THOMAS E. STARZL, M.D.
1926 - 2017
Tom Starzl's extraordinary career ended with his death at age 90 on March 4, 2017. He is sometimes referred to as the father of liver transplantation but to view his career in this context would be to overlook its much broader significance. The evolution of transplantation is one of medicine's great stories. Much of it was written by Tom Starzl. There are few instances in which a single individual has been so predominantly responsible for establishing an important field. He transformed human organ transplantation from science fiction to reliable treatment of fatal diseases, virtually changing medical practice. Even this underestimates Starzl's influence, considering the overall impact and downstream effects of transplantation on other disciplines. For example, most would agree that modern immunology owes its maturation to transplantation rather than the other way around.
While growing up in Le Mars, a small town in Iowa Tom enjoyed the usual boyhood activities, Boy Scouts, high school basketball and football and playing the trumpet in a jazz band. Another experience was an uncommon one, working at lowly jobs and then as a reporter for the town's newspaper which was owned and published by his father. This may have given him a start toward being a gifted writer who would one day become the most highly cited medical author of his time. After graduation from Westminster College and a year and a half in the Navy he was influenced by his mother, a nurse to pursue a career in medicine.
Entering medical school at Northwestern he supported himself as a copywriter for the Chicago Tribune. He then developed a serious interest in neuroscience and dropped out of medical school for a year of full-time research. He implanted electrodes deep within the brain of experimental animals. Recordings from these electrodes helped to define the ascending reticular activating system. The five resultant papers that formed the basis of his PhD thesis are still being cited. Although urged by his mentor, Horace Magoun to become a career neuroscientist Starzl instead completed medical school and then began a surgical residency at Johns Hopkins. There he did research on cardiac physiology. In dogs he developed a model of complete heart block and its treatment with the first epicardial pacemaker.
After 4 years at Hopkins he moved to the University of Miami to complete his surgical training. There in a laboratory he built for himself in an abandoned garage he continued to do research. He had become fascinated with the double blood supply of the liver. To investigate the importance of the portal blood flow he developed a model of liver transplantation in dogs, hooking up the new liver in various ways with or without a portal vein. He found that unless portal blood was supplied the transplant was damaged and shrank. Later he proved that insulin was the crucial hepatotrophic facter. These experiments were done without any thought of using transplantation to replace failing livers but only to study the physiology and metabolism of the organ. At this time, it would have been pointless to pursue liver transplantation as a therapy since there was no way to prevent rejection. Immunosuppressive drugs had yet to be discovered. So far the only human transplant that had been successful was one from an identical twin.
After he finished his residency, Starzl wasn't sure what to do next. He had explored neuroscience, cardiac physiology and liver metabolism without committing himself to a career in any of these fields. Discouraged and frustrated he considered going into private practice to support his growing family. He remembered himself as bursting with energy and ambition to achieve something meaningful. But what? He likened himself to a missile searching for a trajectory. Ultimately he decided to further extend his education by training in thoracic surgery. He acknowledged the criticism from his wife's family that he had become a perpetual student.
But then, just at this time, he learned that Roy Calne in England and Charles Zukoski working with David Hume in Richmond had discovered in animal experiments that the anticancer drug 6-mercaptopurine and its derivative Imuran would delay rejection of kidney transplants. He later recalled saying to himself, “Wow, this (liver transplant) operation that I developed only for study of liver physiology could be used to treat people dying from liver failure.” He had found his trajectory. It would be transplantation and especially transplantation of the liver. Starzl spent the next 3 years back in Chicago at Northwestern. After completing his training in thoracic surgery under the pioneer of open heart surgery, John Lewis he returned to studies of the liver, but now with the goal of transplanting it as a treatment. Since he did not yet have access to the new immunosuppressive drugs these studies were of unmodified transplant rejection. Rejection of his transplants always began within a few days but occasionally and quite mysteriously and without any treatment it seemed to slow or almost stop for a time. This was provocative. He began to wonder if he could find a way to reverse rejection. This notion would become the key to a major breakthrough, perhaps his most important one.
In 1962 Starzl accepted a faculty appointment at the University of Colorado. Also just at this time he was able to obtain a supply of the new immunosuppressive drug, Imuran. He began to test it in dogs with liver and kidney transplants. He soon made a crucial observation that was missed by other investigators who were testing the same drug. They had administered Imuran as a single agent or simultaneously with prednisone or other cytotoxic drugs. Rejection was modestly delayed by these protocols but it always resumed and was always fatal. For the next 2 years Starzl experimented with many different ways of using the drug. Eventually he found one way that allowed consistent success. When Imuran alone was given rejection always began within days or weeks. But then if he treated the dog with massive doses of prednisone he could always reverse rejection, something that had never before been considered possible. Subsequently he could reduce or sometimes even stop immunosuppression without recurrence of rejection. Encouraged by his dog experiments Starzl began to try his immunosuppressive trick in human kidney transplants, finding it equally effective. He started with the kidney, realizing that until he could succeed with this simpler procedure it would be unwise to undertake liver transplantation.
