PerspectiveSCI COMMUN

E. Donnall Thomas (1920–2012)

Science  30 Nov 2012:
Vol. 338, Issue 6111, pp. 1163
DOI: 10.1126/science.1232395

With the death of E. Donnall (Don) Thomas on 20 October, the field of oncology lost an inspiring figure and the individual most responsible for developing human bone marrow transplantation. Don had what seemed to him a simple idea: Because normal marrow was easily destroyed by irradiation, shouldn't it be possible to destroy an abnormal marrow and replace it with marrow from a normal donor? Although simple in concept, Don's struggle to make marrow transplantation a clinical reality was long and difficult. Early attempts were unsuccessful, either because the transplanted marrow was rejected, or because the marrow rejected its new host. These failures led many to criticize Don's efforts as dangerous and futile. But his persistence paid off in the development of a therapy that has saved hundreds of thousands of lives.

Don became interested in hematopoiesis while training at Harvard Medical School (where he earned an M.D. in 1946). He witnessed Sydney Farber's first use of antifolates to induce remission in acute leukemia and Allan Erslev's search for erythropoietin. He also learned of Leon Jacobson's studies showing that shielding the spleen or bone marrow protected mice from the lethal effects of irradiation. When studies showed that irradiated mice infused with donor marrow could recover, Don was convinced of the potential of human marrow transplantation.

In 1955, Don moved to the Imogene Bassett Hospital in Cooperstown, New York, to work with Joseph Ferrebee. They published the first experience with human allogeneic marrow transplantation. Six patients were treated with radiation and chemotherapy followed by infusion of normal donor marrow. These were only transient grafts and none lived beyond 100 days. Attempts at allogeneic marrow transplantation by others, including some in victims of a nuclear-reactor accident, also failed. Because histocompatibility was not understood and no efforts were made to match donor and recipient, these results are not surprising.

Yet Don remained convinced of the potential of marrow grafting and turned to a canine model. He found that after total body irradiation and infusion of littermate marrow, most dogs developed the problems seen in humans, including graft rejection or graft-versus-host disease. But some dogs became long-term survivors with marrow completely of donor origin. Don reasoned that the successful donor-recipient pairs were somehow genetically matched and that discovering methods for donor selection was critical. In 1963, he moved to Seattle, where he and his colleagues developed rudimentary canine histocompatibility testing. They also determined appropriate doses of radiation to ensure engraftment and developed methotrexate postgrafting to prevent graft-versus-host disease. By the mid-1960s, they could reliably transplant canine littermates. Meanwhile, methods for human leukocyte antigen typing became available and, with these advances, Don returned to the challenge of human marrow grafting.

CREDIT: SUSIE FITZHUGH

He assembled a team of physicians, nurses, and technicians and in 1969 began clinical trials of allogeneic transplantation from matched siblings for patients with advanced leukemia. They went to extraordinary lengths to support patients, housing them in sterile laminar airflow rooms, asking staff members to donate platelets, and working with Robert Hickman to develop a catheter for intravenous alimentation. Most of the initial patients died of progressive leukemia or complications of transplantation, but a few survived. In 1975, now at the newly formed Fred Hutchinson Cancer Research Center, Don published results showing a plateau in the survival curve, demonstrating that a minority of patients with otherwise incurable leukemia had been cured. The group started transplanting patients earlier in their disease, while in remission, and soon was reporting cure rates in excess of 60%. This success led the Seattle team to explore transplantation for other diseases of hematopoiesis, including sickle cell anemia, thalassemia, myelodysplasia, multiple myeloma, and lymphoma.

Transplantation was initially limited to the approximately 25% of patients with a matched family member. In the late 1970s, the Seattle group performed the first successful marrow transplant from a matched unrelated donor. This success encouraged the creation of donor registries in the United States, Europe, and Asia. Remarkably, more than 20 million potential donors are now typed and listed in these registries. With the broadened indications for transplantation and the increased availability of donors, the use of marrow transplantation has steadily grown. This year, about 65,000 transplants will be performed worldwide, and the cumulative number of transplants performed since Don began his work will surpass 1,000,000.

Don was born on 15 March 1920 in Texas. He liked to mention that between him and his father (a physician), they spanned the period from horse-and-buggy house calls to modern high-tech medicine. He studied chemistry at the University of Texas where he received his B.A. and where he met his wife, Dorothy (Dottie). Besides raising three children together, Dottie was Don's partner in every aspect of his professional life, from working in the laboratory to editing manuscripts and administering his research program. If Don was the father of marrow transplantation, then Dottie is surely the mother. For his work, Don deservedly received a multitude of awards, including the 1990 Nobel Prize in Physiology or Medicine, which he shared with Joseph Murray. He was equally admired for his pioneering scientific discoveries and the way in which he achieved his success. He was hardworking, uncompromising, and a demanding critic. But he was also humble, witty, generous with ideas, and quick to deflect praise to his co-workers. Most of all, he was dedicated to his patients and the development of a therapy to give them a better chance at life.

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