"I think that that field has been one of the most progressive fields impacting medicine in the last part of the 20th century. Probably the most progress in terms of what it has done in other areas around it, in cancer and infectious disease, atherosclerosis, the degenerative coronary artery disease, and so forth. A lot of the progress in these fields has come as a result of findings either in the laboratory or in the clinic in transplant recipients."
Joshua Miller, MD, is a founding member of the ASTS and served as its 25th President in 1998-99. Following a residency in general surgery at Yale University, Dr. Miller served at the Walter Reed Army Medical Center Transplant Service, Stanford, and the University of Minnesota, prior to moving to Miami where he worked for 27 years as a leader at the University of Miami multi-organ Transplant Program. His interests continue to include marrow and stem cell research which may lead to tolerance. Dr. Miller moved to the Northwestern University's Feinberg School of Medicine in Chicago in 2006.
Josh Miller: I am Josh Miller and I spent 27 years at the University of Miami as Director and Co-director of the Multi-organ Transplant Program, but now I am at Northwestern in Chicago and I have been there for a year. I got started as a transplant surgeon in 1968 after I had finished my residency at Yale New Haven. Bob Chase who was Chairman of the Department of Surgery at Stanford asked me to come out. I was already in the Berry Plan so I was only going to spend a little over a year there before I went into the service and I did my first kidney transplant in 1968 at Stanford. For me it was a very memorable one, and I still remember the patient’s name. It was a very unique transplant because in 1968 Starzl had just described hyperacute rejection and as luck would have it the first patient that I operated on, I was a member of triumvirate out there, was a Hispanic lady who had had a previous transplant, had a multiparous history. Many, many transfusions and one would say today she had a PRA of 99%.
Rosie Payne, who is one of the most famous pioneering tissue typers at Stanford, said that she was untransplantable because hyperacute rejection had been described already as an anti-body reaction against the vessels of the graft, but we had some hints from Starzl that this might be preventable and so we anti-coagulated that patient and at the time we were using mg/kg rather then units and it was 3 mg/kg of heparin. That lady definitely had a positive cross match against cadaver organ donor, and we transplanted her fully heparinized and kept her fully heparinized for a month. Everybody had their stick at that time and one of ours was that we would feed a little polyethylene catheter through the common iliac vessel into the internal iliac, the hypogastric artery and through the anastomosis, it was an end to end anastomosis, with the internal iliac. That heparinized catheter was kept in for several weeks. That was with every patient. We would feed Solu-Medrol into the catheter and what ever we thought might help prolong the life of the transplant.
Well it went very well. Her creatinine came down to 1.4 and did not budge. Unfortunately, the wound budged. About two weeks later, we had to re-operate on the patient because she had a massive hematoma, kept fully heparinized at 3 mg/kg. A week later, we had to re-operate on her with another massive hematoma. A week later, we had to re-operate on her with another massive hematoma, creatinine still at 1.4, and at that point, she developed a mitotic aneurysm in her transplant. We oversewed the aneurysm and re-operated on her a week later. Finally, we had to take the transplant out. She actually survived, went back on dialysis. A very heroic lady. But, when we took the kidney out, it was pristine. We were treating her with azathioprine and prednisone only, again, fully heparinized until the time we took the kidney out and the creatinine was 1.4 when we removed it.
So, we had a way of preventing allograft rejection at the hyperacute level, but I guess we had to go back to the drawing boards. The ? went back to get another implant perhaps. I never found out.
Arthur Matas: 1968 was obviously the beginning of transplant. What do you remember about those early days?
Josh Miller: Well, I remember fighting a lot of battles that are still being fought. It is interesting because at that time, nobody wanted to do dialysis and I ran the dialysis unit at Stanford. We had the Kiel boards, they were washboard type dialysis. These corrugated things that we put the cellophane layers on and I was the director of the dialysis unit. The nephrologists were very, very ariadite people, but they were very interested in micropuncture work in the Rad(?) and very disinterested in taking care of dialysis patients who were only on dialysis so that they could get a kidney transplant. So, they are few and far between in the way of nephrologists that were interested at that time in transplantation. So we had to do the whole deal and it was that way I think around the country. So, that is one of my earliest memories of how things were.
