A Medical Giant in Our Midst
The year is 1958. Northwestern University nominates one of its bright young physicians, Thomas E. Starzl, for a prestigious Markle Scholarship. He is told to come up with a big idea to propose during his interviews with the selection committee.
Something that would be recognized as a remarkable achievement in medical science. Something to build a career on. Something grand.
He narrows it down to two: discover a cure for cancer or transplant a human liver.
“Then, as now, the cure of cancer seemed right around the corner and I thought: ‘Well, I got here too late,’” Dr. Starzl says 48 years later. “So, I went to the interviews and I said I was going to transplant the human liver.”
If curing cancer wasn’t the blank slate he was looking for, transplanting a liver certainly was. Nobody had ever done it. Little of the underlying science had been developed. Nobody knew how to stop the body’s immune system from destroying the donor organ, which would be its natural response. No one knew how to preserve organs outside the body. New surgical techniques were required. It would ignite controversy. Some of the best scientific minds had already judged it to be biologically unsound and impossible to make practical.
Something grand, indeed.
“I told them it might take awhile,” Dr. Starzl says.
It took him nine years. In 1967, he performed the world’s first successful liver transplant following a hugely successful series of human kidney transplants begun five years earlier.
But it was not enough for the surgeon-scientist who disliked operating and whose relentless drive to achieve better outcomes was fueled more by the memories of patients lost than of those rescued. He spent a career guiding transplantation from a concept of dreamers to an entirely new field of medicine, leaving his fingerprints on every major breakthrough along the way.
Retired from surgery for some 24 years, he has been anything but idle. Afforded more time for research, he discovered the natural mechanisms that allow the body to tolerate a transplanted organ and, again, introduced a new era in transplantation with far-reaching implications, including a much higher quality of life for patients young and old.
Outside the lab, simply keeping up with the tributes and requests for interviews has been a demanding job of late. A biomedical research tower was recently renamed in his honor at the University of Pittsburgh, where he has been a member of the School of Medicine faculty since 1981. A gala was held in March to celebrate his 80th birthday and 25 years of groundbreaking work at the university. And the nation’s highest scientific honor, the National Medal of Science, was bestowed by President George W. Bush at a White House ceremony in February.
The remarkable journey began in LeMars, Iowa, a small town in the northwest corner of the state best known as the Ice Cream Capital of the World, thanks to an Iowa General Assembly proclamation. His was a newspaper family. Dr. Starzl’s father, Rome, ran the family-owned local paper, the Globe Post, and an uncle, Frank, reached the executive level of the Associated Press news agency. But there were stronger influences. His mother, the former Anna Laura Fitzgerald, had been a surgical nurse before she married, and her battle with breast cancer exposed her son to more than his share of doctors and medical discussions. As an adolescent, he would be invited by a family friend, a local surgeon, to observe operations and would eagerly and frequently accept. “I knew very early what I wanted to do,” he says. “The die was cast.”
Dr. Starzl graduated from Westminster College in Fulton, Mo., with a bachelor’s degree in biology in the early summer of 1947, a few weeks before his mother’s death. That fall, he left for Northwestern University Medical School in Chicago, where he earned a master’s degree in anatomy, a Ph.D. in neurophysiology and a medical degree. Residencies at Johns Hopkins University in Baltimore, the University of Miami and Chicago’s Veterans Administration Hospital followed. When he returned to Northwestern to join the medical school faculty, transplantation was not a foreign concept to him.
While in Baltimore, Dr. Starzl had assisted in an operation to treat a patient with liver cirrhosis. The patient was also diabetic. He was struck by the fact that after surgeons rerouted the blood flow to the liver, the patient’s diabetes was no longer an issue. When he left for Miami, he took with him the idea that diabetes might be a liver disease rather than a disease of the pancreas. Experiments in dogs failed to support his hypothesis, but to do them he developed an operation in which he managed to remove the liver and keep a dog alive for up to 24 hours.
He had performed the first half of a liver transplant. While that was not his intent, he recognized the implications. A year later, he proposed transplanting a human liver to the Markle Scholarship committee knowing he had already begun laying the groundwork for the idea that seemed more precocious than possible.
As a surgeon, Dr. Starzl had few peers. Confident, precise, innovative, little wasted motion, extremely well planned is how colleagues describe his work in the operating room. As his reputation grew, so did the shadow he’d cast over those hand-picked to work with him.
