A History of Organ Transplantation: Ancient Legends to Modern Practice

11 Transplantation Tolerance and Beyond

221 11 Transplantation Tolerance and Beyond D uring the early 1950s, while human and experimental organ transplant attempts were under way, in the laboratory steady progress was being made toward understanding graft rejection, and the advance of great significance resulted. In 1949, Peter Medawar met Hugh P.Donald, an Edinburgh veterinarian, at a scientific conference in Stockholm, and he asked for Medawar’s help in solving a familiar problem : distinguishing at an early stage between identical and nonidentical twin cattle—that is, between mono- and dizygote twins. Dizygote, or nonidentical twins, when one was male and the other female, could look very similar, since the female twin had been masculinized during gestation. This female twin or “freemartin” will produce no milk and thus is of no economic value. Medawar told Donald that the results of a skin graft from one twin to the other would distinguish between these two types of twin, since he was confident that only the identical twins would accept grafts exchanged between them. Later Medawar recalled the events and his advice: “Let him only assemble a collection of twin pairs of doubtful classification and we would exchange skin grafts between them. If the skin grafts survived the twins could be classified as monozygotic [identical]; if not, not. In the relaxed and matey atmosphere of international congresses one sometimes enters upon commitments that one later regrets; being busy at home I was not overjoyed when Hugh Donald wrote to me a month or two after the congress and reminded me of my promise to carry out skin grafting in twin cattle.”¹ Reluctantly, but under this obligation and knowing that surgery and skin grafting in such animals was technically difficult, Medawar and his group started the research at Cold Norton Farm in Staffordshire, near their Birmingham laboratory, where Donald had the necessary animals for study. The skin grafting was carried out on the animal’s ear, using local anesthetic. As expected, the identical twins accepted each other’s 222 Transplantation Tolerance and Beyond grafts. To the researchers’ surprise however, they found that grafts exchanged between mature nonidentical twin cattle, even those of a different sex, were also accepted. The finding broke the very paradigm that had been established with such difficulty by Medawar and his school—that grafts between different adult individuals are always rejected. The team’s other projects, including some difficult pigment spread experiments and studies of the interesting but modest immunosuppressive properties of steroids, were not going well. The cattle puzzle was certainly a diversion. Ray Owen’s Observations Donald was told of the skin graft findings, and he then informed Medawar that there was a more than useful lead from earlier work on the freemartin cattle by Ray D.Owen, a veterinarian then working in Wisconsin, the dairy farming heartland of the United States. Owen’s research work was supported by grants from the Guernsey Association because freemartin cattle were a financial loss to the industry. Owen had studied one family of quintuplet freemartin cattle and showed that they shared each other’s blood types, a condition that he called “mosaicism.”² All looked different and were genetically diverse, but each animal’s red blood cell population had some red cells from the other four. F.R.Lillie explained the phenomenon of the freemartin cattle twin as the result of shared circulation due to the fusion of the placentas from two separate pregnancies, one in each uterine limb. From F.R.Lillie, “The Theory of the Freemartin,” Science 43 (1916): 611–13. Transplantation Tolerance and Beyond 223 Owen had gone further and had solved the puzzle of these changes by unearthing a 1916 study by Chicago veterinarian Frank R.Lillie that showed the curious anatomy of the twin cattle placentas: “Development begins separately in each horn of the uterus. The rapidly elongating embryo sacs meet and fuse in the body of the uterus. The blood vessels from each side then anastomose in the connecting part of the chorion . . . so that either fetus can be injected from the other. . . . If one is male and the other female, the reproductive system of the female is largely suppressed . . . . This [freemartin state] is unquestionably to be interpreted as a case of hormonal action.”³ This arcane matter had been well known in the field of reproductive endocrinology, but Owen was first to detect the provocative blood...