The next memory I have was actually with Minnesota ALG. I think that is typical of what went on in those days because there were no controlled trials that were being done. There were leaps of progress, but it was because of the willpower and the drive of giants in the field like John Najarian and Tom Starzl who introduced therapy and did not have a controlled trial because it would have been considered unethical, at least in the eyes of those who were introducing the therapy, and so Minnesota ALG was a typical agent that that was happening with and John had just moved in 1967 to Minnesota from California and very rapidly thereafter came up with an anti-lymphocyte globulin. Tom Starzl had actually introduced it clinically and was injecting patients with an anti-lymphocyte globulin that was made in rabbits subcutaneously intramuscularly. You got these tremendous sterile abscesses. Patients were really very, very uncomfortable during that period with fevers and inflammation, but it did prolong graft survival and prevented acute rejection.
Polyclonal anti-lymphocyte globulin by the way that is such an old agent it was introduced actually in immunology back in 1898 by Metchnikoff and Tony Monaco had done a lot of work and Sir Peter Medawar in England, Tony Monaco in Boston, on using it to prolong skin allograft rejections in mice. As I said, introduced clinically by Starzl, but John was able to give this stuff intravenously. It became much more purified especially when Dick Condy joined that team in 1971 or 1972. There was a very interesting side light to ALG that might be, I think it ought to be documented, and I wish John were here to do it at this point and he might eventually. You might want to interview him about it, but there were two centers that were used to evaluate ALGs that were being made around the world.
One was in Holland, it was run by Hans Boller an early transplant immunologist and the other was at Bethesda Naval in Bethesda here in Maryland and that was run by Kencell and there were primates that we were putting skin grafts on and testing various preparations of ALG that were being made. There was one being made in Vanderbilt, another in Virginia and several others. One was Tom Starzls and being made by different lymphocyte preparations, either thymus or spleen or lymph nodes and in horses or in rabbits primarily.
Well Minnesota ALG did prolong skin allograft rejection, prolonged the acceptance of skin allografts in primates, but it did not have much of cytotoxicity titer. One thought that the way that stuff worked was with cytotoxicity and lympholysis. So unbeknownst to John there was a another guy in Minnesota who decided he was really going to rev up Minnesota ALG and immunized horses to the lymphocyte cultures that they had obtained from Roswell Park after Moore had raised these lymphocyte cultures for many years. That was what they used as their immunization substance. He immunized horses with Freund’s adjuvant and that really revved up the lymphocyte toxicity. Well, everybody was interested especially myself, but many others in using Minnesota ALG and it was sent around the world. People were writing John and imploring letters to please send them and so it went around the world and that revved up ALG.
Unfortunately, it had not been quality controlled and people were experiencing thromboses, strokes, cephalic vein and renal artery thrombosis. I was at Walter Reed at the time and we used a product on one of the first transplants that we did there in 1970 and the patient while we were making rounds had stopped making urine. We could not believe it. We thought it was ATM. By the time we got the patient back to the OR the renal artery had completely thrombosed. The product was eventually withdrawn and the horses were immunized as they had been before, but that thrombosis was a preceding event to many other types of complications that we have seen today with various monoclonals, etc, producing unexpected events. So Minnesota ALG was a great product over the years and people who used it including myself would swear by it.
One interesting side light again of Minnesota ALG was that the FDA finally said John you have got to do a controlled trial.
I do not know, but that some people might even remember this in the current day, Dick Condy, who really quality controlled the product and made it a wonderful product came up with a controlled of human immunoglobulin in a double bind study in about 10 patients were done. They either got ALG or IV IG, human immunoglobulin. Surprisingly, there was prolongation, there appeared to be, with the use of human IG, human immunoglobulin, and of course we see that today. We still do not know the mechanism faction of IV IG, but it does have allograft prolonging effects, it is an immunosuppressant in many other respects.
So a lot of the early work with Minnesota ALG seems to have been repeated as we get into more controlled environments today. Anyway, that was one of my early experiences and of course things happened later on with Minnesota ALG that, it is too bad it was taken off the market because it was a wonderful product. I think Thymo today is probably comparable to it.
Arthur Matas: What do you remember about the beginning of the ASTS in the first few years of the ASTS?
