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Dr. Kahan

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I think really the most rewarding thing has been training young people in science and in clinical transplantation and watching them develop their own programs. I think that's been the most rewarding aspect of the transplantation field. Of course there's always the rewards of patient care and seeing people reborn from a state of infirmity to a state of relatively good health.

Biography:

Barry D. Kahan is Emeritus Professor and Director Emeritus of the Division of Immunology and Organ Transplantation at The University of Texas Medical School at Houston, where he was Chief of the Organ Transplant Services at The Hermann Hospital for more than 30 years. He received both his PhD (physiology) and MD degrees from the University of Chicago and completed his internship and surgical residency at Massachusetts General Hospital in Boston. Before his academic appointment at the University of Texas, he held Assistant and Associate Professor posts in Physiology and Surgery at the Northwestern University Medical School in Chicago. Dr. Kahan has served on numerous scientific editorial boards, including Transplantation, Clinical Transplantation, Transplantation Proceedings, and Clinical Nephrology. He has been a consultant for the FDA Advisory Committees on Anesthesia and Life Saving Drugs, and he served two terms on the Department of Health and Human Services Advisory Committee on Transplantation. Dr. Kahan is a Past President of the American Society of Transplant Surgeons.

Transcript:

Dr. Kahan: I am Barry Kahan, emeritus professor of surgery at the University of Texas at Houston. It gives me great pleasure to talk about my career over the course of the last 50 years.

In 1960, I was awarded a Danforth Fellowship, which allowed me to work in the field of transplantation at the University of Chicago in pursuit of a PhD in physiological chemistry. At that time, I developed a method for solubilization of transplantation antigens.

After an internship at the Mass General Hospital, I then went to the National Institutes of Health and worked on the solubilization of antigens from a variety of rodent species, and then, in collaboration with Chapolini in Italy, identified the heavy chain of the HLA class I antigen. We showed that the specificity was due to the amino acid sequence.

Following that, I took a residency at the Mass General Hospital and then joined the faculty at Northwestern University, where we showed that the isolated antigens would provoke delayed type hypersensitivity in patients who had rejected renal grafts.

After a period of four years in Chicago, I accepted the position of Director of the Division of Immunology and Organ Transplantation in Houston. During that period, we developed a variety of immunosuppressive drugs. Most prominently, we developed cyclosporine, sirolimus, and basiliximab as primary investigators. Unfortunately, along the way there were a number of speed bumps of drugs that didn't meet approval, including anizoprast, brequinar, anti-T-cell receptor monoclonal antibodies, and FTY720, a sphingosine agonist.

After 1998, we began the first inpatient studies of sirolimus and eventually brought that to clinical reality with approval by the Food and Drug Administration. Along the way, I was very blessed with a variety of colleagues and mentors who helped me in this process.

One of the highlights of my career was the presidency of the American Society of Transplant Surgeons, which occurred between 1989 and 1990. During that period, I introduced The Chimera newsletter, which became the main communication instrument to our members.

In addition, I started the postgraduate course, which was originally intended for fellows and has now become this Winter Symposium. Thirdly, I worked with the government to develop the resource base relative values scale for transplantation. At that time, renal transplantation was well underpaid by the feds, and we had to work quite a bit with the agency to get reasonable reimbursement and we achieved reimbursement at the level of an aortic bi-iliac vascular procedure, which was an increase in our fee compared to what it had been in 1972.

Finally, I testified before the Senate for the renewal of the National Organ Transplant Act, which had originally been approved in 1984 and was then renewed at that time. So I would say that in transplantation, my interests have been in isolation, purification, and use of soluble transplantation antigens, the development of new immunosuppressive drugs, and particularly the refinement of the concept of drug synergy versus antagonism, which led to the development of rapamycin.

Along the way, I've had many excellent colleagues and mentors. I'd like to particularly talk about Bill Adams, who was Chairman of Surgery at the University of Chicago, and Dwight Ingle, a member of the National Academy who was my sponsor for my doctoral research. I've had several excellent research fellows in the area of antigen: Ralph Reisfeld, whom I collaborated with throughout my period at NIH, subsequently Stan Stepkowski, Rafik Ghobrial, Norio Yoshimura, among others.

