It was a failed transplant that saved his life. In 1958, Radojko Maksic became the first person to receive a bone marrow graft from a stranger, after he was accidentally exposed to a lethal dose of radiation in Belgrade, in what was then Yugoslavia. He still lives in Belgrade, almost 60 years after the procedure.
It is quite amazing that Maksic survived, given that doctors at the time did not know that donor and patient tissues had to be matched for a transplant to succeed.
Now routine, bone marrow transplants can cure leukemia and other blood disorders by replacing a patient’s damaged marrow – the source of stem cells that give rise to all cell types in the blood – with that of a healthy donor.
More than one million transplants have been carried out, with 50,000 people worldwide receiving a graft every year. But the success of the procedure depends on finding the right donor – someone who is of the same immune type as the recipient. Without this, the graft won’t take and it will be rejected.
None of this was known in 1958. Toronto scientists James Till and Ernest McCulloch didn’t discover blood stem cells until 1960. But experiments in rodents, done in the early 1950s, showed that bone marrow transplants can rebuild new blood in animals whose own marrow was destroyed, raising hopes that a similar approach might also work in man to treat leukemia or radiation damage. These studies, however, were done in inbred mice that did not see the grafts as “foreign.”
Maksic was a 24 year-old physics graduate in a nuclear research institute in Vinca, near Belgrade, when the accident happened on October 15, 1958. Also in the room with him were five other physicists. One of them escaped with a lower dose of radiation, but the rest of the group were lethally exposed. They were to become the first people to receive bone marrow grafts from unrelated donors.
The day after the accident, the five Yugoslav physicists were flown to Paris to be treated by Dr. Georges Mathé, a French transplant pioneer who was an immunologist at the Institut Curie. Much of what we know about this time is in large part thanks to Dr. Goran Milasinovic, a Belgrade physician and writer, who wrote a nonfiction novel based on a diary kept by one of the physicists.
Despite taking the best drugs available at the time – antibiotics – the Yugoslavs’ condition continued to worsen in Paris. The radiation had caused widespread DNA damage, followed by cellular breakdown, hitting hardest at the dividing cells, such as the stem cells in the bone marrow, gut and skin. The Yugoslavs’ hair had fallen out and they were plagued night and day by bouts of sickness and infections, which their destroyed immune systems could not fight. A month after the Yugoslavs’ arrival, Dr. Mathé decided to try something unorthodox. He would look for healthy donors and use their marrows to replace the Yugoslavs’ destroyed tissues.
This had never been done in humans before, although the previous year an American, Dr. Donnall Thomas, did try, unsuccessfully, to transplant the marrow, taken from foetuses or corpses, into terminally ill patients. Donnall’s work did show, however, that receiving the marrow does not kill the patients immediately. But the potential side effects in the patients weren’t the only cause for concern. No one knew how the donors would fare after a portion of their marrow had been taken out.
To find suitable donors, Mathé turned to the hospital’s blood donor registry. Without immune-typing, matching donors by blood type was the best he could do.
Four brave Parisians returned the hospital’s call: Marcel Pabion, Albert Biron, Raymond Castanier and Odette Draghi, a mother of four young children. The fifth donor was Dr. Leon Schwartzenberg, who was one of the doctors on Mathe’s team and later became a politician and a cabinet minister in France. In an heroic act of humanity, the Parisians assumed full responsibility for any side effects that might follow – pain, fatigue, infections and even death. When they arrived at the hospital on the day of the procedure, they couldn’t be certain they would return home.
On November 11, 1958, Maksic became the first man to receive a graft from an unrelated donor. Mathé had drawn the marrow from a bone in Marcel Pabion’s lower back, before injecting it into a vein in Maksic’s arm. The procedures on the other four Yugoslavs followed suit. Tricked into thinking that they were getting another blood transfusion, the physicists were apparently relaxed. This would be unimaginable today, when patients’ consent is a must before undergoing an untested treatment. Presumably, Mathé believed that the Yugoslavs had nothing to lose and wished to spare them unnecessary anxiety. Besides, in those days, doctors could take extraordinary risks with patients’ lives, and Mathé’s Lancet obituary hints at a towering figure whose decisions weren’t questioned: “He was one of the last of the old generation. He used his standing to force things through. If Mathé had an idea, everybody had to believe it.”
Amazingly, Maksic and three other physicists began to recover within a week after the transplant. The fifth physicist, who was a young graduate like Maksic and had received the highest dose of radiation, died.
As the Yugoslavs’ condition continued to improve, they celebrated the arrival of the new year with a party on the hospital ward, toasting to each other’s recovery. They socialized with the donors and their families, visiting them in their Parisian homes and learning French. By all accounts, they were cured.
“I celebrate November 11 (date of transplant) every year by sending a card to my generous donor’s family. As long as I live, I am bound to the Pabions. Marcel, unfortunately, is no longer with us, but his wife, children and grandchildren have become my wider family,” said Maksic in an interview given to the Serbian paper Vesti in 2015.
But by mid-January 1959, two months after the transplant, the donors’ cells could no longer be detected in the Yugoslavs’ blood, which suggested that the grafts had been rejected. There was no doubt that the transplants had saved them; they started to feel better within days after receiving the graft. Yet, now it appeared that the procedure had failed. How could this be?
As Elizabeth Csaszar, a development manager at CCRM explained to me, the physicists’ fast recovery was probably thanks to the rush of the donors’ white blood cells, also present in the marrow, which could finally ward off infections that had plagued them since the accident. The Yugoslavs ultimately rejected the mismatched tissue, but only after the grafts had helped them overcome radiation poisoning to the point where their precious few remaining stem cells recovered enough to churn out fresh blood.
What’s also amazing is that the Yugoslavs had a double stroke of luck, and no one even knew it at the time. The bad blood of unmatched blood goes both ways: just as the graft can be rejected by the recipient, so too can the graft’s immune cells launch an all-out attack on the recipient’s body in what is known as graft versus host disease (GVHD). So powerful is this attack, GVHD still remains the main cause of death in transplants that are not perfectly matched.
By rejecting the grafts, the Yugoslavs escaped GVHD, which would have almost certainly killed them.
It was Mathé who later defined GVHD and reasoned that it was caused by tissue incompatibility. He was also behind the first, but often overlooked, bone marrow graft that cured a patient from leukemia in 1963, and many in transplant medicine believe that Mathé should have shared a Nobel Prize in Medicine with Donnall Thomas, who received the award in 1990.
Despite enormous progress in the last 50 years, finding a matched donor remains the biggest challenge in transplant medicine. One solution to meeting the global demand for stem cell grafts is to use cord blood as a source of cells. Because they come from a newborn baby, which hasn’t yet had a chance to build its immune system, the cord blood stem cells are less likely to trigger rejection or GVHD. In a recent report of an ongoing clinical trial in the U.S., cord blood grafts have shown promising results in treating some forms of leukemia.
Mathé left the stem cell field behind in the mid 1960s, focusing on immunotherapy as a way of treating leukemia. He died in Paris on October 15, 2010 — the anniversary of the Belgrade nuclear accident.
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