The evolution of organ transplantation is one of medicine’s great stories, and much of it was written by Thomas E. Starzl, MD, PhD, FACS, who died March 4 at age 90. A Fellow of the American College of Surgeons since 1961, Dr. Starzl added a new dimension to the field of medicine by innovating and perfecting methods of replacing failing vital organs. There are few instances in which a single individual has been so primarily responsible for establishing an important field. Even this statement understates Dr. Starzl’s influence, considering the overall impact and downstream effects of transplantation on other disciplines. For example, most physicians would agree that modern immunology owes its maturation to transplantation rather than the other way around.
Lifelong interest in scientific research
Tom Starzl grew up in Le Mars, IA, a small town where his father was the editor, publisher, and owner of the local newspaper. As a boy, Tom worked on his father’s paper doing everything from acting as a printer’s devil (apprentice) and delivery boy to reporting. After graduation from Westminster College, Fulton, MO, and a year and a half in the U.S. Navy, his mother, a nurse, persuaded him to pursue a career in medicine. Entering medical school at Northwestern University School of Medicine, Chicago, IL, he supported himself by working as a copywriter for the Chicago Tribune. He developed a serious interest in neuroscience and dropped out of medical school for a year of research, earning a PhD in neurophysiology and publishing several papers still considered important classics.
After medical school, he began a surgical residency at Johns Hopkins, Baltimore, MD. At Hopkins, he did research in cardiac physiology, developing a model of complete heart block in dogs and its treatment with the first epicardial pacemaker.
After four years at Hopkins, he finished his surgical training at the University of Miami, FL. There Starzl became fascinated with the liver and its double blood supply. At first, this part-time research was aimed not at transplantation but at studying changes in the liver’s metabolism when a portacaval shunt deprived this organ of nutrients and other elements in portal blood.
Returning to Northwestern for a year of training in thoracic surgery under the pioneering open-heart surgeon John Lewis, MD, FACS, and then two years on the faculty, he continued his investigation of the liver, now with the idea of transplanting it. Because immunosuppression did not yet exist, he studied the course of liver transplant rejection in unmodified dogs. Surprisingly, he uncovered a provocative finding—occasionally a recipient, after beginning to reject its allograft, would spontaneously recover. This led him to hypothesize that rejection might be reversible, a notion that became the key to one of his major breakthroughs.
In 1962, just as Dr. Starzl moved to the University of Colorado, Denver, he learned that Roy Y. Calne, MB, BS, FACS(Hon), FRCS, at Cambridge University, U.K., and Charlie Zukowski, MD, Medical College of Virginia, Richmond, had reported that the anti-cancer drug methotrexate and its derivative Imuran could briefly delay rejection of kidney allografts in dogs. This was the first use of chemical immunosuppression. Dr. Starzl obtained a supply of the new drugs and began testing their effect in dogs with liver and kidney allografts. He soon made a crucial observation that others had missed. When Imuran alone was administered, signs of rejection always occurred within days or weeks. However, if high dose prednisone was added, rejection was consistently reversible. Encouraged by these dog experiments, he embarked on human kidney transplants and found that his unique immunosuppressive protocol was equally effective.
A watershed moment
Meanwhile, in Boston, MA, Joseph Murray, MD, FACS, and Professor Calne began to employ the new immunosuppressive drugs in human kidney recipients. In September 1963, the National Research Council (NRC) convened a conference to assess the outcome of human kidney transplantation. Approximately 25 of the world’s transplant clinicians reviewed the status of 200 kidney transplants that had been performed. The results presented were extremely discouraging. Less than 10 percent of the allograft recipients had survived three months. Most of these patients had been treated with total body irradiation. Only six patients had survived a year. Dr. Murray reported on his first 10 patients treated with Imuran instead of radiation. One had survived for a year; the other nine died within six months. At this point, the new drugs seemed no more effective than radiation. The mood at the conference became so gloomy that some participants questioned whether continued human transplantation could be justified.
The pessimism was dispelled by a single presentation—the one by Dr. Starzl. He presented the results of his first 30 transplants. He described his immunosuppressive protocol that had allowed about 80 percent one-year graft survival. He had more surviving patients by far than the rest of the world’s participants combined.
Dr. Starzl’s presentation caused a sensation. It was a watershed event. The outlook for transplantation was completely changed. Harvard University School of Medicine, Boston, surgeon and transplant historian Nicholas Tilney, MD, FACS, described it as “letting the genie out of the bottle.”* Many conference attendees promptly followed Dr. Starzl to Denver to learn about his immunosuppressive protocol. The news of the breakthrough spread quickly. Before the NRC conference, there had been only three active renal transplant centers in North America—Boston, Denver, and Richmond. As the effectiveness of Dr. Starzl’s innovative immunosuppression became known, within a year, 50 new transplant programs began in the U.S. alone. All of them and others that began subsequently adopted the Starzl “cocktail immunosuppression.” In fact, this protocol remained the world standard for almost the next two decades.