In the area of tumor immunology, Yamigishi, who is now President of Kyoto University, and Tanaka and Neal Pellis, as well as Kim Jessup; in the area of immunosuppression and development, Bruce Kaplan, who worked with me for many years.

Ann Vathsala, who developed the initial concepts of drug synergy together with TC Chou late in the 1980s. Then for new drug development, Rob Kirkin was very involved, together with Franco Citterio, who worked on the mechanism of action of cyclosporine.

I have had many excellent clinical fellows, and these include Oka, who was president of Kyoto University and subsequently of the Red Cross Hospitals. In addition, Marc Lorber, who was Director of Transplantation at Yale, Amante, who was Director of Transplantation in the Philippines, and a variety of other individuals, Paolo Rigotti at the University of Padua, Tony Smith at the University of New Mexico, Joe Loewen, who was professor at Dalhousie in Canada.

So, in the course of 50 years, I feel I have had a very rewarding career in the field of transplantation and given the opportunities provided by the American Society of Transplant Surgeons, had the opportunity to interact and make a positive impact on the field. Thank you for your interest.

Interviewer: Probably more than any of us, you have had a very positive relationship with industry. These kinds of relationships have not been viewed as nicely now as they had been in the past for a variety of reasons. In addition, you've been involved with a lot of regulatory issues. I would like you to talk a little bit about each, and I think that I certainly would judge that your industry relationships have been so positive in so many ways, but that those kinds of relationships that you developed would not be so easily developed today. And I'd just like to hear what you have to say about that.

Dr. Kahan: I've had a very positive interaction with industry as a professor in a university, and I've learned quite a bit from that experience, which may be of use to others. First of all, one must not become a slave to industry; one has to maintain your individuality. You have to insist that industry provide you with raw data before you go before a federal group, either for an investigational new drug application or you publish. I've never accepted industry writing a paper for me. I've never accepted industry modifying in any major way any paper that I have written. In addition, I've insisted that industry pay the full load of the costs of doing a study, including not only the direct costs of laboratory tests or compensation to patients, but also compensation for all of the key personnel who are working in the study. So I think by maintaining somewhat of a distance, I've been able to work productively with industry without jeopardizing my own scientific standards in terms of reputation and in terms of evolution of robust knowledge.

Interviewer: Looking at it from the university side, is that easier to do today or more difficult to do today?

Dr. Kahan: Examining this issue from the university side, I think that the problem that most young people have today is they're too anxious to participate and not distant enough from the company to insist that their standards be met. And this is in part related to the fact that there are too many young people who are willing to get on the train, who are willing to have industry write their papers, and who really are not paying attention to what's being done with their reputations.

The regulatory environment has changed completely from the 1960s. As you know, in the 1960s, transplantation was done through National Institutes of Health grants. In 1972, when Medicare came aboard paying for kidney transplantation, that changed the whole complexion of the field and allowed us to develop as independent kidney transplant surgeons, not relying on doing a variety of other miscellaneous procedures, but focusing our efforts in transplantation.

In the early 1980s, after the introduction of cyclosporine, there were considerable debates within the community about the direction to go. Some of our colleagues strongly advocated getting the federal government involved. I have to admit that I was totally against it. However, I went with the major opinion, which was let's get the feds involved. Getting the federal government involved led to the creation of the OPTN, which I would contend has not been entirely a smooth relationship for our field, and could've been executed just as well without federal intervention. In addition, it led the feds to get involved in a variety of other transplantation endeavors and to adopt the controlling position that they have.

I was fortunate to serve on Tommy Thompson's advisory committee on transplantation. And one of the things that was a mandate to that committee was tell us what you want to do, but make sure it doesn't cost any money. Well of course, everything that we wanted to do, such as prolonged donor follow up, such as extended immunosuppressive drug therapy, our major goals, were not within that mandate. So therefore, that committee was progressively emasculated and its role as a guidance to the HHS was thus diluted. So therefore, the intervention by the federal government has in some ways I guess been good, but in many ways it's been very dangerous. And as we see now, with CMS now coming to do audits in transplant centers, it appears that their main rationale is to disqualify about one-third of the existing centers, which will then lead us to rationing of transplantation care and bring the number of available donor organs in concert with a limited number of centers approved to do this kind of care. So regulation has its downsides as well as potentially some upsides.