“He was very much respected, but he was also feared,” says John J. Fung, M.D., Ph.D., who worked with Dr. Starzl in Pittsburgh for 20 years before leaving for the Cleveland Clinic, where he is chairman of the department of general surgery and director of the hospital’s transplant center. “Not because he was verbally abusive. Once in awhile, if it was a really difficult situation, he would let go with a few expletives. It was just that you would try so hard to please him, to prove to him that you were worthy of being there.”
“One guy, every time he was called to do a transplant, he would get physically sick. He’d throw up because he was so nervous about operating with Starzl.”
What that surgeon had no way of knowing was that Dr. Starzl himself experienced near-crippling anxiety before each case. Its source was different, however: an intense fear of failing his patients. He sought relief in surgical texts, reviewing procedures he knew by rote until it was time to operate. Still, he’d arrive in the operating room sick with apprehension. This didn’t just happen before the big operations, when new drugs or techniques were to be introduced. “Every time,” he says, adding in a whisper: “It was terrible.”
He kept this to himself until after he retired from surgery. In his 1992 memoirs, “The Puzzle People: Memoirs of a Transplant Surgeon,” he observes: “The incongruity was that I did not like the one thing for which I had become uniquely qualified.”
It did not stop him. That would only be accomplished by the more powerful forces of aging and heart disease. “One thing about Tom,” says Dr. Fung, “he just doesn’t give up.”
Surgical technique is only a piece of the transplantation puzzle. Donor availability, organ preservation and tissue matching are others. But even if all of the other pieces are made to fit, failure is certain unless the patient’s body is prevented from destroying the foreign tissue that is sewn into it. Identical twins not withstanding — their tissue matches perfectly, so rejection isn’t an issue — if the immune system is allowed to do its job, the patient is doomed.
The great eras in transplantation are defined by the drugs introduced to control rejection: azathioprine, prednisone, antilymphocyte globulin, cyclosporine and FK506, also known as tacrolimus. Dr. Starzl’s legacy is that he showed the world how each could be exploited to its fullest potential and, in doing so, advanced transplantation step by step to the service it is today.
The first was azathioprine, which inhibits production of the cells responsible for rejection. Early kidney transplants hinted at its potential, but survivors died within weeks or months. Few made it through a year. Critics howled. Interest in transplantation flickered.
Undaunted, Dr. Starzl began his first series of kidney transplants at the University of Colorado in 1962, combining the same drug with a steroid and using a method he had developed to preserve donor organs by infusing them with a chilled fluid. Five of his first six patients survived the first year; four would live for longer than a quarter century. Interest in transplantation was immediately revived. Within a decade, transplantation would become a widely accepted treatment for patients with end-stage kidney disease.
Transplanting the liver was another story. His first patient was a 3-year-old boy with biliary atresia, a disease that prevents the liver from draining bile. Today, treatment would offer him hope. In 1963, the disease was a death sentence. Transplanting the liver was a far more complex procedure than the kidney. Dr. Starzl honed his skills by performing nearly 200 liver transplants in dogs, but it was not enough to prevent disaster. The boy’s blood would not clot and he bled to death on the operating table as the frantic surgeons fought to save him. A clot-promoting strategy allowed the next four patients to survive the operation, but they died after blood clots traveled to their lungs. He shut down the liver program.
Four years passed before Dr. Starzl tried the operation again and made history. The world’s first successful liver transplant was performed using improved surgical techniques and an anti-rejection cocktail that added a new drug, antilymphocyte globulin, to the standard azathioprine-prednisone mix.
His Markle Scholarship goal was satisfied, but he wasn’t. Liver transplantation was possible, but unreliable. Some patients did well, while others with similar conditions died. The line between too much and too little immunosuppression was too fine; the consequences of not finding the right balance, too great; the margin for error, too narrow.
Never really satisfied at any point in his career, he would set a standard, then go off and find a better way of doing things. This habit constantly agitated those entrenched in the status quo. Each breakthrough invited resistance, controversy and criticism, all of which would subside with time and overwhelming evidence in his favor.
“The main thing was, I was always watching the patients,” Dr. Starzl says. “The insulation many people have is that they remember the good things, the shining examples of success. If I have a weird side, it’s a tendency to remember the bad things, the death, the suffering, the complications. There is a lingering sense of failure that not everyone makes it.”
