"There are not a lot of things I can take credit for, but I take credit for having Belzer step back in the laboratory and develop UW solution. And the reason was, when I started the pancreas transplant program, the preservation time for a pancreas at that time, this Collins solution, was 4 to 6 hours. It was like a heart transplant nowadays. And Belzer always said to me: ‘You know Hans, I developed the kidney preservation machine so I can go to bed, get up in the morning, and do my kidney transplant electively.’ And now because he helped me with the pancreas transplants, he had to get up at night, and after about 15 he was cranky enough, and I said: ‘Doctor Belzer, you just have to develop a better solution for pancreas preservation.’”
Hans W. Sollinger, MD, PhD, is the Folkert Belzer Professor of Surgery at the University of Wisconsin–Madison. After receiving his MD and PhD in Munich, Germany, he did his residency and fellowship in immunology research at the University of Wisconsin Hospital and Clinics. He was president of ASTS 1996-1997 and has also been president of the International Society of Organ Sharing and treasurer of The Transplantation Society. He also serves on the editorial board of several academic journals, including Transplantation and the Journal of the American College of Surgeons.
Dr. Odorico: I’m Jon Odorico, Professor of Surgery and Transplantation at the University of Wisconsin in Madison, and here with me today is the Folkert Belzer Professor of Surgery, Hans Sollinger.
Hans, you were in the field very early, even before there was a specialty called transplantation. What made you go into transplantation, and who influenced you in that decision?
Dr. Sollinger: Jon, this is actually a very easy answer for me because it was a very defining moment. I was a first-year medical student at the University of Munich in 1967, that was the end of 1967. Walter Land gave a fascinating lecture about transplantation to us as medical students. Four weeks later I worked in his laboratory and a short while afterwards in the spring of 1968, they asked me to bring a vial with anti-lymphocyte-globulin to the airport and this was the anti-lymphocyte-globulin which reversed the rejection episode of Doctor Barnard’s second heart transplant patient which was performed in Cape Town in 1968.
Dr. Odorico: What a pivotal moment, what an influential moment. So what after that brought you to Wisconsin? Why did you come to Wisconsin?
Dr. Sollinger: Again, the laboratory was a very, very interesting place at that time because the chief of the laboratory, Professor Walter Brendel, was just a fascinating man who wanted to bring transplantation interaction, worldwide interaction among transplantation forward. So he organized a ski symposium in the Austrian Alps every January and he invited the best people like Sir Peter Medawar, Roy Calne, Tom Starzl, and others, so basic scientists and surgeons. Because I was a pretty good skier, my task was to make sure they get ski lessons and they make it safely down the hill. I do remember very well that Jean Medawar, Peter Medawar’s wife, was my ski student for several seasons because Sir Peter was disabled from his stroke, so I had to make sure that she was safe on the mountain.
Dr. Odorico: Great story. So, you met Doctor Belzer there?
Dr. Sollinger: No, Doctor Belzer did not participate in these meetings but Fritz Bach did, you might remember Fritz Bach was known for discovering the mixed leukocyte culture. And he invited me to come to Madison to finish my PhD. So I arrived in January of 1975 in Madison, worked for a year and half to finish my PhD but traveled over to the hospital quite a bit to attend transplant conference, and that’s where I met Doctor Belzer. And also at that time, I met a young lady who was born in the United States and didn’t want to move back to Germany, so I had to somehow manage to get a residency in the United States. Doctor Belzer gave me a residency in Madison and that was the beginning of a 20-year relationship.
Dr. Odorico: The rest is history, and the woman you met in Madison is your wife now, is that right?
Dr. Sollinger: Is still my wife, it’s 42 years now.
Dr. Odorico: Great. You worked with Doctor Belzer for many years, so tell us some of your most fond or poignant moments with him and interactions with him. Or some funny stories as well.
Dr. Sollinger: This was a wonderful 20-year relationship. I think right from the beginning he wanted to make me a transplant surgeon. After his mode, which means not just a clinical transplant surgeon but also to become an innovator. So he constantly gave me ideas, and we were always discussing things. I have to say it was a little bit different from today because after the clinical work was done, we met in his office, Saturdays, Sundays, it didn’t matter. And then we talked science, we talked preservation, we talked immunology, we talked about physics, hemodynamics, it didn’t matter. But we always had something to discuss. And it was his mind which never stopped. I think he never stopped thinking and having new ideas.
Dr. Odorico: And those were real formative moments, obviously.