In September 1963 Starzl was given the chance to reveal his exciting findings. A small conference had been organized by the National Research Council to assess the experience with human kidney transplantation. About 25 of the world's transplant authorities were assembled. Starzl a young and virtually unknown newcomer to the field had been invited to the meeting as an afterthought. One by one the established experts reviewed the status of the field up to this time altogether about 200 transplants. Their results were all terrible. Less than 10% of their recipients had survived as long as 3 months. Most of their patients had been treated with total body irradiation as an immunosuppressive maneuver. Hope was expressed that the new immunosuppressive drugs might be more effective. But when Joe Murray reported his first 10 patients treated with Imuran only on had survived for a year and at the time of the conference was undergoing rejection. The other 9 had died within 6 months. Thus at this point the new drugs seemed no more effective than radiation. The mood at the conference was so gloomy that some participants questioned whether continued activity in human transplantation could be justified.
The gloom was then dispelled only by a single presentation, the one given by Tom Starzl who described his first 30 drug treated patients. His unique protocol had reversed rejection and allowed almost 80% graft survival. Starzl realized He had more surviving transplant patients by far than the rest of the world's experts combined. The audience was incredulous. The subsequent discussions were acrimonious, but eventually Starzl's results had to be believed because he had brought with him charts detailing daily progress of each patient including laboratory tests, urine output and immunosuppressive drug doses. Starzl's report caused a sensation. It was a watershed event that completely changed the outlook for transplantation. Boston surgeon and transplant historian Nick Tilney described it as “letting the genie out of the bottle.” The news of the breakthrough spread quickly. Before the NRC conference there had been only 3 active renal transplant centers in North America- Boston, Denver and Richmond. As the effectiveness of Starzl's innovative immunosuppression became known within a year 50 new transplant programs began in the United States. All of them adopted the Starzl cocktail immunosuppression. In fact, Starzl's protocol remained the virtual world standard for the next 2 decades.
Starzl now felt ready to approach his primary goal, liver transplantation. But despite his extensive experience with the procedure in dogs it proved to be very difficult in humans. In 1963 his first patient, and the world's first bled to death on the operating table. The next 4 died within a few days causing Starzl to impose a moratorium on his program. The procedure was so violently controversial that Starzl's medical colleagues refused to send him their end stage liver failure patients. For the next 3 years with further research and animal experiments he addressed the problems of earlier failures. One important modification was the introduction of another new immunosuppressive agent, anti-lymphocyte globulin which Starzl was the first to employ clinically. In 1967 Starzl performed the world's first successful liver transplant and soon after 4 more that were initially successful.
For the next 10 years Starzl struggled to improve his results without much success. Many of his liver recipients survived but at least half died within a year. Thus he had proved that liver transplantation was feasible but it was still a qualified success. To be accepted as a practical clinical service further improvement would be necessary. In 1979 Starzl saw the chance for this improvement. Cyclosporine a new immunosuppressive drug had been introduced in England by Roy Calne. After encouraging experiments in animals Calne began to use it in human kidney transplant recipients. He found this drug more potent than Imuran but also very toxic, sometimes causing infections, lymphomas and kidney failure. Other trials of the drug in Canada and Boston were similarly disappointing causing many to believe it should be abandoned. In fact, Starzl learned that the company making it seriously considered taking it off the market. But at this point he came to the rescue of the new drug. Once again as he had 20 years before with Imuran by using it in appropriate doses and adding prednisone Starzl made cyclosporine work safely and so effectively that it revolutionized the field. It strikingly improved kidney transplant results and was the key to transforming transplantation of extra renal organs to a practical clinical service.
Shortly thereafter in 1981 Starzl moved to the University of Pittsburgh taking with him cyclosporine. There for the next decade he worked at a furious pace, performing as many as 600 transplants a year with excellent results. His consistently successful use of cyclosporine had transformed liver transplantation into a practical clinical service. Starzl's consistent success with cyclosporine led to it's acceptance as the standard baseline immunosuppressant worldwide. It remained so until 1989 when It was shown again by Starzl that rejection of liver and other organ allografts resistant to treatment by cyclosporine, could often be reversed by an even more potent new drug that he introduced. This drug, FK 506 or tacrolimus has now in large part replaced cyclosporine as the usual baseline agent. In addition, it has allowed successful small bowel and multi-visceral transplants which Starzl was also the first to accomplish.