He also operated on a large number of children. An exceptional five-year survival rate with adults is one thing. But the perspective is quite different with a 3-year-old. Another five years, while certainly a blessing, still means never making it to Algebra I, let alone the high school prom. And then there was the necessity of prescribing heavy doses of anti-rejection drugs with their unpleasant side effects and tendency to retard a child’s growth and development.
“I never thought we were doing well enough,” Dr. Starzl says. “It wasn’t good enough. And it isn’t good enough today.”
British surgeon Roy Calne was the first to experiment with cyclosporine, a Swiss-made anti-rejection drug far more powerful than anything used before. But his small series of kidney transplants 1978 was widely seen as a warning of the drug’s most serious side effect — kidney damage. None of the survivors had normal kidney function following surgery.
While skepticism gave others pause, Dr. Starzl was busy finding a way to tap cyclosporine’s potential. As he had done with azathioprine, he mixed in a steroid, which allowed him to ratchet down the dosage necessary to prevent rejection and reduce cyclosporine’s toxicity. He put this cocktail to the test in 1979, using it first in kidney transplants, then in liver transplants — all under a cloud of opposition that had gathered within the Colorado medical community and would hasten the fall of the university’s transplant program.
The outcomes were exceptional: all but one of the first 22 kidney patients and 11 of 12 liver patients survived at least one year. He had introduced the golden age of transplantation only to see the Colorado program collapse from within. With cyclosporine in hand, he left Denver for the University of Pittsburgh in 1981. He was taking transplantation to unprecedented heights and Pittsburgh was coming along for the ride.
It was a tumultuous first year.
The 106 kidney transplants done at Presbyterian-University Hospital, now UPMC Presbyterian, was three times the volume ever attempted at the hospital in a single year. Pittsburgh was suddenly flooded with hopeful patients.
At the same time, the liver program was off to a rocky start. Dr. Starzl’s first four patients died. News coverage of the failed operations was intense. Worse, 54 medical residents and interns signed a resolution denouncing liver transplantation as unrealistic and possibly unethical. After only a few months, the imperiled program was testing the resolve of Dr. Henry Bahnson, chairman of the university’s department of surgery, and other key supporters.
Then, in August, he married Joy Conger, 30 years his junior. She had been working as a lab technician in Dr. Starzl’s program in Colorado when they first met by accident on a Denver street: He was biking to the hospital and she was driving when bicycle and car collided. For Dr. Starzl, it was his second marriage. Neither are topics he is willing to discuss much in interviews. In his memoirs, he cites “mistress surgery” as the chief reason for the failure of his first marriage to Barbara Brothers, the mother of his three children. As for the reasons his marriage to Joy has survived similar demands and stresses, he says, “I’ve done a better job” and leaves it at that.
The poor liver outcomes were short-lived. Seventeen of the next 22 patients would become long-term survivors. Pittsburgh became a mecca for both patients desperate for a new lease on life and surgeons eager to learn how to provide them with one. “In the blink of an eye,” Dr. Starzl says, “we were doing 600 liver transplants a year.”
Tom Burke was one of the early pilgrims. “I was 26 at the time and had never heard of a liver transplant,” says Burke, now 51. “I said, fine, that’s no big deal. Let’s go ahead and do it.”
Not that he had many options. He was unmarried, living in New Jersey and working on Wall Street in corporate planning in the summer of 1981 when what he thought was a stomach spasm turned out to be pain inflicted by a tumor encasing his liver. A New York liver doctor advised him to fly to Pittsburgh and see Dr. Starzl. His condition was terminal without a transplant, which Dr. Starzl performed on July 11. Two months later, he started graduate school.
Burke lives in Squirrel Hill today with his wife and their two young children. It is not lost on him that it was more than his life that Dr. Starzl rescued that warm Saturday evening nearly a quarter of a century ago. “I can’t put into words what he means to me. The day that Tom Starzl is no longer here will be a very tough day for me, let’s put it that way.”
Pittsburgh proved to be the perfect incubator for the transplant boom. Dr. Starzl found the University of Pittsburgh leadership willing to weather controversy and provide the resources necessary to support his work, whether that meant beds, talent or money. The community did likewise, as evidenced by its support of the Family House project, which provides housing for patients and families, and the willingness of several Pittsburgh corporations to loan their jets free of charge so surgeons could fly to far-off places on a moment’s notice to retrieve donor organs.
The road was not without potholes. Medical experiments that bump up against ethics and egos never come off without a hitch. A bitter turf war was waged during the early days of the Pittsburgh kidney program. And Dr. Starzl was stung by a series of articles published in The Pittsburgh Press that raised questions about the equity of the program’s system of allocating donor organs, which were never plentiful enough to go around.
