Fred Appelbaum’s “Living Medicine” tells the story of bone marrow transplantation and Don Thomas’s discoveries

Frederick Appelbaum: What was it like?

FA: I first became aware of Don in 1970 when I was a medical student, and I had a wonderful mentor who was teaching me how to do a physical exam. She happened to mention this radical new therapy that Don Thomas was working on—marrow transplantation.

The idea of transplantation just seemed amazing to me. It hadn’t been worked out in humans yet. But the idea that you could get rid of someone’s entire hematopoietic system and transplant a normal one in place of it just seemed extraordinary to me.

And so when she mentioned it, I went and read one of Don’s earliest works that he had published in Blood. And from then on, don’t ask me why, it was like having my brain tattooed. I just couldn’t get it out of my mind. It was something that just appealed to me.

Why does somebody love classical music or someone love poetry? There are things that just appeal to us.

And then it came time for me to do my fellowship, and I did it at the National Cancer Institute in Bethesda, Maryland. There, I started to do some work in marrow transplantation, which caught Don’s attention. And one day at the end of 1977, the phone rang and it was him calling me up and asking me if I was interested in working with him. It was like the heavens opened up and God was looking down at me and saying, “Would you like to come?” It was really quite an honor to be noticed and to be able to work with him from the beginning.

FA: Well, it was very exciting. It lasted about a minute. Don was not one for chit chat.

FA: I think the reason I wanted to write the book was to memorialize Don and the whole team, and everyone really, throughout the world that’s worked on the topic of marrow transplantation. It’s a terrific story. If it hadn’t been told, and if the story had been lost to history, I just thought that would be a tragedy.

I mean, we’ve gone from a setting where Don and just one or two other people were the only ones that thought marrow transplantation was even possible in the 1950s, to today, where there are 100,000 transplants performed worldwide every year and 40 million people have signed up and registered to be potential stem cell donors. That’s a monumental achievement. That was the primary motivation for writing the book. In addition, and I know that no single book makes any measurable difference, but I just thought that anything that increases our scientific literacy in this day and age has to be a good thing.

FA: I think there are a number of lessons that you can get from Don’s story. They may not all be applicable to everyone, but if you were to ask what was the secret sauce Don had, it had lots of ingredients in it.

Don had a terrific idea to start with. So let’s start with that. He had this wonderful idea—he didn’t know how to do it, but it was a great idea that you potentially could transplant bone marrow, and the implications of that were just enormous.

He did not stray from that. He was, throughout his career, incredibly focused on that goal. He didn’t become much broader, he became much deeper, and continued to focus on that with sort of a single mindedness and a persistence that was really, I think, quite extraordinary.

So there’s that. The second thing is that he didn’t know how to solve the problem, but he kept working one step at a time. As he said, if he’d gotten to a true dead end, he probably would’ve quit and tried something else, but he never did.

There were multiple steps it took to achieve the goal. There’s a quote from E.L. Doctorow, which I like a lot. He was talking about writing, but he said, “it’s like driving at night in the fog. You can only see as far as your headlights, but you can make the whole trip that way.” I think that was sort of the lesson from Don that, you might not know how to solve all the problems, but if you keep one step at a time, you may be able to get there.

One other thing about Don was that he knew that it would take many, many different kinds of input to solve the problem. So he created, at the Fred Hutch, his own small department of medicine, all just focused on the issue of marrow transplantation.

He was taking in people that were focused on infectious diseases in the transplant patient, in GI complications in the transplant patient, pulmonary problems in the transplant patient. He had his own dieticians, his own social workers, his own pharmacists. It really took—it’s a cliche now, but it did take a village to solve the problem. If you asked me what was unique about Don, it was his focus, his persistence, his ability to draw a team, to solve a very difficult problem.

FA: So Don—he got into medical school in an unusual way, actually. It was during the buildup in World War II. In World War II, there was suddenly this huge shortage of physicians because so many physicians were being taken out to take care of the military. So there were not a lot of physicians left at home.

Harvard and some other medical schools started taking new classes every nine months and condensing the training into three years, and providing funding for the housing, and for the tuition. Don was dirt poor. He couldn’t afford to go to medical school. He was in this little town in Texas. But when that was available, he applied for that special training and was able to be accepted at Harvard.

When he was at Harvard, he saw different diseases, but was instantly drawn to leukemia. In his own words—I won’t quote this exactly—but he said it was a terrible disease. People were dying within weeks to months. He just felt he owed it to patients to try and do better.

With leukemia, you could take a drop of blood from a vein, and you could actually see the malignant cells. It’s like a biopsy, as opposed to pancreatic cancer where you can’t get your hands on the tissue. Studying leukemia just made sense to him because it was something that was a terrible disease, but you had ready access to the cells.

