dictaphone and dictated the paper, including references, from a stack of cards and I think probably he made no more than two or three corrections, unbelievable ability to verbalize complex information.
And he was unbeatable in any debate because if the facts were on your side, he’d beat you with humor. And I think after a while, people kind of resented how much power he had in Richmond and began to call MCV the surgical college of Virginia because he was responsible for the recruitment or physiologists and you name it to the school. It was a real loss to the world when he died in his airplane.
Thomas Peters: Tell us about your own evolution as a kidney transplant surgeon and when and where you began doing kidney transplants routinely?
Melville Williams: Well it all began at MCV where I worked closely with H.M. and H. M. really basically taught me how to do these procedures. And there was one occasion I’ll never forget, I did the 100th transplant at MCV which was from a cadaveric donor. H. M. had one kidney to put in and I had the other one. Dr. Hume was out of town. When I was closing, I noticed that my kidney was all blue and soggy, so I went over across the hall and H. M., you know is your kidney alright and looked at me, “Yeah it looks pink, beautiful, urine…Ureter was peristalsing.” Gosh you know.
So I closed up and later that night the patient had a fever, the platelet count fell out of sight and Dr. Hume came back the next day. “What did you do, Williams?” You know, did you make good connections or what is going on here?” I said, “Dr. Hume, you know I checked everything because the kidney looked good to begin with but then sort of petered out as we were watching it.”
And then it was our custom to do these biopsies at the conclusion of the case and a report came back from the pathologists that the kidney was full or polymorphonuclear leukocytes in the peritubular capillaries. So then Hume said, “Did you wash your hands?” you know because we had never seen anything like this in animals or anything. But then I remembered that in some of the heterograft procedures where there was clearly preformed antibody, you ended up with poly’s in the peritubular capillaries. And so you know I think this is anti-body mediated rejection and boy I was scoffed at, you know. This is a technical issue and so on and so forth.
Well the patient got so sick we had to take the kidney out in two days and by that time the arterioles had thrombus in them and all of that. And to make a long story short, this led to collaboration with Felix Milgram, a good immunologist in Buffalo and we were able to elute antibody from the kidneys and it led to a paper in the New England Journal, which eventually I think established the cross-match which Paul Kurosaki before hand had always advocated.
But we had considerable clinical data, including one case where the first patient that Dr. Hume had done with whole body irradiation had lost that kidney and was in for a second transplant. The cross-match was positive. By this time, Peter Mars had joined our group and was doing these cross-matches. The cross-match was positive but Hume didn’t necessarily believe ti because how can you do 100 transplants before you finally have one that reacted like Williams, it was always “Williams’s kidney”?
So we went ahead and Dr. Hume presided over the case, did the transplant and after about 15 minutes, the kidney turned blue and soggy, just like mine. And I remember today him dividing the renal vein with scissors and then putting a little beaker to catch the blood flowing out of the kidney and he timed it in one minute. And the flow through that kidney was 40cc. So it was pretty well established that something was going wrong.
We put the second kidney from the same cadaver donor into her with a thought that maybe we’d absorbed antibody from the first kidney and that kidney did not hyperacute reject, but never functioned long-term. So that was a real learning experience for me. I became really quite interested in antibodies from then on as mediators of rejection.
Thomas Peters: Let’s shift gears a little bit. You were President of UNOS and President of the ASTS. Can you give us some recollections of the years that you were in leadership in transplantation in America?
Melville Williams: Yes, I think they were great honors for me to be President of these societies. The Presidency of the ASTS came first and is was dismayed having been one of the engineers of the Southeastern Organ Procurement Foundation and organ sharing at our inability to utilize good kidneys, that we were discarding 28% of good cadaver kidneys because we could not find a home for them because of pre-existing immunity chiefly. And it was clear to me that we needed some better system nationally in order to utilize kidneys and this was at the same time that the citizens of the United States were demanding a system for the distribution of these organs.
So in my Presidential address at the ASTS, I appointed a committee. I pointed out the fact that we were wasting organs and this was intolerable. And I appointed a committee under the chairmanship of John McDonald to look into establishing a national system for the utilization of kidneys. On that committee, I remember Oscar Salvatierra was on it, Tom Markiero was on it and John and I was on it.
SEOP had expanded into what they…Into a sort of pseudo-national system, they called it UNOS, but there was no system. It was just if you wanted to see if you could find a home for your kidney, you could deal with Richmond and they might find a home for you, but it wasn’t anything that was established, no priority set or what not. And in SEOP, we had things to the point to where if I had a good kidney and on kidney that was a little bit marginal because of anatomic considerations from a donor, I would never send out the bad kidney. I would always do that myself and give out to the system the better kidney because I’d be embarrassed to show a colleague less than an ideal kidney. And this was just not happening, you know nationally or what not.
And so this committee met several times and I remember very well taking out a pencil and carving up the United States into various regions and saying, “What we want is each region like this to function like a SEOP and see if we can’t get some national organization here.” SO I think we were pretty well primed when all of these things began coming out through the hearings at Congress and so on, to go ahead with something that I though we could run as surgeons rather than have it dictated by people who weren’t surgeons. Now that would prove to be only about half true and Tom Starzl has said that “Probably the creation of UNOS was either the best thing I have ever done or the worst and it remained to be seen.” (Laughs) Which was which?
Thomas Peters: You were the founding President of UNOS?
Melville Williams: During all of these committee meetings and things like this, for some reasons the committee pointed a finder at me and nominated me to be the President, the first President of UNOS, which was quite an honor and was followed by appointing John McDonald who had been on the committee as well to be President. And since he was doing well and we were getting along pretty well with national guidelines and everything, he served a second term as President of UNOS. And Oscar Salvatierra was instrumental in working with government agencies and flying from California to Washington and spending an enormous amount of time and he was also an early President of UNOS.
Thomas Peters: Now what do you see 10 or 15 years down the road? You’re still doing research in transplantation biology and we learned yesterday that your younger colleagues value your presence in the laboratory. What do you see in the future for organ transplantation?
Melville Williams: I think we’re heading down the road toward a better understand of how to achieve tolerance through the T-regulatory system and I think we’ll have more studies like the ones recently published in the New England General from Mass General where patients are not required to take immunosuppression forever. I think we’re getting close to that in the liver, or closer in the liver than we are the kidney. And I am very excited about the role that progenitor cells might have in replacement of injured kidney or liver cells. So I think that there is a lot of interesting things that are coming down the pike, not he least of which is stem cell transplantation.
Thomas Peters: Anybody? Melville is there anything else you’d like to add in closing?
Melville Williams: I think I’m long-winded enough.
Melville Williams: Yeah. One of the interesting clinical things that happened to me and I don’t know why I am the guy that always writes about bad things happening to kidneys and hyperacute rejection and stuff. But I had a kidney that was sent to me, it had been machine-preserved and I sewed it in and boy it looked rotten. And I found a second artery that was small and obviously you know had not been connected to the preservation machine and so I put that one in as well.
And then after the clamps came off, part of the kidney was pink and part of the kidney was blue. But paradoxically the part that was blue and not doing well was the part that had been “preserved” and so we wrote another article that machines can hurt kidneys. And I think that still is a little warning light in my mind because I think we have gone a lot and seen a lot of the value of machine preservation but it’s also a risk if it’s not done correctly. Fred Belzer has offered me thousands of dollars for that picture, but I refused to part with this picture of the half blue and half-pink kidney.
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