Dr. Sollinger: Absolutely. I had three great mentors, Walter Brendel from Munich, Fritz Bach as far as basic science is concerned, and Fred Belzer. I would say Fred Belzer was by far the most important of the three. They were all great but Belzer really was my mentor.
Dr. Odorico: When you were working with Doctor Belzer clinically, you were in the early days of organ preservation research. Tell us about your experiences with the early days of UW solution and organ preservation.
Dr. Sollinger: You know, Jon, there are not a lot of things I can take credit for, but I take credit for having Belzer step back in the laboratory and develop UW solution. And the reason was, when I started the pancreas transplant program, the preservation time for a pancreas at that time, this Collins solution, was 4 to 6 hours. It was like a heart transplant nowadays. And Belzer always said to me: “You know Hans, I developed the kidney preservation machine so I can go to bed, get up in the morning, and do my kidney transplant electively.” And now because he helped me with the pancreas transplants, he had to get up at night, and after about 15 he was cranky enough, and I said: “Doctor Belzer, you just have to develop a better solution for pancreas preservation.”
So he sent Jan Wahlberg from Sweden, from Uppsala, he sent him in 1985 to the lab. I helped Jan to do pancreas transplants in dogs, and within one year we have 72-hour preservation of the canine pancreas. That was actually the first paper, it wasn’t liver preservation. UW became popular because of liver preservation, but the pancreas really started it, and me nagging him really made him go back to the lab.
Dr. Odorico: Fascinating story. One could say that UW solution had its greatest impact on the pancreas of any organ, perhaps.
Dr. Sollinger: You know, I was fortunate enough to be involved in kidney, liver, and pancreas preservation, and I did see the changes of the organ after reperfusion. And I still would say after all these years that the changes which I saw in the pancreas were by far the most remarkable. Because with the previous preservation solutions, we had so much pancreatitis. Even during the case, you could see the organ becoming white and the stigmata of pancreatitis, and the moment we used UW solution, it was like a new organ.
In liver transplantation you can’t see it as well, probably also it’s very important, but I think for pancreas it made a huge difference.
Dr. Odorico: And in the early days of transplantation it definitely had an impact. Tell us some stories of the early days and the challenges.
Dr. Sollinger: Because of this tragic event in my family where my adopted brother died after duct-injected pancreas transplant, he had a pseudoaneurysm and bled out six weeks after pancreas transplant. And at that time the IPTR showed a one-year mortality of 40%. It was run by David Sutherland, and Belzer said to me: “I will not allow you to do a pancreas transplant unless you come up with a technique which has a lower mortality.” So for about a year or so, I played around in the laboratory and then came up with the idea: “Let’s drain the pancreas through the bladder.” We do not have a contaminated organ, and we can put a Foley catheter in until the anastomosis is healed, and perhaps we could measure urinary amylase as an indicator of rejection.
So I think I did about 20 dogs and none of these dogs had any complications. So we moved forward to men. That was the start of the bladder drainage.
Dr. Odorico: A classic large animal, perfect the technique into humans.
Dr. Sollinger: Without human subjects’ permission. We did not go through an IRB; it was a modification of surgical technique.
Dr. Odorico: Fascinating. And your influence and impact on the success of pancreas transplantation did not stop there. There were several other innovations that you’ve been involved with. Tell us about some of those including immunosuppression.
Dr. Sollinger: The immunosuppressive therapy you are referring to is probably mycophenolate mofetil; it was not really related to pancreas transplantation. It was a very, very strange story. In 1988 I got a call from a scientist called Anthony Allison from a medium sized company in Palo Alto. And he said, “We have this compound on our shelves and we have been working to improve the bioavailability, supposedly inhibits T cells and B cell proliferation. We know you are doing animal experimentation in transplantation. Do you think you have an interest to test it?”
Now we did test it, and the experience was awful. The intestinal toxicity was so bad because within about 7 to 10 days the dogs’ intestines became necrotic. But then I said to myself, I think the drug is immunosuppressive because we got some prolongation. If we just lower the dose and give a dose of cyclosporine, a lower dose of cyclosporine and perhaps a tiny little bit of prednisone, very, very similar to what Tom Starzl did with cyclosporine.
You know the story that the high dose cyclosporine caused a lot of lymphoma, then it came to the United States and Tom Starzl added prednisone and so the drug was well tolerated. So I used the same maneuver, and the majority of the dogs made it beyond 150 days.
The next step was a simple study with 30 patients. And what we did was a 1000 mg, 2000 mg, 3000 mg, and we measured the incidence of rejection episodes: the higher we went with the dose, the fewer rejections we had. The FDA said go ahead, do your paperwork, file, and in June of 1995, I got a telegram--email I don’t think existed at that time--I got a telegram from the CEO of Roche: “You are a father.” with a big bottle of champagne. So I knew the FDA had approved mycophenolate (CellCept).