Dr. Starzl now felt ready to approach his primary goal of liver transplantation. Despite his extensive experience with this procedure in dogs, it proved to be difficult in humans. In March 1963, his first patient bled to death on the operating table. The next four died within days, causing a self-imposed moratorium for three years of further research. One important modification was the introduction of an additional immunosuppressive agent antilymphocyte globulin; Dr. Starzl was the first surgeon to employ the agent clinically. In July 1967, he performed the world’s first successful liver transplant and followed with four more that were initially successful. Yet the procedure remained so controversial that Dr. Starzl’s colleagues at the University of Colorado refused to refer their end-stage liver failure patients to him. Although many of Dr. Starzl’s patients survived, approximately 50 percent died within a year. Thus, he had proved liver transplantation feasible, but it was a qualified success. To be accepted as a clinical service, further improvement would be necessary.
The next innovation that can be credited to Dr. Starzl is successful application of cyclosporine. This wonder drug revolutionized transplantation by strikingly improving kidney transplant results and greatly facilitating successful extrarenal transplants. Professor Calne originated the use of this new immunosuppressive agent. He found it more potent than Imuran but also toxic in high doses, leading to infections, lymphomas, and renal damage. Initial clinical results ranged from unimpressive to poor, causing health care professionals to believe the drug should be abandoned. Once again, as he had before with Imuran, Dr. Starzl found that adding prednisone and using the new drug in appropriate doses could lead to strikingly improved outcomes for kidney transplants. In addition, this protocol was the key to transforming transplantation of extrarenal organs into a practical clinical service.
After moving to the University of Pittsburgh, PA, in 1981, Dr. Starzl was soon performing as many as 600 transplants a year with excellent results.
Cyclosporine soon became the standard baseline immunosuppressant and remained so until 1989, when Dr. Starzl showed that rejection of liver and other organ allografts resistant to treatment by cyclosporine, steroids, and antibodies could often be reversed by an even more potent drug, tacrolimus. Tacrolimus has now largely replaced cyclosporine as the usual baseline agent. In addition, it has allowed successful small bowel and multivisceral transplants, which Dr. Starzl also was the first to accomplish.
Dr. Starzl’s immunosuppression innovations with agents such as cyclosporine, tacrolimus, and T-cell antibodies now allow excellent short-term and mid-term survival of allografts. Nevertheless, because of morbidity from drug toxicity and late graft loss from chronic rejection, achievement of drug-free immunosuppression remains 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 lymphoid cells allowed acceptance of donor strain skin grafts.† But in large animals and humans, exploration of donor cell inoculation for introducing tolerance was disappointing. In addition, because transplants were often successful without inoculating the recipient with donor cells, it seemed that donor cell chimerism was irrelevant. For 30 years, no one had suggested that successful organ recipients possessed donor leukocyte chimerism. But it was Dr. Starzl’s hypothesis that the recipients did.
In 1992, Dr. Starzl dramatically refocused attention on the role of chimerism by demonstrating that in a group of his patients who had maintained successful kidney or liver grafts for up to three decades, donor leukocytes were indeed present. Sensitive immunochemical and molecular assays were used to detect the donor cells. In some patients, donor cells could not be found in blood—only in biopsies of skin, lymph nodes, and other tissues. Dr. Starzl’s extensive search showed that a microchimeric state was present in all 30 patients studied. Because these recipients had never been given donor cells, the chimeric cells could only have reached them as passengers migrating from the donor organ transplant. Many patients appeared to be tolerant since they were off all immunosuppression. Dr. Starzl’s demonstration of microchimerism in these patients has been an important stimulus for the present re-exploration of chimerism to promote allograft tolerance.
For a more complete review of Tom Starzl’s contributions, I recommend his autobiography, The Puzzle People: Memoirs of a Transplant Surgeon. In addition to that book, Dr. Starzl was the author of some 3,000 scientific publications and remains the most cited medical author in the world.
Among his many other honors, Dr. Starzl had 26 honorary degrees from U.S. and foreign universities and was a fellow of 20 international surgical organizations. The breadth of his more than 200 other awards include the King Faisal Prize, the Friend of Israel Prize, the key to the City of Venice, the Medallion for Scientific Achievement of the American Surgical Association, the Medawar Prize of the Transplantation Society, the President’s National Medal of Science, the Benjamin Franklin Award of the American Philosophical Society, and the Lasker Award. He also held memberships in the French Academy of Medicine and the National Academy of Medicine, and he was elected to the National Academy of Sciences in 2014.
Dr. Starzl stopped operating more than two decades ago. At that time, he professed the intent to slow down and devote time to his nonmedical and scientific passions and interests, including Joy, his wife of 36 years; music; his dogs, which accompanied him everywhere, including his office; and the cinema. This never happened. Instead, until the time of his death, he continued to direct the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh and to pursue perhaps the most important research of his career as he sought the Holy Grail of transplantation—immunologic tolerance.
When asked if he missed surgery, Dr. Starzl replied that he could never really enjoy operating because he was not emotionally equipped to deal with the loss of a patient. As he put it, “All triumphs in medicine are the forgotten sorrows of past days.” To the end of his life, he remained haunted by memories of tragic outcomes during his early transplant experience. He formed a lasting bond with his surviving patients, remaining in close touch with them for the rest of their lives.
Dr. 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 for his 90th birthday celebration.
Tom Starzl—the consummate surgeon-scientist of our time—will be greatly missed. 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.
*Tilney NL. Transplant: From Myth to Reality. New Haven, CT; Yale University Press; 2003.
†Billingham RE, Brent L, Medawar PB. “Actively acquired tolerance” of foreign cells. Nature. 1953;172:603-606.