He took a hematology fellowship there, and was able to see Sidney Farber treating the very first children with aminopterin,an anti-metabolite, and getting some complete remissions.

Now, the complete remissions were short-term, but this was the first time people were really seeing complete remissions in acute leukemia. And so Don was very drawn by that. He then read about the spleen shielding experiments that were going on by Leon Jacobson, and suggested to Don that marrow transplantation might be possible.

He was at the Brigham at that time, and Farber was his boss. He wanted to try some experiments to do this, but Farber thought it was a terrible idea and wouldn’t give him any space. Interestingly, Farber had become surprisingly conservative after his first successes with single agent chemotherapy, and didn’t even want to try combination chemotherapy, much to the chagrin of some other of the investigators at the time.

And so Don had this idea, but unfortunately wasn’t able to pursue it at the Brigham because he had no space. That was when he decided that he would prefer to pursue the idea than to stay at Harvard, and that’s when he moved to Cooperstown.

FA: Yes. In 1955, he moved to Cooperstown to work with a guy by the name of Joe Ferrebee. Ferrebee had been at Harvard, and Don had met him at that time. Ferrebee was doing some research in what was then a pretty nascent field of immunology. Ferrebee also had the idea of the potential for marrow transplantation. When Ferrebee and Thomas got together, they really wanted to pursue this idea. And so they did. They both did some early experiments in a canine model, but also in humans.

And in 1956, they did their first human transplants, which failed very quickly in six patients that were reported in the New England Journal of Medicine. But, you could give marrow intravenously at least, and it didn’t all just clog up in the lungs.

There was perhaps short-term engraftment in one of the patients, but only really temporary and very minor. It certainly was a failure by any stretch of imagination. Don realized that he needed to have an animal model in which to conduct his work if he was ever going to make it work in humans.

He chose to work in a canine model. I suspect today there would be a lot of pushback and controversy about that. It wasn’t as if Don didn’t like dogs. Don was a great outdoorsman and a terrific hunter, both ducks and deer. For a duck hunter, you treat your retrievers like a family member, and it was for Don.

The reason he chose to work in dogs is that all the mouse experiments at the time were using inbred mice. The immunology of inbred mice can teach you certain principles for sure, but it’s nothing like the outbred human species. That’s what Don wanted to try and do, is develop a cure for patients. And so he chose the canine model where it is an outbred species, and you have litters. So it’s much like humans where you can have things that are akin to brother and sister.

FA: Well, it was a group of individuals that were sort of a precursor to the American Society of Hematology—people that were interested in research in hematology.

Each year they would have a meeting, and then one topic would be the central topic. In 1957, there was enough interest in marrow transplantation as a potential science for them to meet. They did meet, and as you point out, Alex, there were different people presenting the little work that they had done in animal models. That was the first time that Don and Joe Ferrebee presented their information. They had actually tried this in humans, and there was a lot of pushback saying, “We’re not ready to do that—and please don’t do that, that there just isn’t enough knowledge to think that it would have much of a chance of success.”

I think that’s a tension that happens all the time. There are people who want to push the envelope a little bit more, and other people who are more conservative about it. Certainly, today, there are different regulations that didn’t exist at the time that Don was doing this work. You could argue—is that good or bad? I’ll just say it’s different.

FA: Some people would say it’s determination. I’m not sure that’s the right word, because to me, determination is something that’s totally internally generated. It’s sort of like the push. I think for Don, it was not a push. I think it was a pull. I think it was the pull of the potential cure of patients with horrible diseases.

It was just so appealing that you might be able to figure out a cure for these horrible diseases that kept Don working in that direction.

You mentioned the ethics of it. As I say, it was a different time, but Don, for those of us who worked with him, I don’t think any of us ever had any question any time about his ethics. He was, as far as informed consent was concerned—he had really in-depth conversations with every family member and every patient. It may have not been as formalized as it is today, but it certainly happened. Don was a stickler all the way through that everything be done by the book, the way it was supposed to be done.

FA: I have no doubt whatsoever that if Dottie had decided to go to medical school, or become a science writer, or anything else, she would’ve done it and had succeeded enormously. But again, it was a different time and things do change.

She was willing—and not just willing—she was eager to help Don in his success. A lot of us would say that if Don was the father of marrow transplantation, then Dottie was surely the mother. They met when they were in college. She was a major in journalism at the University of Texas. When they got to Boston they had no money—the government only paid for Don’s medical school training and a room in a dormitory where Dottie couldn’t stay. They were married. So Don, when they started, was staying in a dormitory, and she was staying in a rooming house.