Interviewer: Think back to some personal moments, triumphs in the operating room, blunders in the operating room.

Dr. Kahan: Well, I think probably some of the most exciting times I've had was when we introduced new drugs and we had international conferences. The first conference was the introduction of cyclosporine and the congress in Houston. That was followed by another congress in Houston where we introduced cyclosporine for autoimmune diseases.

At a third congress, we introduced the concept of the use of electronic media to help in transplantation, which has been a very slow growth area. The next congress we had introduced Neoral as a formulation of cyclosporine and then the congress that was held in Istanbul introduced basiliximab and Certican as agents for immunosuppression. So I particularly enjoyed organizing those congresses, which I felt served to bring the community up to speed with the experience that existed with the use of new drugs.

I can't think of anything that happened in the operating room that I can recall, although I did have that case where anesthesia woke up the patient. The retractors dehisced the artery and the vein and we had a pool of blood. I mean I think that's happened to everybody who's been in the field for any length of time.

I think really the most rewarding thing has been training young people in science and in clinical transplantation and watching them develop their own programs. I think that's been the most rewarding aspect of the transplantation field. Of course there's always the rewards of patient care and seeing people reborn from a state of infirmity to a state of relatively good health.

Interviewer: I could not have imagined when I was Wes Alexander's medical student in 1968 what this field has become. I simply couldn’t imagine it. I wonder if you could reflect upon what you might have thought organ transplantation would come to when you were a young clinician because I think the speculation on the clinical side would have been something that the public would've kind of recognized and related to.

Dr. Kahan: Well, as I began 50 years ago in transplantation as a field, it was based on the fact that I believed that if we presented or modified a soluble antigen, we would induce tolerance. And I had the unrealistic expectation that within 10 or maybe 15 years of manipulating antigens, that we would consistently produce immunological tolerance.

It was only the frustration of playing with antigens and finding that we couldn't really manipulate the host response like we wanted, that I was forced to turn to looking at immunosuppressive drugs because I recognized that tolerance induction was nirvana and that it was unlikely to be achieved in my lifetime. And fortunately, that proved to be very productive, both for the field of transplantation and for my career.

Interviewer: Where do you think transplantation will be 10, 15, 20 years from now? What's the future of clinical transplantation?

Dr. Kahan: The future of transplantation is a matter of great concern to me because I see increasing regulation. I see increasing invasion by people who don’t really know much about transplantation as the sort of field that I grew up in, namely transplantation immunology, the basic elements of transplantation. There has become much more of an interest in delivery of transplantation and in many of the aspects that aren't as academically challenging. I see the emergence in our field of transplant surgery of purely technical people; very few people are willing to make an investment in learning the basics of immunology and immunosuppression, and the surgeons have given up much of our prerogative for these areas to internists who have a much broader range of interest and who aren't as focused as those of us who began in this area 50 years ago.

Interviewer: Tell us how transplantation has impacted your personal life, your family life, hobbies or interests.

Dr. Kahan: Well, transplantation is an all-consuming vocation. This mistress leaves no room for anything else if you really are dedicated to the area. The majority of our work occurs as emergencies; very frequently these pull you away from other elements of your life.

And I think what you find as you approach retirement, and I'm in semi-retirement now, as Editor-in-Chief of Transplantation Proceedings, is that there is a certain vacuum by not having to go to the operating room on Saturdays or Sundays, and it used to be that when you would be sitting watching TV at night, you would think gee, wouldn't it be great if a donor came in and we could actually do a case. (Laughing) But now you don't have that refuge and our life has a number of other opportunities. But I think it's important to maintain your interpersonal relationships with colleagues in this field because it is a small, international, very tightly woven field and it can be very rewarding in retirement.

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