Dr. Pruett: We are here today with Dr. David Sutherland, emeritus professor of surgery at the University of Minnesota and an old mentor of mine. Dr. Sutherland went to college in Augustana and medical school at the University of Minnesota, training briefly at West Virginia, but he’s been at the University of Minnesota since, where he did his surgical residency, transplant training, and PhD over the course of the 60s and 70s.
He is one of the founders of pancreas and islet transplantation. He was the 17th president of ASTS and a Medawar Award winner. We are happy that he could share with us some of his thoughts.
Dr. Sutherland, thank you very much. How did you get into transplant, in particular pancreas transplantation?
Dr. Sutherland: Transplantation in general, I became interested in when I was a medical student. I was working in the laboratory of an immunologist, Dr. Robert Good, who was the discoverer of the role of the thymus in the development of immunity. And then I was on the surgical service of Dr. Richard Lillehei, one of the legendary surgeons here on the faculty. He got me interested in surgery. I thought: “Well, transplantation is just beginning.” They already had done some kidney transplants here and elsewhere around the world, and this is a developing field that I would like to be in. So my long-term goal was to do that.
As you mention, I was at West Virginia for two years of surgical training there, then I went into the Army and then I went to Vietnam. On the way to Vietnam I stopped at Minnesota to meet with Dr. John Najarian; that was in 1969. He had been here about two years. And he was an unbelievable leader. And so we talked and he said, “Well, you would be welcome back here when you get back from Vietnam.” So I came to Minnesota.
And meanwhile, Dr. Lillehei continued to do pancreas transplant. He did the first one in 1960. He and Bill Kelly did the first one in 1966 after I graduated from medical school. And he was still doing a few without really good results, and Dr. Najarian and I talked about it and we had the idea that we could do islet transplants. There already was in the department of anatomy here a group that had developed islet isolation technique. We thought we could adapt that to humans; they were doing animal models.
So when as a resident, I went into the laboratory, that’s actually what I pursued, while at the same time doing pancreas transplants in the animal models. We were in rats, dogs, pigs, everything. We started an islet transplant program where we were able to isolate islets from the human pancreas and we did a few transplants, but none of the patients became insulin independent. That was really disappointing.
And I joined the faculty in 1976. We continued to do islet transplants for another two years, and we are still doing them, with Doctor Bernhard Hering.
But we developed a technique of islet auto transplants. In 1977, we did our first islet auto transplant in a woman with small duct, painful chronic pancreatitis. Actually, we injected the islets into the portal vein, and lo and behold she was insulin independent from that time on for the rest of her life. It was sort of beginner’s luck to have such a successful case. We always had that to look at.
But still our islet allografts were not functioning. We knew we could make good islets, but islet allografts were not tolerated as well then as they are now.
So we had the idea we should go back to do pancreas transplants together. Meanwhile I had been working in the laboratory and we developed techniques. And one of the techniques that actually worked quite well was open duct graft. We had actually picked up on the technique that Max Dubernard in Lyon had developed injecting the pancreatic duct with neoprene.
So we did a series of experiments in dogs using silicone rubber instead of neoprene, and as a control we did open duct grafts. And we found that the dogs with the open duct graft actually did better than the neoprene or the silicone injected dogs. So that was the technique that we first used when we resumed doing pancreas transplants in 1978.
And the first case, a pancreas after kidney transplant, functioned for 17 years until the patient was thrown off a horse and died. So we always had that case in front of us, long term. And even though we had failures, we knew we could succeed. As we did pancreas transplants, every year we made some improvements.
We were able to diagnose rejection early by adapting a technique that Hans Sollinger had developed in Wisconsin of doing bladder drainage. We could measure urine amylase as a marker of rejection. We found that that a decrease in urine amylase preceded development of hyperglycemia, and if we treated for rejection as a rejection episode, we could reverse that trend and maintain islet function.
Dr. Pruett: There have been many technical changes in pancreas transplantation from 1978 to present, some of which have been vascular in terms of reconstruction of the vessels with Y-grafts, some of which has been venous in terms of drainage and systemic or proximal or distal or even into the portal system. Some of it has been immunologic with the change in drugs, some of it has been, as you mentioned, the duct drainage. Can you put it in sort of an order? Because our results today are so spectacularly different than they were when you first started.
What do you think were the steps which moved us from poor to good functional results?
Sutherland: Well certainly the development of immunosuppressive drugs, calcineurin inhibitors, cyclosporine in the late 1970’s, tacrolimus in the early ’90s, have contributed to the improvement you see in all organs. The other drug that was developed was valganciclovir to prevent CMV infection, and that allows you to give adequate immunosuppression.