Josh Miller: Well, I was there at the first several meetings. I was at the ASTS inaugural meetings in Chicago in the Drake Hotel and it was a much more free willing group and there were only a few abstracts on the program. We all were vying to get out abstracts in and presented, but there was a lot more give and take. It would be someone would present the paper and then there would be probably a bit longer discussion than the paper actually took. We all knew each other. It was a club really because it was so small and the people who were there were really I felt not only my colleagues, but people that I had a tremendous respect for and had done such pioneering work. It was a wonderful time because of that. The Drake Hotel we outgrew over a period of many years, but those early meetings were very stimulating. We would go back and try to reproduce things that somebody else had or could not reproduce and then come back the next year and be screaming at each other.
Arthur Matas: What about you as a surgeon, are there any stories or memorable moments, funny or horror stories?
Josh Miller: I am going to go back to tell you a story about the Minnesota ALG. When I came to Minnesota, I was there for seven years between 1971 and 1978 after I got out of the service were we started the Army organ transplant program at Walter Reed. I left the Army in the end of 1971 and came back to Minneapolis to work at the Minneapolis VA Hospital. The VA system did not have many transplant programs, so I actually went to the regional VA to try to drum up some business and I was done in Iowa in December of 1971, and I got a call from someone who has a lot of memories of this, Les Olson, who was in charge of the organ donor program at Minnesota telling me that he had a transplant kidney that was a perfect kidney for one of our patients at the VA and here I was at Iowa City in the middle of a blinding snow storm. It took me about 48 hours to get back by plane. The kidney was 72 hours old when I put it in. It was on the Minnesota Pulsatile Preservation machine and it functioned immediately. We gave the patient ALG for 10 days or two weeks and about two weeks later he was readmitted with fevers.
Now this was 1971, people knew about cytomegalovirus, but they could not really diagnosis with anything serological, any virological assays, but we knew this patient has cytomegalovirus. That was the other interesting thing about Minnesota who spread so many transplant surgeons around the world during the era of the John Najarian’s training, because if you learned to work with Minnesota ALG, that was a very potent immunosuppressive. You learned to see almost every immunosuppressive complication there was in the book, but you learned how to treat them.
Here was Lavern Coreman, my first kidney transplant in Minnesota who was spiking fevers to 105 and 106 every day. I would come in to see him and he would be chilling and shaking, 105 and 106, and I said Lavern after two or three weeks of this, I do not know what I am going to do with you. He said, “don’t worry doc, I am going to get better.” And he did. In a couple of weeks, we had totally stopped immunosuppression and his fevers went away and his kidney was fine. I do not know if that is humerous or not, but it was a very interesting experience on the will of patients that get themselves better. I think that is what we rely on today too.
Arthur Matas: In those early days, could you have imagined how transplantation would have evolved to where it is at today?
Josh Miller: You know, I almost regret that transplantation became a clinical entity. I got into this field as a medical student. Presented a first paper on immunological unresponsiveness in 1962 when I was a first-year resident. I had done the work as a medical student at Albert Einstein on picro chloride as a haptene introducing it into the mesenteric vein because Merrill Chase had fed this haptene to guinea pigs and could reproduce unresponsiveness through the oral route and then we bypassed the gut. This was a fascinating area to me and all of a sudden in the 60’s it became a clinical entity, and I said if I am going to do any investigational work in this field I am going to have to get involved clinically and it was very hard because there were so many problems, so many immunosuppressive problems, and we did not have the antibiotics and we did not have the anti-virals and, of course, we did not have the potent immunosuppressant that we have today. But I cannot say that I regret it. I have had a very, very interesting and fruitful career.
Arthur Matas: What about advancements in transplantation were you thought the ASTS played a role? In your perspective over the years, were do you see ASTS really help advance transplantation?
Josh Miller: Well, I think we have to take the credit and several of the pioneers are still, thank goodness, amongst us Oscar Salvietierra. Unfortunately, Rob Corey is not, who helped with the organ transplant act. I think having an organization at the national level was able to impact legislative progress. If we did not have that which was one of the reasons actually for the formation of the ASTS, it was not only to advance the science, but to have a voice in how the government might be able to help us rather than taking a passive view. That, plus the brain dead laws, plus other legislative acceptance of organ transplantation. I think that has been a major area where the ASTS has been of great value. I would say the main force in transplantation has been the ASTS because of that and still is.
