Rupert Billingham and the Role of Serendipity in the Discovery of Transplant Tolerance

T he Presidential Address gave me an opportunity to pay tribute to my teacher, Rupert Billingham, by recounting the early history of transplantation. Informal conversations with Billingham during the six years I spent in his department and during a recent visit to his retirement home on Martha’s Vineyard provided me with some little known details of the story. Even ASTS members may not be familiar with all of the contributions that Billingham and others made (many of them largely by chance) to the discovery of tolerance for which Peter Medawar was awarded the 1960 Nobel Prize. Others who could have argued for a share of the prize include John Hunter, Frank Lillie, Ray Owen, Hugh Donald, Emile Holman, J. Barrett Brown, Charles Danforth and Francis Foster, Thomas Gibson, Bill Longmire, and Jack Can­ non. The story begins in the first decade of this century with the realization that even technically successful skin homografts uniformly fail. One of the first good descrip­ tions of rejection is in a paper published in 1922 by Emile Holman, a 32-year-old sur­ gical resident in Halsted’s program at Johns Hopkins. He transplanted many small skin allografts to the leg of a 5-year-old boy who had lost most of the skin of his lower extremity in an accident. A month later, Holman performed more pinch grafts to obtain better coverage of the wound. The boy’s mother was the donor of both sets of skin grafts. Holman noted that the “second set” of grafts were rejected more rapidly than the earlier ones, thus becoming the first one to describe the so-called second set reaction. Holman, who became chairman of surgery at Stanford, said later that one of the great missed opportunities of his life was a failure to follow up on this observation. Rediscovering the phenomenon, Medawar used it to prove that rejection was an immunological process. In 1929, two Stanford veterinarians, Charles Danforth and Francis Foster,