Frederick R. Appelbaum, MD
Executive Director, Seattle Cancer Care Alliance; Clinical Research Division, Director, Fred Hutchinson Cancer Research Center; Professor, Medical Oncology Division, University of Washington School of Medicine
|Photo by Susie Fitzhugh
Don Thomas wanted to solve big problems. When asked how he chose to work on marrow transplantation, Don explained that while completing his training in hematology, he asked himself what the largest problems in the field were. He first considered hemoglobinopathies, with the idea that they might be cured if the switch from Hb F to Hb A could be prevented, but he didn’t know how to attack the problem. So he turned to what he considered the second greatest problem, leukemia. It was the early 1950s, and he learned of the experiments of Leon Jacobsen and others showing that marrow of normal mice could be destroyed by radiation but animals could recover if infused with marrow from a syngeneic donor. With that knowledge, he became convinced of the clinical potential of marrow transplantation. He wasn’t alone. Joseph Ferrebee at the Imogene Bassett Hospital in Cooperstown, NY, was also inspired by that same concept, and in 1955, after completing his training, Don moved to Cooperstown to work with Dr. Ferrebee. There, in 1957, they made the first attempts to treat patients with total-body irradiation and chemotherapy followed by intravenous infusion of normal donor marrow. Transient marrow grafts were seen in a few patients, but none lived more than 100 days. Similar attempts by many others also failed, either because grafts were rejected or because grafts rejected their new host. In retrospect, since nothing was known about histocompatibility matching, these results were not surprising, but they certainly were discouraging, leading most to abandon the field.
But not Don. Whether persistent or stubborn, he remained convinced of marrow transplant’s potential and began experiments using an outbred canine model. Most transplants between littermates failed, but occasionally a dog would become a long-term chimera. Don reasoned that the successful donor-recipient pairs were somehow genetically matched. In 1963 he moved to Seattle and, with colleagues, began developing methods for canine histocompatibility typing. They also worked out appropriate doses of irradiation to assure engraftment and found that posttransplant methotrexate helped prevent graft-versus-host disease. By the late 1960s, they could reliably engraft canine littermates, and with the knowledge gained from those rigorous animal studies, together with advances in human histocompatibility typing, Don returned to the clinical challenge of human marrow transplantation, 12 years after his first failures.
He assembled a team of nurses, technicians, and physicians and, in 1969, began clinical trials of matched sibling marrow transplantation for advanced leukemia. The initial study patients were very sick with life expectancies measured in weeks. The team went to extraordinary lengths to support their patients, housing them in sterile laminar flow rooms, asking staff members to donate platelets, administering prophylactic granulocyte transfusions, developing with Bob Hickman methods to allow intravenous alimentation, and creating homemade anti-thymocyte globulin by inoculating and subsequently phlebotomizing horses (Don performed this procedure himself). Despite these efforts, most patients died, but a few survived. In 1975, Don published results that showed a plateau in the survival curve demonstrating that a minority of patients (13 of 100) with otherwise incurable leukemia had, in fact, been cured. These results led to exploration of the use of transplantation earlier in the disease course, while patients were in remission, and soon cure rates in excess of 60 percent were being reported. This success led the Seattle team to explore transplantation as therapy for other hematopoietic diseases, including thalassemia, sickle cell anemia, myelodysplasia, lymphoma, and myeloma. In the late 1970s, the Seattle group performed the first successful, unrelated donor transplant for leukemia. With expanded indications and increased donor availability, the use of transplantation grew steadily; this year approximately 65,000 transplants will be conducted and the cumulative number performed since Don began his work will surpass 1 million.
Don was an extraordinary person, extremely bright, with a remarkable memory and real curiosity. If you were working in an area that he didn’t fully understand he would come by and modestly ask for a lesson. He was quiet and soft-spoken, letting others lead most discussions. And yet, he projected a remarkable aura of authority. When he did talk, everyone listened. Papers and proposals were expected on time and carefully done. Shoddy work or sloppy thinking was not acceptable. At faculty meetings, someone might make a joke but no one would laugh, at least not until Don did, and then everyone would laugh, until Don stopped, and then everyone stopped. Yet, he was modest and quick to deflect praise to his coworkers to whom he was very loyal, and those of us who were the recipients returned that loyalty.
Two aspects of his career stand out to me. First, Don truly believed in the idea of marrow transplantation and was willing to bet the house on it. While other cancer centers were developing broader clinical programs, Don focused almost the entire clinical efforts of the Fred Hutchinson Cancer Research Center on marrow transplantation. Virtually every recruit for well over a decade was dedicated to the general topic. A second defining aspect of Don’s approach to tackling the complexity of marrow transplant was his appreciation that it would take a team to achieve his vision. The group Don assembled included nurses, administrators, lab techs, and medical subspecialists focused on the spectrum of complications of marrow transplantation, including infectious diseases and pulmonary and gastrointestinal disorders. Don firmly believed that it took such a team to achieve the clinical outcomes that led to the eventual success of marrow transplantation. When Don learned he was awarded the Nobel Prize, one of the first places he went was to the transplant unit’s nursing station to thank the nurses (who he called his secret weapon) for their contributions.
As hard-working and focused as Don was, he also understood that there was life outside of work. When recruiting faculty to Seattle, he used to jokingly ask if candidates were skiers or fisherman, because he wanted to balance the two to ensure that enough people would be at work both winter and summer. He and his wife Dottie were avid hunters and fishermen, and every meal we shared at Don’s house featured elk, moose, or steelhead trout. He particularly enjoyed having young faculty over and pointing out pictures of Dottie with a shotgun in one hand and several dead ducks in the other, commenting with a smile that he sure hoped their paper was going to be turned in on time.
Editor’s Note: Professor Thomas, a past president of ASH, died this past October in Seattle. He was 92. Dr. Thomas shared the 1990 Noble Prize in Physiology or Medicine with Dr. Joseph E. Murray, who pioneered solid organ transplantation, performing the first kidney transplant in 1954. Notably, Dr. Murray died this past November at the age of 93. The E. Donnall Thomas Lecture and Prize was created by ASH in 1992 in recognition of the singular impact that Prof. Thomas’ work had on hematology and to acknowledge the many contributions that he made to the Society. The E. Donnall Thomas Lecture and Prize, awarded annually, is intended to recognize pioneering research achievements in hematology that have represented a paradigm shift or significant discovery in the field.
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