Dr. Thomas E. Starzl, a surgeon and researcher who performed the first successful liver transplant on a human patient in the 1960s and later helped advance the breakthrough drugs that made organ transplants markedly more survivable, died Saturday at his home in Pittsburgh. He was 90.
His death was announced by the University of Pittsburgh, with which he had been affiliated since 1981.
In 1967, Dr. Starzl led a surgical team at the University of Colorado in a procedure that many in the medical community had dismissed as impractical, if not impossible. Although kidneys had been transplanted successfully since the 1950s, all previous attempts to replace a liver had resulted in the death of the patient.
Indeed, Dr. Starzl's first four attempts at liver transplantation, in 1963, had failed when the patients experienced complications from the use of blood-clotting agents, which in some cases caused lethal clots to form in the lungs.
After a self-imposed moratorium that lasted three years, Dr. Starzl and his colleagues tried again. They first considered inserting a second liver, to function beneath the impaired one, as a possible route to avoiding the heavy bleeding caused by organ removal. But promising results obtained from liver surgeries on dogs could not be replicated in human patients, and that avenue was abandoned.
The team then operated on a 19-month-old girl and replaced her cancerous liver. The transplanted liver functioned without ill effects for more than a year, before the infant died of other causes. In the next year, as surgical techniques were improved, this groundbreaking success was repeated in six children and, ultimately, in adults.
Dr. Starzl later described those early liver transplants as both a "test of endurance" and "a curious exercise in brutality." It involved, he explained, "brutality as you're taking the liver out, then sophistication as you put it back in and hook up all of these little bile ducts and other structures."
"Each one," he said, "is a thread on which the whole enterprise hangs."
While the early liver recipients survived for months and sometimes for years, organ researchers soon realized that survival rates would largely hinge on the patient's long-term immunological response to foreign tissue. In the late 1970s, Dr. Starzl helped investigate the efficacy of cyclosporine, a drug that laboratory tests indicated could inhibit the body's immune response.
In drug trials held at Colorado and at Brigham Young University in Utah, cyclosporine was subsequently used to prevent rejection by the patient receiving a donated organ.
Dr. Starzl applied the drug in combination with steroids to avoid a toxic effect on the kidneys. After further trials conducted at the University of Minnesota and the University of Texas, cyclosporine was approved in 1983 by the Food and Drug Administration.
In 1981, when he moved to the University of Pittsburgh, Dr. Starzl expanded his success with liver transplants by working on the transplantation of multiple organs. He provided Stormie Jones, a 6-year-old suffering from a hereditary condition that produces dangerously high cholesterol levels, with a new liver and heart in a novel combined operation in 1984. Dr. Starzl later helped transplant her liver a second time, after damage to the organ from hepatitis. In that operation, Dr. Andreas Tzakis and Dr. Starzl used FK-506, an experimental anti-rejection drug, which went on to become widely used in transplant surgeries.
Dr. John Lake, a professor of medicine and surgery at the University of Minnesota and an expert on transplants, said the drug turned out to be "easier to use than cyclosporine, particularly in liver transplants, and was rapidly proven to be a more effective, and more potent, immunosuppressant."
He added: "It was Thomas Starzl who lobbied hard and generated the enthusiasm for using FK-506. In the process, he drove the early program that thoroughly tested the drug."
With Dr. John Fung, a surgeon and immunologist, and others, Dr. Starzl evaluated FK-506, also known as tacrolimus. They published their findings in the British medical journal The Lancet in 1989.
Their investigation was not without risk; other scientists showed that tacrolimus had proved toxic when tested in dogs, and they doubted that it could be safe for humans. But the unexpected result was a medical breakthrough for patients and lavish headlines for the University of Pittsburgh, which Dr. Starzl helped fashion into an international centre for training transplant specialists.
The university appointed Dr. Starzl director of its transplant unit in 1990, in what six years later was officially renamed the Thomas E. Starzl Transplantation Institute.
A former colleague from Pittsburgh, Dr. Byers Shaw Jr., praised Dr. Starzl's "indomitable spirit" and said that FK-506, eventually approved in 1994 by the FDA, was a shining example of tenacity in a career spent "challenging the conventional thinking."
Dr. Shaw, who is now chairman of the department of surgery at the University of Nebraska, observed Dr. Starzl in the operating room in the 1980s, when a patient appeared to be dying during surgery. Dr. Starzl, he recalled, showed "persistence when everything else looked hopeless."
"It affected everybody in the room," Dr. Shaw said, "as if a fear of failure was driving all of those around him."
After the death of Stormie Jones at 13 in 1990, Dr. Starzl announced that he was weary of surgery and emotionally exhausted from "an uncompromisingly difficult life." He decided to stop performing surgery, although he continued to consult on difficult procedures.
He also experimented with transplanting baboon livers into human patients – animal transplants have long been suggested as a potential solution in dealing with periodic shortages of human organs – but the results were disappointing.
And he advanced a theory that involved the weaning of patients from the very drugs that had made their transplant possible. In the years since the advent of cyclosporine, researchers had become aware of cancers, diabetes and other serious health problems that could in some instances be tied to long-term use of immunosuppressants. Dr. Starzl's theory was based on his studies of patients from the 1960s who had survived even after stopping their medications – in effect, weaning themselves off anti-rejection drugs. Working with a Nobel Prize-winning Swiss immunologist, Dr. Rolf M. Zinkernagel, and others, Dr. Starzl explored the phenomenon and found that some patients' immune systems ultimately seemed to tolerate foreign tissue, without need for continued suppression.
Dr. Shaw said other studies suggested that 25 per cent to 33 per cent of transplant patients might be candidates for reducing their drug intake to some degree, but the majority of patients were unlikely ever to be weaned.
Thomas Earl Starzl was born on March 11, 1926, in Le Mars, Iowa. After graduating from Westminster College in Fulton, Mo., he earned both a medical degree and a doctorate in neurophysiology in 1952 from Northwestern University.
Starzl was a former president of the Transplantation Society and of the American Society of Transplant Surgeons, and he was a member of the Institute of Medicine, part of the National Academy of Sciences.
In 2004, he was awarded the National Medal of Science, the nation's highest scientific honour. His many other honours included the Lasker-DeBakey Clinical Medical Research Award, which he received in 2012 from the Albert and Mary Lasker Foundation.
He leaves his wife of 36 years, the former Joy Denise Conger; a son, Timothy; and a grandson. Another son, Thomas, and a daughter, Rebecca Starzl, died before him.