In 1990 Starzl developed angina and was forced to stop operating. After an emergency coronary artery bypass he recovered completely but he decided that he would never operate again. Instead now freed of a previously all-consuming surgery schedule he elected to turn his full attention and energy to research. Later he was asked if he missed operating. He responded, “No, I was relieved to get sick and have an excuse to stop. I was too much emotionally ruined by the loss of people I came to love. I always felt if somebody died who could have lived it was a doomsday event for me, and the burden of memories got to be too heavy. Of course the retreat was that I went back into research. And that turned out to be good too.”
His assertion that research also might be good proved to be an understatement. His goal now was to discover the Holy Grail of transplantation, immunologic tolerance which would allow drug free immunosuppression. Starzl's innovations with immunosuppression had allowed excellent short and midterm survival of allografts. But because of the toxicity of immunosuppressive drugs and late graft loss from chronic rejection drug-free immunosuppression or tolerance remained the ultimate goal. Plans for introducing tolerance invariably start with review of the 1953 demonstration by Billingham, Brent and Medawar that chimerism induced in neonatal mice by inoculating them with donor strain lymphoid cells allows acceptance of donor strain grafts. In animal models there has been continued exploration of this strategy for inducing tolerance. But in humans this approach has been disappointing. In addition, since many successful transplants were accomplished without inoculating the recipient with donor cells it seemed that donor cell chimerism must be irrelevant. For 30 years no one had suggested that allograft recipients had been successful because they harbored donor lymphoid cells. But it was Starzl's hypothesis that they did.
In 1992 Starzl decided to search for donor leukocyte chimerism in a group of his patients who had maintained successful kidney or liver grafts for up to 3 decades. Sensitive immunochemical and molecular assays were used to detect donor cells. When these cells could not be found in blood he searched for them in biopsies of skin, lymph nodes and other tissues. He eventually found that small numbers of donor cells were in fact present in all of the 30 patients studied. Because these recipients had never been inoculated with donor cells the chimeric cells could only have reached them as passengers migrating from the donor organ. Many of the patients appeared to be tolerant since they were off all immunosuppression. This finding was the basis of Starzl's belief that chimerism an important cause, not a consequence, of successful transplantation. His demonstration of micro-chimerism in these patients has been an important stimulus for re-exploration of this approach for allograft tolerance in many centers.
In recent years Starzl occasionally professed an intent to slow down and devote time to his non-medical and scientific passions and interests including Joy his wife of 36 years, music, his dogs which he took with him him everywhere including his office and since he was a serious student of the cinema to catching up on movies his work load had caused him to miss over the previous six decades. This never happened. Instead he continued to direct the Thomas Starzl Transplantation Institute at the University of Pittsburgh and to search for methods of inducing tolerance.
For a more complete review of Tom Starzl's contributions I recommend his autobiography The Puzzle People. The JAMA described it as a hard to put down book more interesting than a thriller. The New York Times reviewer attributed to Starzl a flair for clear vivid writing, a flair probably stemming from his early work on his father's newspaper and his employment as copy editor for the Chicago Tribune. His style was further honed by his writing of some 3000 scientific publications. These by the way according to the Institute for Scientific Information made him by far the most cited medical author in the world.
Tom Starzl was almost certainly the most widely honored surgeon of his time. He had 26 honorary degrees from US and foreign universities and 20 honorary fellowships of surgical colleges of other countries. His more than 200 other awards included the highest ones of the American Surgical Association, the International Transplantation Society and the American Philosophical Society. Also the President's National Medal of Science, the Lasker award and membership in the National Academy of Sciences.
To the end of his life Tom remained haunted by memories of tragic outcomes in his early transplant experience. But he had every reason to be proud of the changes he had brought about in the field. A fitting close to this incomplete summary of Tom Starzl's contributions to transplantation might be his own comments on the progress made in his time and its impact on the field of medicine. Starzl said, “What looked like a hopeless dream, a fantasy has become a regular and reliable service, so good that the only limit is that there aren't enough donor organs. Within one or two generations it transformed the philosophy that guides medicine. Until the last 40 or 50 years if you had something like end stage heart or kidney or liver disease there was nothing you could do except try to squeeze out the last day of life sustaining function and that's all she wrote. Then all of a sudden, turn to the next chapter and you can replace the whole engine, not just a spark plug or two. So it's not hard to see why it changed the philosophy by which medicine is practiced.”
Tom Starzl's influence has been multiplied by the accomplishments of the hundreds of surgeons who traveled to Colorado and Pittsburgh to learn from him. His disciples and subsequent generations trained by them continue to lead the transplant programs of the world. To show their admiration and affection for him more than 200 of them returned to Pittsburgh in 2016 to celebrate his 90th birthday.
Tom Starzl, the consummate surgeon scientist of our time, will be greatly missed by his trainees, his colleagues, his family and his many friends. He is survived by his wife Joy, his son Timothy and his grandson Ravi. He was predeceased by his daughter Rebecca and his son Thomas.
CLYDE F. BARKER, M.D.