He would go on to develop a system for the harvesting and equitable distribution of donor organs that remains the worldwide standard. He also addressed the donor shortage — the last great challenge facing transplantation — playing key roles in the first baboon-to-human liver transplant and the successful effort to genetically modify a pig to make its organs more acceptable for transplanting into humans.
His cyclosporine strategy enabled kidney, liver, heart and other transplant procedures to mature to the point that each would become established treatments. Still, Dr. Starzl was not satisfied.
In 1986, he heard whispers out of Japan about a powerful new anti-rejection drug. The fact that few others were interested was evident later that year at a Transplantation Society meeting in Helsinki, Finland. Most of those in attendance packed an amphitheater to hear about progress with cyclosporine. Dr. Starzl, however, had come to hear a paper on the Japanese drug, which was presented in a smaller venue to a sparse audience.
FK506, or tacrolimus, was purported to be 100 times stronger than cyclosporine. Early animal tests in England led British surgeons to dismiss it as too toxic for human use. As he did with azathioprine and cyclosporine, Dr. Starzl refused to allow the failure of others to dampen his enthusiasm for the new drug. He began a series of animal experiments with FK506 that spanned three years and involved nearly every department in the medical school.
Rats, mice, dogs, monkeys, baboons — in each, the drug proved enormously effective and did not appear too toxic. He began using it with patients who had a history of rejecting their transplanted livers.
“He really relied on laboratory data,” says Dr. Fung, who was in charge of managing the early FK506 trials. “To think that it would work in an animal, but not work in a human — he wasn’t going to buy that.”
The drug reversed rejection in seven of the first 10 patients. Patients yellow with jaundice regained healthy tones. FK506 quickly improved the outcomes of kidney, liver, pancreas and heart transplants, and finally made it possible to successfully transplant the intestine, an organ highly susceptible to rejection and other serious complications. The Starzl team’s experience with FK506 in transplant patients was presented for the first time at a Transplantation Society meeting in San Francisco in August 1990. Dr. Starzl delayed open heart surgery to attend.
It had been discovered earlier that summer that his right main heart artery was 99 percent closed. Surgeons reopened it with angioplasty, but it proved to be a temporary fix. The day after he returned to Pittsburgh, Dr. Starzl underwent coronary bypass surgery.
That year would be his last as a practicing surgeon. The endless days of multiple surgeries, flying from state to state on organ runs and surviving on catnaps were over. “He used to say, ‘Just make it work and somebody else will figure out how it works,’” Dr. Fung recalls.
Nobody did. How transplantation worked was still a mystery in 1990. “Transplantation succeeded in a sea of ignorance,” says Dr. Starzl. “People didn’t know why.” Retired from surgery, he could now give it some thought.
He brought 30 long-surviving transplant patients to Pittsburgh for biopsies and study. They included some of transplantation’s most curious subjects — patients who had quit taking their anti-rejection medication years earlier, yet had not rejected their transplanted organs. What the Starzl research team discovered would again upset conventional thinking in the field.
They observed that a spray of cells from the donor organ managed to co-mingle with those in the body of the patient in a process called chimerism. This process of benign co-existence, they concluded, is what allows patients to accept the foreign tissue sewn into their bodies. It suggested that tolerance is a natural process, one that heavy doses of anti-rejection drugs might actually interfere with.
In an amazing reversal of thinking, Dr. Starzl, who had spent a career pioneering the use of immunosuppressants to make human organ transplantation possible, had launched a movement to eliminate the use of those same drugs. The discovery led to strategies for inducing tolerance and weaning of patients off high doses of anti-rejection drugs. It also created a firestorm because it meant revising transplantation immunology at just about every level. Today, inducing a state of tolerance that will allow patients long lives free of anti-rejection drugs has yet to be routinely achieved. There are those who doubt it ever will be.
To that, Dr. Starzl jabs at a tape recorder: “Turn that thing off for a minute.” He is in his Oakland office, a cramped and cluttered space in a Fifth Avenue storefront that belies his accomplishments. With his dogs barking for attention, he starts to talk about a paper being prepared for publication, then thinks better of it. The protocols for release of the data are strict and disclosure now would violate them. Reluctantly, he leaves it at that. But he gives every indication that he is holding an ace, evidence that might leave doubters unsettled and further thin their ranks — something that after 50 years still gives him pleasure.