I think the techniques are interesting. Portal drainage has become popular and the metabolic effect is more physiological. If you compare it to the ones that have systemic venous drainage, it doesn’t really make much of a difference. And, enteric drainage is used now as a primary drainage procedure. The segmental grafts are not done much, except when doing a living donor. And we did a series of living donors at Minnesota. We’ve done well over a hundred, but it’s also being used in countries where deceased donors are not acceptable, like Korea.
And I think that also preservation has become better using the UW solution (University of Wisconsin) developed by Fred Belzer, really a long time ago but preservation times tend to be a little shorter than they used to be. So the technical failure rate is less. In fact, what do you think the technical failure rate is now today?
Dr. Pruett: It’s certainly much less than it was when I was training.
Dr. Sutherland: Right, because everybody has learned the techniques.
Dr. Pruett: I think it’s amazing the way that it has evolved. Now the expectations are very, very high that the pancreases will work. The question for the future is: Where do you foresee biologic treatment, either islets or the whole pancreas, fitting into the treatment of diabetes as we keep pushing forward? Pancreas transplantation seemed to hit a peak ten years ago and has been gradually declining in frequency since, and I would like to know your thoughts on that.
Dr. Sutherland: Actually in the early, I would say the early 2000’s, there was an article comparing the survival of pancreas transplant patients to those that remain on insulin, and that article seemed to show there was a lower survival rate of the pancreas transplant recipients and patients undergoing diabetes. And that article had an impact to decrease referrals for pancreas transplantation. On the other hand, we were able to show with Rainer Gruessner that that actually wasn’t the case and that was published also as well.
But, that’s quite a few years ago, and so now to explain the lower interest in pancreas transplantation I think it still is expected that islet transplantation will be a simpler procedure for the patients. Unfortunately, it is not as widely applied as I think it should be. Islet transplantation has developed to the point where insulin independence does occur in most of the recipients. As we’ve shown here with Doctor Bernhard Hering, even with a single donor you can have insulin independence.
But I think the day will come where the survival rate of islet transplants will be such that you’ll see a resurgence of it. But it’s logistically difficult now with getting the human pancreases, and there are groups working on islet xenografts with really quite remarkable success in the pig to diabetic monkey animal model. I think that this is something that will be developed; all of it will be applied widely. But it’s still sort of a mystery as to why the pancreas transplants have decreased the way it did. But diabetic management may be better today too, with people working on the insulin pumps.
Dr. Pruett: You certainly trained a huge number of folks who do pancreas transplant around the world. Every time I go anywhere, I always get large numbers of people who come up to make sure that they are recognized and remembered to you. What do you think of the legacy at the University of Minnesota from Dr. Najarian and yourself in terms of the role of training of transplant surgeons and innovation and particularly in the light of pancreas stuff?
Dr. Sutherland: Yes, the program here, we did large volume for many years and we had fellows come from all over the world who actually did training here. First we had the local or US based group, but many of them have come from other countries. You know we had fellows like Jacques Pirenne from Belgium, and others from Mexico, from Brazil, from Asia. And, I think that has helped spread pancreas transplant around the world.
Dr. Pruett: Diseases are pretty common but mixing cultures is often times not so. Do you have any thoughts on the mixing of culture with transplantation?
Dr. Sutherland: Well I will say that because in some of the countries and particularly Asia the deceased donors were not being used because of the cultural differences, we gave them an option with the living donor of not having to do that. So certainly there is a lot of cultural differences that we see.
Dr. Pruett: Did it work out when we brought the folks from different cultures here that they got along well with the upper Midwest people, or were there any issues?
Dr. Sutherland: I think so, they actually liked the culture here and they wanted to take part of it back.
Dr. Pruett: It’s sometimes hard.
Dr. Sutherland: It’s not easy and not everybody was able to establish a program, but the majority of them did, actually, and we did really train people from all over. Meanwhile, pancreas transplant programs sprung up around the world, Stockholm, Munich Germany, and then the major program in Lyons, France, which was developed by Max Dubernard. Many countries now have pancreas transplants programs, but I’m not sure how many are credited as growing from ours.
Dr. Pruett: I think the issues which have always been here, which is what we talked about a bit earlier, was the idea of finding ways to improve outcomes and to address the major barriers which are coming forward and still exist in diabetes, and in particular with biologic treatment for diabetes, whether it’s through simple beta cells or whole organs. The challenges of research as we go forward today are real. Can you describe briefly for us your PhD project that you did and then how you would foresee redoing it today for the next decade?
Dr. Sutherland: I did my PhD thesis actually on islet transplantation. I had the fortunate experience of having a very active laboratory. So we did islet transplants in all animal models from rats to dogs to pigs, and we studied the islet mass that it would take to cure diabetes. We could do islets counts under the microscope. We could do insulin content which was proportional to islet yield; we could show that we actually could get fairly good engraftment with islets even up to 50% or so, and we were able to use, in some of the models, single donors to achieve insulin independence. That was in my thesis which nobody reads [laughs] but it’s still in the library.