And the name CellCept, just for the people who might be guessing where it came from, means cell accept. We were trying to come up with a name. We were about 20 people who were involved in the development, and we all put a little piece of paper in a hat and Cell Accept made it. But I put one in too and mine was Microphortic—isn’t that irony? Novartis coming out a few years later with Myfortic, so I was very close [laughs] and we wrote that up in an article in Transplantation, the early days of mycophenolate.
Dr. Odorico: All those pivotal trials are really exciting. That was an exciting time, and they were in kidney transplants.
Dr. Sollinger: These were 1,500 patients I believe in 12 centers and here I have a little story, and this story is for the younger people.
It was a triple-blinded prospective randomized trial. We had 12 centers, and after three months one of the very well-known transplant surgeons who we all know, actually former president of ASTS, called me up and said: “Oh Hans, your drug is just wonderful and it’s great!” And he was very excited about it, but guess what? After we analyzed the data, his center was the only one where the drug was not statistically better but statistically worse. So I always tell this story to make sure the students understand why trials have to be properly designed.
Dr. Odorico: Speaks to proper randomization and proper blinding.
Dr. Sollinger: Yes, that’s right.
Dr. Odorico: And after the successes in kidney transplantation you were experiencing on the ward in the clinic, at UW, you had the idea that this drug would be good for pancreas transplantation also.
Dr. Sollinger: I felt from the beginning it was an immunosuppressant which was valuable for all types of transplant. Wolf Bechstein in our lab did liver transplants and of course we did pancreas transplants, and I think to my knowledge in 2018, now, it’s commercially the most successful. Mycophenolate, for most companies, is the commercially most successful compound in the history of immunosuppression. And it’s been used for auto-immune diseases.
I’m not familiar with the details, what the trials are, but it’s a drug which has spun out throughout immune diseases and other applications. It has been to me a gratifying series of experiments and developments.
Dr. Odorico: Absolutely, a huge, huge important impact.
Dr. Sollinger: Yes.
Dr. Odorico: You are still operating, and you are also an amateur athlete. What do you think accounts for your longevity in the field?
Dr. Sollinger: I like the question because, amateur athlete, probably I consider myself more like a professional athlete. But you know like all of us, we come from good athletic background, many of us do, and then we become junior faculty. We have to write NIH grants, we are in the operating room, we spend 12-14 hours in the hospital, the food is not good, and we come deconditioned. And this is one piece of advice I want to give to all the young transplant surgeons. When the time comes and your children go off to college, go back and get back in shape. So that’s what I did. Our children went off to college when I was about 50 years old, and so I went on my bike and went on my cross country skies and tried to get back in shape. As you know, the two of us just skied two weeks ago, and I think you were left behind right?
Dr. Odorico: I was. We skied the Birkebeiner last year and that was great fun, and we look forward to it again this year, the marathon ski race in Northern Wisconsin. I think your advice for young surgeons to maintain a healthy lifestyle so that they can maintain stamina and durability in the operating room is very sage advice.
Dr. Sollinger: And it’s not just so that you can stay in the operating room, because as you may know, what I am doing right now is actually just a very new interest, and this is the only reason why I am interested in this compression syndrome. It has nothing to do with transplantation but it’s something I have developed an interest in. But it’s just, you know, you want to ski with your grandchildren. And you want to be fit and do things. And I strongly encourage that.
Dr. Odorico: Hans, you were president of ASTS. Can you tell us about that experience?
Dr. Sollinger: First of all, it really came as a surprise. Nowadays, people are being groomed; they are secretary or treasurer; they move up and get to know the workings of the Society. I didn’t do that. I was on the Council, and I do remember I came to the meeting and I think it was Clyde Barker and Robb Corry came out and shook my hand and said congratulations, and I said for what? They said: “Oh, we just elected you president.” Perhaps they didn’t have any other candidate that time, but it was a big surprise to me.
Also, at that time, it wasn’t a full time job as it is today. I mean the president gave a presidential address; the president made sure the meeting is good and the program is good. But it wasn’t really that much work.
So I was very honored, and fall came along and then I realized that the Wright Organization, which had run the meeting since its inception, a very small company, didn’t seem to be up to the task of the growing membership of the Society. The meeting was getting bigger. So by October, November, I kind of was in a dilemma because we didn’t have anybody who could put up the meeting. So I went to the physicians and said you’ve got to help me. They had a very mature organizing management group, Slack Company at that time (I don’t know who is doing it now), but they helped me, they got an individual who later actually for a long, long time ran the ASTS, and we started afresh. We put up a nice meeting in Chicago and that individual worked for a long time for the ASTS as the director, Katrina Crist.
