'Commander' Spurs Researchers In Development Of FK-506

Transplant surgeon Satoru Todo is sitting in his tiny University of Pittsburgh office, wearing blue scrubs and singing the praises of Thomas E. Starzl, the neurologist and surgeon who leads the team that has developed FK-506, a drug that has been hailed as a breakthrough in preventing the rejection of transplanted organs. "He is like a commander," Todo says cheerfully. "Or a dictator." While such epithets might seem inappropriate in describing the inspirational force behind a harmoniously functioning and successful research effort, the members of Starzl's team claim they would have it no other way. A dictator's single-mindedness and a commander's resourcefulness were the characteristics needed to take FK-506 from test tube to bedside, they agree. Starzl's team cuts across the usual department boundaries; immunologists, pharmacologists, transplant surgeons, and pathologists have all pooled their skills to make this powerful new agent a useful drug for humans. Starzl was responsible not only for coordinating the logistics of this army of talent, but also for keeping the spirits of his troops high when early reports from Cambridge University declared the drug intolerably toxic and, thus, useless. The development of FK-506 began in 1986, when Starzl was scanning the advanced program for the annual meeting of the European Society for Organ Transplantation. One abstract piqued his interest. It was a description of a powerful new immunosuppressive agent derived from a fungus found on Mount Tsukuba in Japan by scientists at Fujisawa Pharmaceutical Co. Starzl was intrigued by the drug's chemical structure and wondered whether FK-506 could be used to prevent rejection in patients with newly transplanted organs. He had been instrumental in developing several antirejection drugs, most notably cyclosporin, yet patient survival rate after one year was still not ideal, hovering at about 70%. In addition, cyclosporin patients frequently suffered adverse side effects. In August, Starzl and Todo flew to the conference in Helsinki, Finland. There, Starzl gave a speech at a plenary session and then attended exactly one other presentation: that of scientists from Chiba University in Japan, who were describing their FK-506 rat studies. A few weeks later, Starzl and Todo were on another plane, this one returning to Pittsburgh from Japan, where they had spent a week persuading Fujisawa officials to allow them to work with the drug. With them were 600 milligrams of the potent agent, enough to begin their work. Within just a few months, FK-506 emerged from the pack of promising new agents as the backstretch leader. Dog studies were being planned when Starzl got wind of news that threatened the development of the drug: Cambridge University results indicated that FK-506 caused widespread arteritis (arterial inflammation) in dogs, a toxic side effect that indicated the drug was unfit for human use. Suddenly the members of the Pitt team faced a crisis in confidence. Should they continue their research? And even if their results were promising, could the reputation of FK-506 within the transplant community be resuscitated? "This was very discouraging," recalls Starzl. "I brought that information back, and we had some serious discussions here and decided to go forward anyway, because everything we had seen so far had been remarkable." This divergence of opinion between the British and United States squads emphasizes the roles of intuition and sheer determination in scientific research. The members of the Cambridge team, led by Roy A. Calne, were not novices. Indeed, Calne, a longtime colleague and friend of Starzl's, is one of the pioneers of transplantation. But his group lacked the conviction shared by Starzl's team - that widespread arteritis was a side effect specific to dogs. The Pittsburgh team was convinced that careful administration of FK-506, informed by long study of the metabolism and pharmacokinetics of the drug, would prove the agent to be safe as well as powerful. Of course, this conviction was nothing more than a hunch in late 1986, a gut feeling that resembled intuition and luck but was actually born of years of hard work. "Dr. Starzl has always had a sixth sense about drug development," says John Fung, director of transplant research at Pitt and a member of the FK-506 team. With an M.D. and a Ph.D. in neurophysiology, Starzl "has a very keen understanding of basic science," says Fung. He adds: "You'll find some people who are good clinical surgeons and some people who are good basic scientists. It's very rare to see somebody who does both as well as Dr. Starzl." Fung, who is both a surgeon and an immunologist, explains the theory that governs research at Pittsburgh. "We try to look for how a basic science problem has a relationship to a clinical problem. And then we use the clinical material to probe into the basic science question." This synergy became an important part of the FK-506 work. As the development of the drug continued, more and more Pitt researchers, from a variety of departments, were tapped for their talents. In 1988, studies headed by Todo demonstrated that FK-506 did not cause widespread arteritis in baboons and, in fact, was remarkably free of any other unwanted effects. The team received the go-ahead for clinical trials, and attendance at the regular Monday evening meeting of the group continued to swell, from a handful of scientists in 1986 to more than 50 interested researchers by 1989. Pharmacologist Raman Venkataramman is one of the original group members. His responsibility has been to develop tests with which to measure the presence of the drug in the body, to study the metabolism of the agent, and to determine its proper dosages and formulations. When clinical trials with FK-506 began in February 1989, the interplay between the lab and the clinic became even more crucial, and Starzl, Venkataramman, and others stayed in close communication through their beepers. Venkataramman recalls a time when the team was faced with a patient whose liver was functioning poorly and whose body was storing very high levels of FK-506. Right away, Venkataramman and Starzl sat down to design an animal experiment that would simulate the same conditions in the lab. By conducting such an experiment, the researchers would be able to determine what was happening mechanistically, "so we [could] translate that into patient care," the pharmacologist says. Through this kind of exploration, the team discovered that FK-506 is metabolized primarily in the liver and that one of its metabolites performs the crucial work of inhibiting the production of T cell-derived lymphokines such as interleukin 2. In liver transplant patients, the drug not only prevents rejection from starting, but also is capable of halting rejection that has already begun. "We were stunned at what we could do," Starzl says. The Pittsburgh team members weren't the only ones stunned. When the results of the clinical trials were published in The Lancet (II:1000-4, 1989) and presented at the annual meeting of the European Society for Organ Transplantation, other transplant scientists took notice of this drug. FK-506 was 100 times more powerful than cyclosporin, yet had none of that drug's adverse effects. Although there are still a few "conservative hold-outs," observes Starzl, the tide of opinion regarding the superiority of FK-506 has turned. Other major transplant centers are clamoring to run clinical trials of their own. Meanwhile, the Pitt team plans to begin looking for other applications of the immunosuppressant agent. The success of the FK-506 work, say the members of the team, is the result of the group's multidisciplinary composition and Starzl's unique brand of leadership. "His way is to go full steam ahead and get the question answered, and then go back and look at the problems," Fung says. "His philosophy is: Don't pussyfoot around, doing one or two patients here and there and have a study take two or three or four years. Just try and get the study done. It has its benefits, because something that is good gets done faster and something that's bad gets kicked out quick." This kind of research can be addictive. Todo had intended to return home to Japan three years ago, while his children were still young enough to adapt to Japanese schools. Yet here he still is, working in Iron City. Was it the thrill of developing FK-506? Or the gratification of being part of the world's busiest transplant program? Todo pauses to think, then answers, "Probably Dr. Starzl's passion." He leaves unspoken that it is a passion shared by many. Liz Marshall is a freelance science writer based in Pittsburgh.

'Commander' Spurs Researchers In Development Of FK-506

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