And we studied secondary complications. We could show a diabetic rat after a few months of being diabetic, after inducing diabetes, develops lesions of the kidney, diabetic nephropathy. We could show that we could actually reverse that, and we also showed that in humans with diabetic neuropathy. The eyes were a little harder; you might stabilize them but they didn’t seem to reverse.
I think there’s ample evidence if you can get euglycemia, true euglycemia, you could actually have a profound impact on secondary complications even when they are pre-existing.
Dr. Pruett: If you were to advise somebody today for a PhD thesis on islets or pancreas transplants, what would you advise them to pursue?
Dr. Sutherland: I would say that, in general, I think they could go back to the premise that we want to able to lengthen preservation time so it’s easier logistically, and there are still probably some immunological barriers to improve on. So they could pursue allografts and then xenografts. I think that xenografts would solve any shortage problem; there is a pig for everybody.
Dr. Pruett: So the ASTS has been a big part of your life in terms of a society for colleagues and trainees. When you were president back in 1991, would you have any recollection of issues that you were confronting then which are manifesting now?
Dr. Sutherland: One of the things I remember about the ASTS—I was actually there at the first meeting in 1973. And what were amazing were the discussions of the papers. This continued through all the years; the give and take between the transplant surgeons was remarkable, and I think that carried over universally. For example, the development of the United Network for Organ Sharing: actually the founding individuals were actually members of the ASTS and that is still active today. We still share organs and I think the ASTS has a large role in that.
When I was president, it actually was at a time when results where improving, just like—I forget when you were a fellow, that was in 19...
Dr. Pruett: I forget too, ’87 I think.
Dr. Sutherland: ’87, that was at a time when, as you said, the results were not as good, there were more technical failures, but by the early 90’s a lot of that was resolved.
Dr. Pruett: The Society as it’s moving forward has been very engaged in advocacy with the government. As you look at the way that we interface today with oversight, with UNOS, with the SRTR, what would be your counsel in terms of trying to make the world a better place for the patients who come through?
Dr. Sutherland: Well the reimbursement policies are one thing that’s not so friendly, but at least Medicare does cover kidney transplants, and that helps. But it stops drug coverage after three years when you have a successful kidney transplantation, and one of the things I would advocate for is to continue the medication coverage if you can. It should be able to be done.
Dr. Pruett: Are there any other points that you would like to put as a recollection for the Chimera Chronicles?
Dr. Sutherland: You had asked me before what were humorous happenings I might have encountered. One of the ones I remember was actually when I used to go out on donor runs, we were on a donor run to obtain a pancreas for transplantation for islets, and I remember that the pilots thought we said eyelids [laughs] and they were commenting on the fact that these surgeons would transplant anything.
I think there is a need to get back to actually improving the results. I do think in beta cell replacement therapy the islets will ultimately replace pancreas transplantation because it is simpler for the patients, even though we’ve got the surgical techniques down well. I do think that xenografts will solve shortage problems so you can transplant nearly anybody.
We need to develop tolerance, which has been worked on since Medawar. We’ve got a ways to go with that, so I’m not seeing that happening right away, but I think that it will happen.
Dr. Pruett: So one of the problems that we have today has been organ availability for people, and although it’s not exactly in the pancreas world, you’ve had a relatively unique experience with live donations. Can you tell us a little bit about your experience?
Sutherland: Well fortunately, my wife Vanessa had had previous transplants from her family that she had rejected or lost for having disease reoccur. And she was on dialysis, and I was actually fortunate to be a match. She had no antibodies to me, and so I was able to be a donor and that gave me perspective from being a donor.
It was laparoscopic left nephrectomy. I just remember the thrill of waking up and finding out how well Vanessa felt just in a day, recovering from symptomatic uremia. I think I was able to translate this when I would see prospective donors, to tell them what a thrill it was to actually do this and encourage it. But Vanessa did well for several years, and she finally did lose my kidney. She got another one from a deceased donor which is still functioning, fortunately. But she’s been a big supporter of everything I try to do in transplantation in the last 20 years.
Dr. Pruett: So what do you think are the hurdles? Having walked through the live donor role, what are your thoughts on what do we as a profession need to talk to people about, from your perspective having been a donor?
Dr. Sutherland: I would say we should emphasize the emotional high it gives to be a donor and also emphasize that it’s very difficult to get organs for transplantation from deceased donors. There is a limited supply. And if one could be a donor, one should just do it. It will be well worth their while. And now with the laparoscopic technique, you know, it’s much easier. Not necessarily easier for the surgeon, but it’s easier on the donor.
But we have to encourage this donation. I would share my experience, as I counseled donors when I was actually in practice and seeing them. Not that every transplant surgeon is going to be a donor; I’m probably not the only one. But if the opportunity arises for a loved one, then one should do it.
Dr. Pruett: Well Dr. Sutherland thank you so much for your thoughts and your time.