E. Donnall Thomas, M.D.
October 20, 2012, saw the passing of Dr. E. Donnall (Don) Thomas, a physician-scientist whose vision and force of will established the procedure known as bone marrow transplantation, thereby launching the field of stem cell and regenerative medicine.
Don was born in Mart, Texas, and attended the University of Texas at Austin where he received his B.A. in 1941 and M.A. in 1943. During that time he was the unintended target of an errant snowball thrown by Dorothy (Dottie) Martin, who was to become his wife of nearly 70 years. With Don's admission into Harvard Medical School in 1943, Dottie switched from aspiring journalist to bread-winning laboratory technician, and they became partners in all things. He taught her to hunt and to fish, and she taught him to like opera. Together, they formed a team that would transform medicine.
Graduation in 1946 was followed by internship and residency at the Peter Bent Brigham Hospital, hematology training under lifelong friend Dr. Clement Finch, and a research fellowship at the Massachusetts Institute of Technology (MIT). As chief resident and then instructor at Harvard, he helped care for Dr. Joseph Murray's first kidney transplant patient, and 36 years later, he and Dr. Murray shared the Nobel Prize for Physiology or Medicine. Dr. Murray's recent death, on November 26, 2012, marked the final intersection of their remarkably interconnected lives.
Don's fascination with leukemia and the bone marrow began while in medical school. Dr. Sydney Farber provided him with his first independent laboratory in the recently opened Jimmy Fund Building, an exciting clinical environment. It was here that Don witnessed the first child with acute lymphoblastic leukemia achieve remission on an anti-folate drug. An initial research interest in hematopoietic growth stimulatory factors was to be replaced, concomitant with his move to the Mary Imogene Basset Hospital in Cooperstown, NY, in 1955, by an obsession with hematopoietic stem cell transplantation. This transition was spurred by a spate of papers, including Dr. Leon Jacobsen's report that shielding the spleen protects mice from otherwise lethal irradiation and Dr. Egon Lorenz's finding that a marrow infusion was similarly protective.
Recruited to Cooperstown by Dr. Joe Ferrebee, Don immediately began an allogeneic marrow transplant program. Initial clinical results, published in 1957, made clear that the road ahead would be long and hard. All six patients died, and only two showed evidence of transient engraftment. The authors commented on “the complexity of the problem of marrow transplantation, with its unknown quantities and potential hazards.”
Other attempts were similarly unsuccessful; even transient engraftment was attained infrequently, and occasional reports of “secondary syndrome” (later known as graft-versus-host disease [GVHD]) hinted at possibly insurmountable obstacles. Many believed that allogeneic bone marrow transplantation would never succeed. A glimmer of hope came from leukemia remissions achieved by the irradiation of patients with identical twin donors, although they almost invariably recurred. In 1962, at the invitation of his old friend Clem Finch, then Chief of Hematology at the University of Washington, Don traveled to Seattle to perform a syngeneic transplant for a patient with aplastic anemia. The following year, Don was recruited to be the University of Washington's first Chief of Oncology, and established his program at the U.S. Public Health Hospital in Seattle.
The complexity of bone marrow transplantation demanded a team effort, and Don was a consummate builder of teams. On the heels of his arrival in Seattle, Don attracted a stream of energetic young investigators, many of whom were to become legendary figures in their own right. This group included Drs. Rainer Storb, Alex Fefer, Dean Buckner, Paul Nieman, Reg Clift, and Bob Epstein. Studies in dogs characterized radiation tolerance levels and led to the development of methods for histocompatibility typing. Eventually it was possible to achieve sustained engraftment of allogeneic marrow and to mitigate the effects of GVHD. Don also assembled a superb clinical team; many nurses devoted the entirety of their professional careers to the cause. But when clinical trials resumed in 1969, success in allogeneic marrow transplantation remained elusive. Early patients suffered horrific toxicities. Despite extraordinary precautions such as laminar airflow rooms, devastating infections were commonplace. Seemingly successful transplants would often suffer cruel reversals with patients succumbing to CMV or fungal infections. Acute GVHD could produce skin lesions reminiscent of full thickness burns, and diarrhea that rivaled the results of cholera. Among Don's most remarkable qualities was his ability to infuse his unwavering determination throughout the entire team, inspiring them to stay the course through waves of heartbreak and disappointment. This collectivization of Don's vision proved vital to the eventual success of allogeneic bone marrow transplantation. In 1972, the same year that the immune suppressive effects of cyclosporine were discovered, the first successes of allogeneic transplantation for aplastic anemia were reported, and the first success in acute myeloid leukemia was achieved, in a 16-year-old girl who is still alive today.
In 1975, the transplant program moved to the Fred Hutchinson Cancer Research Center. Desperately ill patients from the world over traveled to Seattle for their last best hope of being cured. Working on the marrow transplant unit was exhilarating and exhausting, and the stakes could not have been higher. Notable patients included tenor José Carreras, Russian helicopter pilot Anatoly Grishchenko, who sealed the breached nuclear reactor at Chernobyl with sand and cement, and astrophysicist and popular scientist Carl Sagan. Carreras became a close friend of Don and Dottie, and returned to Seattle on September 18, 2012, for a performance to mark the 25th anniversary of his successful transplant and to celebrate Dottie's 90th birthday. It is estimated that by the end of this year, more than one million patients will have undergone hematopoietic stem cell transplantation.
From the thousands of patients enrolled in carefully designed clinical trials, an increasingly clear picture emerged of marrow transplantation's challenges and opportunities. Lower leukemia relapse rates in recipients of allogeneic transplants compared with syngeneic recipients pointed to a potent effect of the donor immune system in combating leukemia. This early demonstration of the power of the immune system in treating cancer remains one of the most promising avenues in cancer research today.
Following his retirement, Don remained a fervent proponent of stem cell research, assisting in the campaign to expand the number of human embryonic stem cell lines available for federal funding, and in opposing a Washington State initiative to impose further restrictions on human embryonic stem cell research. In 1981 he cofounded the first journal for stem cells and regenerative medicine, Stem Cells, and remained a member of its esteemed Comite des Sages for 30 years until his death.
As he wrote in his final manuscript, published in 2005: “We simply do not know whether these cells will ever be of use for patients with Alzheimer's disease, Parkinson's disease, or spinal cord injury. We do know that years of research will be required to define the therapeutic use of embryonic stem cells. In the course of this research we will learn much new information that we cannot now predict. As we wrote about marrow transplantation in 1957, it is high time that we get on with it.” Reprinted from Stem Cells, Feb 2013; 31:221–222, with permission from AlphaMed Press and Wiley-Blackwell.