At Pittsburgh, Starzl's colleagues have incorporated his thinking about microchimerism into their procedures. They treat with a powerful immunosuppressant three weeks before surgery, then inject donor cells into the patient and follow with low doses of drugs until the operation. "You're treating the recipient's cells, so they won't cause a host-versus-graft response, but also you're treating the donor's cells, some of which are immunocompetent, so they don't try to reject the recipient," Starzl explains. After surgery, physicians prescribe lower-than-normal doses, trying to wean patients to very low levels or off the drugs completely. According to Ron Shapiro, a colleague of Starzl's at Pittsburgh, various transplant centers are following a similar protocol, including one in Galveston, Tex., and several in Europe. Researchers at Stanford and Harvard universities, among other places, also are working to understand the underlying science of microchimerism and tolerance.
Still, microchimerism as the mechanism explaining tolerance is not convincing to many in Starzl's field, observes Fritz H. Bach of Harvard Medical School. "The microchimerism idea and data have never gained traction; I think most individuals do not believe the concept as explaining tolerance," he sums up. "His hypothesis is in dispute--the evidence isn't there," concurs David E. R. Sutherland of the University of ¿Minnesota, who believes microchimerism is a consequence of not ¿rejecting, rather than a cause. "Why some people don't reject when they come off immunosuppression is not understood. We don't understand why, and there is no reproducible protocol."
In addition, Starzl is legendary for his campaigns, for approaches he has advocated despite their controversy--or, as some of his colleagues describe, despite their lack of supporting evidence. His xenografts in the 1960s were one such passion, and their ultimate failure earned Starzl criticism. In the 1980s he backed a drug called FK506, or tacrolimus, that had proved highly toxic in some animal studies. "Tom persisted in using tacrolimus despite initial problems with toxicity that discouraged his peers, and he turned out to be correct," describes Nicholas L. Tilney of Harvard Medical School, current president of the Transplantation Society and author of the 2003 book Transplant: From Myth to Reality (Yale University Press). The Food and Drug Administration approved tacrolimus in 1994, and today it is used in roughly 80 percent of kidney and 90 percent of liver and pancreas transplants.
"He really did push the envelope," Tilney says. "He did bring things up over the years, many of which turned out to be right and many of which didn't. He likes to stir the pot." Whether microchimerism proves to be the mechanism engendering tolerance, no one disputes the influence Starzl has and continues to have on his field--and his gift for communicating his vision in a compelling narrative. Sutherland compares Starzl with Dostoyevsky. "He has that sense of how to bring things together, and he is doing that now," he says. "He just does things. He darts through, makes end runs, and he moves the field forward."
Shapiro agrees. "The interesting thing is that everyone thinks he is crazy, but when he moves on to the next thing, the first thing he says becomes conventional wisdom," he says. "Everyone knows he is very smart. But he is actually a little smarter even than that." Future organ recipients certainly hope that assessment of Starzl is right.
This article was originally published with the title Graft and Host, Together Forever.