Arthur Matas: How would you say transplantation and being a transplant surgeon has impacted your life?
Josh Miller: It has been my life. I have devoted my career to organ transplantation. As a matter of fact, I did other surgery, but it was on transplant recipients. So, I would have to say that my career was organ transplant surgery and transplantation immunobiology.
Arthur Matas: How is being a transplant surgeon and transplantation impacted your life?
Josh Miller: Transplantation has really impacted my life because it has been my life. I did surgery; I did it on transplant recipients, primarily. General surgery, a lot of it was required in transplant recipients when they got surgical complications. So, I considered myself a pretty good surgeon, but it was on transplant recipients. As I mentioned before, I went into transplantation because it was a field that I was extremely interested in research in the immunobiology of allograft acceptance, rejection, and tolerance and I still am. I might be considered an old timer, but I fortunately I am still active. So, I think that that field has been one of the most progressive fields impacting medicine in the last part of the 20th century. Probably the most progress in terms of what it has done in other areas around it, in cancer and infectious disease, atherosclerosis, the degenerative coronary artery disease, and so forth. A lot of the progress in these fields has come as a result of findings either in the laboratory or in the clinic in transplant recipients.
Arthur Matas: Looking forward, what new developments would you like to see in transplantation and were would you like to see the ASTS play a roll in facilitating most of all?
Josh Miller: Well, we have always been involved in the development of new immunosuppressive agents. ASTS has always been involved in this area, since Joe Murray who was the father of transplantation and Nobel Prize winner and that era in 1961 first reported introduced azathioprine, earlier used in a rabbit, with Schwartz and Danashik, but I think tolerance is where I have always been interested. We are going to get there, but it has been so elusive, it is like Norm Shumway used to say of things that “tolerance is the future of transplantation and always will be.” I do not think that is going to be the case. I think eventually we are going to get to tolerance and it has been my holy grail over the years to get there and that is why I am still in the field. Because I am actually conducting an NIH trial now to induce tolerance with donors hematopoietic stem cells. I think evolution of that type of therapy is going to come to a wonderful step in the next several years. It has been started in Boston and in Stanford. There are some very good ariadite groups that have the immunobiologists and the clinicians to be able to accomplish this.
Arthur Matas: Do you have more ALG stories?
Josh Miller: Well, I have a lot of ALG stories. Do you want me to tell one more? Anybody here? So, I came back to Minnesota from the Army and I had a patient, Hollis Burg, who was on his second transplant because he had a stroke after his first one from that product that was revved up and he lost the kidney. He was a functional patient. He walked with a limp and he had a mild dysphagia. So we put a second cadaver kidney in him and we felt that horse ALG was not going to be the thing because even though he had gotten a first course of ALG we did not want him hypersensitized to ALG, so Dick Condy had another product that was made in the goat and since the two species are not too related as far as you know globulins are concerned, we used it when horse ALG had been used the first time. In the middle of an infusion, Hollis looked at me and said, “doc, I can’t breathe! I can’t breathe”! So we stopped it and he felt better, but I was a very critical scientist at the time and I felt we needed to have postulates fulfilled. So, the next day, we gave Hollis another course of ALG and about 15 minutes into the thing he said, “doc, I can’t breathe,” and we stopped it, but it was enough to prevent rejection. He left the hospital with a good functioning kidney and those are the things that actually happen many times over with many ALG products. As a matter of fact, I think I have seen it happen with Adgan produced by Upjohn. There were, you know, in the early 90’s this major problem with the FDA and the University of Minnesota. It was a horrible time because the product was taken off the market and I think a lot of unjustifiable things happened as that I think history will bear out and I wrote John Najarian a letter at the time because he was being beset upon by people who were new, the President of the University, board of regions, new Dean and I just wrote a couple of lines and said John please turn to Exodus chapter 1, verse 7 and the sentence read “And a new King arose over Egypt that did not remember Joseph”. And that has happened over and over again in academia. That is the way the world goes.
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