So that shook me up a little bit, because I wasn’t prepared for that, but otherwise it was just a great honor to be there and have a great meeting and give the presidential address. By the way I surprised people. The title of my address was “It all began in Wisconsin” and people thought: “Oh, he’s going to talk about UW solution or pancreas technique.” But I talked about Ray Owen and the cattle twins. I thought it was a fun story and it has been printed in various variations since that time, numerous times.
I wanted the younger faculty and the fellows to know who Ray Owen was and where the story for the cattle twins came from. And it’s basically how Medawar got the Nobel Prize. Without Ray Owen, Medawar might not have gotten the Nobel Prize and that wasn’t really widely known until I gave this address and wrote a few papers about it. It was a lot of fun.
Dr. Odorico: It’s a great story and it was a great revelation to me, because I didn’t know that story before I heard it from you.
Dr. Sollinger: What triggered me to do it was when I went to meetings very often people asked me about the Wisconsin cattle twins; they had heard about it but they didn’t know the details. So I thought: “This is my opportunity now; now I can tell them who Ray Owen was, what he did.” And also I could make the link to Medawar and what happened, you know Australia with Burnet who had fully understood what Ray Owen had done, while Medawar didn’t know about it. And only when Burnet’s book about the original antibodies came out and Medawar read that chapter and said okay, intra-uterine injection of antigen could induce tolerance and that triggered the Nobel Prize paper.
Dr. Sollinger: So I am very proud and what makes me even prouder is that my current successor, Dixon Kaufman, was appointed as the Ray Owen Professor. So we are preserving Ray’s memory. As you may know, Ray died at the age of 100 just two years ago, so I had really an opportunity to get know him very well over the years. He was so humble, and one of his things was, as far as the Nobel Prize—because a lot of people said: “You know Ray, you should have gotten the Nobel Prize”—and he always said to me, “Hans, it’s better to be asked why you didn’t get it than the other way round.” Great man, great man.
Dr. Odorico: During your long career you’ve mentored many people, Hans. Tell us about that.
Dr. Sollinger: You know, Jon, there are three components of the academic life and that’s clinical care, innovation and research, and training. Depending on what day of the week you ask me, I might give you a different sequence of importance. Clearly training transplant fellows has been just the most wonderful thing in my career and the people who went through our program, I am a little bit hesitant to say any names because they all have been great. I mean, let’s just take you with your stem cell work, leading stem cell work in the world now. Stuart Knechtle, Allan Kirk, Tony D’Alessandro, and I could go on and on. I mean they all have become real contributors in the field of transplantation. At the last count, during my chairmanship we trained about 65 fellows, Devin Eckhoff became chief of transplantation and we have trained European fellows, and all have made such wonderful contributions. So there has been a multiplier effect which I really, really enjoy.
Dr. Odorico: I know I’m speaking for myself but I’m speaking for every other trainee that you’ve helped mold their careers, Allan Kirk, Devin Eckhoff, and others. I know they would say you’ve been a wonderful mentor.
Dr. Sollinger: This is one of greatest compliments anybody can get. One of our mottos was: we really work hard but we have a little bit of fun as well, and as you know a lot of my fellows became bicycle partners during the fellowship and we did a lot of things outside the hospital. And I would say all of them are still good friends.
Dr. Odorico: You’ve been involved in research in the field of beta cell replacement and of course, pancreas transplantation is the ultimate beta cell replacement for patients with diabetes. Hans, what do you see as the future of beta cell replacement?
Dr. Sollinger: You know Jon, I remember when I wrote my paper on the first 500 kidney pancreas transplants, and here I was working very hard 15 years and all I had done was 500 transplants. And you know as well as I do we have currently somewhere between 1.3 to 1.5 million Type 1 diabetics just in the United States. So I wanted to do something which is not only applicable for a few hundred patients a year, such as pancreas or islet transplantation. I wanted to do something for everybody, and the ideal for us is a 7 year old little kid who just developed diabetes, and is cured by gene therapy. So over the last 20 years we have developed the appropriate tools, the appropriate vector, the appropriate genes. We are now treating diabetic dogs who have natural diabetes like patients. That is my hope, and my last goal is that I can look at about 20 to 30 dogs cured from diabetes, because if we can do that, the jump to patients would be a very, very small one.