A pioneering paper turns 50

Don Thomas' findings on first safe harvest and transplantation of bone marrow led to birth of Hutchinson Center, 1990 Nobel Prize
Dr. E. Donnall Thomas
In the face of a skeptical medical community, Dr. E. Donnall Thomas began infusing patients with donor bone marrow in 1955. In 1975, he joined Dr. William Hutchinson to found the Center, which enabled him to move forward in the establishment of a landmark transplant program. Photo by Susie Fitzhugh

Fifty years ago, on Sept. 12, 1957, the New England Journal of Medicine published a research paper by four East Coast scientists that would launch an era of clinical study of bone-marrow transplantation to treat cancer. However, in the 1950s, public attention focused more on the threat of nuclear war and radiation-induced illness than on random genetic changes in the body that can cause cancer.

"In an atomic age, with reactor accidents, not to mention stupidities with bombs, somebody is going to get more radiation than is good for him," wrote lead author Dr. E. Donnall Thomas. "If infusion of marrow can induce recovery in a mouse or monkey after lethal radiation, one had best be prepared with this form of treatment for man. The leukemic patient who needs radiation and bone marrow and the uremic patient who needs a spare kidney are the people who deserve immediate consideration. From helping them, one will be preparing for the atomic disaster of tomorrow, and it is high time that one did."

The now-defunct U.S. Atomic Energy Commission and the U.S. Public Health Service funded the paper, "Intravenous Infusion of Bone Marrow in Patients Receiving Radiation and Chemotherapy." It reported results of infusing marrow into six patients and showed for the first time that human bone marrow could be collected and stored in significant quantities and then administered by intravenous injection with safety.

"This paper got the whole thing rolling," said Thomas, who went on to receive the Nobel Prize in physiology or medicine in 1990 for his pioneering work. "The transplants were not successful, but we did show you could give marrow intravenously without any harm."

Fortunately, bone-marrow transplantation was not necessary on a large scale to treat casualties of the Cold War. And although earlier research, published elsewhere, showed bone-marrow transplantation could provide radiation protection for mice, dogs and primates, there was only one instance of successful radiation protection using this method in humans — a man in Pittsburgh who was exposed to radiation in a hospital accident in 1967. Thomas and colleague Dr. Dean Buckner, both at the University of Washington at the time, flew to Pittsburgh to treat the patient.

Thomas began his career as an attending physician at the Peter Bent Brigham Hospital in Boston where, in December 1954, Dr. Joseph Murray performed the world's first successful kidney transplant. Thomas was the ward attending at the time. That organs could be transplanted from a human donor piqued his interest in transplantation in general. In the early 1950s, he and colleagues at various institutions were pondering about and conducting experiments on factors that stimulate the bone marrow.

"Some radiation experiments with mice had been going on," Thomas said. "Dr. Leon Jacobson at the University of Chicago found that he could protect mice by putting a lead coil around the spleen. The mice survived. We knew that the most sensitive tissue to radiation is bone marrow. The initial belief was that a hormone in the spleen is what protected the mice."

At the time in 1955 when Thomas joined the Mary Imogene Bassett Hospital in Cooperstown, N.Y., a paper by Dr. Richard Prehn was published in the Journal of the National Cancer Institute about the results of a mouse receiving marrow from another mouse of a different strain.

"The subsequent bone marrow had characteristics of the donor, not the recipient," Thomas said. "This was the first clue that it was transplantation of the cells, not a hormonal effect, which provided the protection."

Thomas discussed the Prehn paper at length with his new boss. What about replacing diseased marrow in humans with new marrow from a donor?

In the fall of 1955, Thomas and colleagues began infusing patients with donor bone marrow harvested from fetal and adult cadavers, from ribs removed at surgery and from hipbones using an aspiration needle. The collected marrow was passed repeatedly through a stainless-steel screen and broken into a smooth cellular suspension. Fat was removed using centrifugation. The marrow cells were suspended in tissue-culture fluid and serum. Unused cells were frozen in glycerol and stored at -80 C.

The medical community was openly skeptical, but Thomas was a tenacious man.

"Nothing was known about this basically," he said. "Our first attempts were just to see if we could infuse bone marrow. We didn't know whether the blood would clot and cause the patient to die."

The infusions did not cause clotting, but most of the patients they treated with unrelated donor marrow during a two-year period died. For one, nothing was known about the critical role of tissue typing. (It took another eight years of research using a dog model to discover that.) The researchers also learned that they hadn't administered enough radiation to kill the diseased marrow.

The long road to human transplants

However, they achieved one transient graft and they discussed in their paper the possibility of graft-vs.-host-disease if a transplanted patient lived long enough, a prescient topic as it turned out.

"We learned that marrow transplantation in man was going to be very difficult," Thomas said. "The next definitive step was to conduct more transplants on humans and dogs."

In 1958, Thomas's team transplanted a 3-year-old girl with end-stage leukemia with marrow donated from her identical twin. This time, a large dose of radiation and marrow from an identical twin resulted in a successful transplant. The patient did well for six months until her leukemia returned.

Thomas moved to Seattle in the 1963 with Drs. Ted Graham and Bob Epstein to join the UW. Over the next several years, Drs. Rainer Storb, Buckner, Paul Neiman, Alex Fefer, Reg Clift and John Hansen joined them. The research team worked out of the only space available at the time at the former Public Health Hospital. Research continued on refining the transplant procedure.

Thomas worked with Dr. William Hutchinson to found the Fred Hutchinson Cancer Research Center in 1975. That same year, he published a review of the entire field of transplantation in the New England Journal of Medicine. In 1977, two decades after the publication of his seminal NEJM paper, he published another landmark work in the journal Blood that reported the results of the first 100 bone-marrow transplants in humans.

"When I joined the Center in 1975, transplantation research had come a long way, but it had been a long time, 20 years," Thomas said. "We knew that tissue typing was essential. We had several successful transplants using brothers and sisters of patients. The whole thing was ready to break wide open."

Thomas credits the creation of the Hutchinson Center with providing the facilities to establish a formal clinical-transplant program. "It made it possible to move ahead on a significant scale," he said.

The rest, as they say, is history.

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