She got a job, first working for the Navy, and then as a medical technician. And working as a medical technician turned out to be really vital. When Don got to Cooperstown, Dottie eventually became his lab technician and headed his laboratory there because there were not enough other technicians around to do it. When they finally moved to Seattle, she was not just a help as his technician, but because of her journalism background she would edit his papers and his grants.

She was there at his side. When they would drive to work in the morning, she would have a copy of Current Contents on her lap, and would circle the papers they wanted to send reprints for. At 11:30 every day, she would go and get his lunch heated up and the two of them would eat lunch together in his office between 11:30 and 12:00 sharp.

She was beside him the entire time. When we would write papers, they would be reviewed by both Don and Dottie, and Don’s comments would always be in blue pen, and they would be conceptual, and Dottie’s would always be in red, and would make sure that there were no split infinitives and that “data” was plural, and that nobody would ever start a sentence with the undefined “it.” She was terrific. It was fun to work with them both.

FA: Amazingly so. If you talk to the kids—they have three children—and if you talk to them, they’ll talk about their parents in glowing terms. Elaine, who’s also a physician, an infectious disease physician, said they were always together and always working—except when they were hunting and fishing—and family. That was it.

FA: There were several of them. The first, perhaps, was when, in the late 1950s, he had a couple kids who had leukemia—small children who happened to have identical twins, and he gave them very high doses of radiation that he knew in an animal model would destroy bone marrow—and you wouldn’t recover your blood counts after that much radiation.

But because he had identical twins, he was able to give radiation and then a marrow infusion from an identical twin. And while the kids weren’t cured—their leukemia did come back—they recovered their blood counts very rapidly.

And then in 1960, he had a patient with aplastic anemia. He did the same thing—he gave the patient identical twin marrow—and she rapidly recovered within two weeks. In fact, she’s still alive today, as is her twin.That’s the first person on the face of the earth who was ever cured with a marrow transplant.

They still are doing well. That was the first insight that he definitely could transplant bone marrow. Though it was only in identical twins—at least he knew that for sure you could transplant bone marrow.

Then the second big breakthrough, really, was in the late sixties, early seventies, when [Human Leukocyte Antigen] HLA typing had evolved enough that it was possible to choose among siblings a donor who was HLA compatible with the recipient. And that allowed Don to make the leap from just this rare, identical twin setting to the more relevant setting of brothers and sisters who are HLA-identical in the very first transplants that were done that allowed for cure of leukemia in 1971.

There had also been a few years earlier, some transplants for kids who had immune deficiencies, also using siblings who were HLA compatible. Those were the two big things: You could do transplants in twins, and you could overcome the histocompatibility barrier by selecting donors and recipients who are HLA matched.

FA: Well, Don was extraordinarily matter of fact. He would tell you—”This is what we did. Here’s what happened.” He was not saying that this was right or wrong. He wasn’t saying that this was the future. He was just—”Here’s what we did. Here’s what happened. It’s up to you to make your conclusions from that.”

I was blown away that you could take patients who had end-stage leukemia, and transplant them, and cure some of them. Now, the problem was that you were only curing, at the end of the day, between 12 and 14% of the patients, and many of the others—you probably were hastening their death because there was a lot of toxicity from the transplants. People were dying from mucositis, from infections, from CMV infections. There were lots of problems. Now, the patients that Don was transplanting also would’ve been dead in another month or two had you done nothing—because they had end-stage leukemia.

There are two phrases in medicine that stand in direct opposition. One is from Hippocrates, who said “first do no harm.” Then there’s the other quotefrom Shakespeare, that says that “diseases desperate are by desperate appliance cured, or not at all”. Those two stand in direct opposition.

If you have someone who has an end stage disease, is it better to do nothing and let the disease take its course? Or is it better to try something, understanding that you may be causing a lot of toxicity, pain, and anguish, and the chances of success are small? I don’t have the right answer to this. I mean, I don’t know that anyone does, but I think that people that get to make the choice should be the patients more than anyone else.

Don explained the situation, and not just Don, but the team explained the situation to these patients and they wanted to try. When he presented this data at the AACR meeting, I was sitting in the back of the room.

I heard a lot of the colleagues saying “That’s butchering. That’s immoral. Look at how many patients are dying. These guys are cowboys that shouldn’t be doing this work.” So, there was a lot of controversy at the time—a huge amount. There are lots of ways of looking at the same problem. I’m not saying that one group was right and one group was wrong, just different.

FA: There were so many problems that Don and the team faced during the early days. There was the problem of these infections that were, oftentimes early on, bacterial and fungal—and then turns out many of them were viral as well. He brought in infectious disease experts, including Joel Meyers and others to work with him to try and solve these.

