The dogs bound into the office, two of them. Not quite Hounds of the Baskervilles, but large enough. It is a dramatic lead. A minute or so later Thomas E. Starzl follows them in, and, while his pets nap and his assistant provides this or that document or letter, he settles in to recount a story, a compelling narrative of a field that has come full circle. All the classical elements are there: a missed turn, bad timing, a paradigm shift, some overturned dogma and a satisfying, hopeful conclusion: organ transplantation without a lifetime of antirejection drugs.

The 80-year-old Starzl, a transplant surgeon and researcher at the University of Pittsburgh, where he has an institute named after him, is legendary for his groundbreaking work over the past five decades. He was the first person to perform human liver transplants. He developed new techniques for transplant surgery, helped to make kidney transplantation viable and was one of the first researchers to try xenografts--in the 1960s he placed baboon kidneys in six patients. (None of the transplants lasted long.)

Crucially, he experimented with, combined and developed drugs to suppress the immune system, thereby preventing organ rejection. He advocated widespread use of these immunosuppressants, and because of these drugs, the number of transplants has grown every year for the past several decades; in 2005 surgeons performed 28,107 transplants of the kidney, liver, pancreas, heart, lung and intestine, according to the United Network for Organ Sharing. But although the drugs permit transplants and save lives, they also have debilitating and sometimes deadly side effects, because the weakened immune system cannot fight viruses or cancers. Transplant specialists have considered the chemicals to be a necessary evil: freed from their dampening influence, the patient's immune system would rebound and reject the foreign organ.

In 1992 Starzl observed something that convinced him to rethink the way immunosuppressants are used. He had brought together many of his former patients, including some he had operated on in the early 1960s. He learned that some of them had stopped taking their drugs long ago and were doing just fine. Starzl tested these patients, hoping to see something consistent; he observed donor cells in various tissues and blood.

The phenomenon is called microchimerism, a condition in which a small number of cells from two individuals coexist in one body. Twins can be microchimeric, having traded cells in utero; mothers and their children can be microchimeric as well, for the same reason. (Often this coexistence is peaceable; there is some evidence, however, that microchimerism could play a role in autoimmune disorders.)

For Starzl, these shared cells are the key to tolerance--?acceptance of the graft by the host. His hypothesis, essentially, is that the body comes to terms with "other" by dealing with it in an incremental way, by coming to see some circu?lating donor cells as "self" and paving the way for acceptance on a larger scale. The presence of large numbers of donor cells in recipients has long been observed in bone marrow transplantation, a discipline Starzl believes has advanced basic science more than organ transplantation has to date. He argues that evidence of microchimerism in his patients finally unites the science of organ transplantation with that of bone marrow, allowing his field to move beyond being ?"totally drug-related, which is kind of humiliating."

 

In microchimerism, a small number of cells from two individuals coexist in one body--a potential key to transplantation without immunosuppressants.

Considering his long advocacy for antirejection drugs, some observers have characterized Starzl's new approach as a reversal. But Starzl insists it is not. He points to a paper he wrote in 1963 about tolerance in kidney transplant patients as anticipating his mind-set today--it was just that the timing was not right; the science was not advanced enough to make sense of what he saw, of the paradigm shift in the wings. "That is the foundation of this idea that I have been pursuing ever since," he declares.

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.