We went through extraordinary efforts to try and prevent infections, including putting patients into laminar airflow rooms where they would stay for 50 days eating sterile food and constantly being bathed in antibiotics. It was very hard on the patients, but it did prevent early infections. The patients had horrible mucositis and so it was very difficult for them to eat. Early on, patients were literally starving to death during the transplant procedure.

A pediatric nephrologist by the name of Bob Hickman was working at Seattle Children’s at the time, and Don asked Bob to come over and see if he could place some catheters, arteriovenous shunts, which Bob did. Arteriovenous shunts are dangerous and clot off in a short time. But at the time, they were also doing some early work with a new material called silastic, which was more compatible with the blood system, and so you could start to develop catheters that were indwelling.

Bob helped invent what it was called Hickman’s catheter, which is used worldwide. Suddenly, we had a way of not having to poke the kids every morning and every evening. Not only could you draw blood, but you could give infusions and you could also start to give hyperalimentation so they wouldn’t be starving.

Patients were coming to Seattle and their whole lives were upset. And while Don was trying to do the best he could to care for them, that wasn’t doing much for their social problems. There was a young boy by the name of Steven McCarty who came for aplastic anemia, and he was cured with a transplant. His mother, Marion, was a social worker from Southern California.

After the transplant when they were getting ready to go home, she asked to meet with Don, and she told Don that she wanted, having seen what she saw, to move to Seattle. She wanted to pick up every patient at the airport and help them while they’re going through the transplant. Don said, “Wow, that’s an amazingly important thing, but I don’t have a salary for you to do that.”

She said, “That’s OK, I’ll do it for free.” So, she moved to Seattle for two years and worked as the first social worker until Don finally was able to find her a salary. Don created his own ward because he didn’t trust the care that patients would get anywhere else.

Key to that ward were the nurses. Don often referred to the nurses as a secret weapon. They were incredible, I mean—it takes a certain kind of nurse to be able to work with incredibly ill patients, knowing early on, that seven or eight out of 10 were going to die. But, to give them the very best care they could, as long as they could, with the hope that there would be survivors. Some of those nurses, some of the very first nurses, are still here 50 years later participating in long-term research and care.

Those are just a few of the supportive care kinds of things that helped early on. It was infections, it was nutrition, blood support, nursing, social work. It was everything.

FA: Part of it was Don recruiting people, but more than half of it wasn’t him recruiting—it was people coming, wanting to work, volunteering, gravitating toward him.

FA: I want to talk for a minute about the future of Don’s work. That is, not just the fact that he developed a curative therapy that’s used 100,000 times a year. But the implications of that, which are profound. Don developed three principles that standout.

The first, is that with marrow transplantation, you can cure virtually every marrow-based disease, including sickle cell anemia, leukemia, lymphoma, and hundreds of others. Second, that part of the way that transplantation cures leukemia is that the transplanted immune system sees the leukemia as foreign and rejects it. And third, that after a marrow transplant, lifelong immunosuppression is not necessary, that you develop bidirectional tolerance.

Now, the implications of those three principles are what’s going to shape the future of medicine to a large extent. The first, the fact that you can cure any marrow-based disease means that for inherited marrow based diseases like sickle cell anemia and thalassemia, what we will be doing in the future is not relying on someone else’s bone marrow, but we’ll be able to take the patient’s own bone marrow, and using techniques that are already available, we’ll be able to correct the defect and transplant the repaired product back into the patient themselves.

That’s already being done in sickle cell anemia and thalassemia. And the approach is already approved by the FDA. This will be something that will be done for not just those diseases, but for virtually every marrow-based disease that’s due to a single gene defect.

This could change the face of medicine. The second principle that the new immune system sees the diseases being foreign, means that what we will be doing is we’ll be able to take cells from either the donor or the patient, and genetically engineer those immune cells to specifically attack the patient’s tumor. That’s adoptive immunotherapy, CAR T cells and TCRs. That is a direct result of the work that Don Thomas did. You can draw a direct line from Don’s first observation of the graft versus leukemia effect to the development of CAR T-cell therapy..

Third, the fact that you can get immune tolerance after an allogeneic transplant and not need lifelong immunosuppression means that if you first do a bone marrow transplant, that individual would then be tolerant to any solid organ from the donor, including a kidney, for example.

That’s already been done. You do a bone marrow mini-transplant, and then you can do a kidney transplant from the donor, and the patient doesn’t have to be on immune suppression for the rest of their life. There’s a long way to go, but boy would that solve huge problems for kidney, heart, liver transplantation.

The implications of what Don did are not just development of marrow transplantation, which is huge in and of itself, but the implications are really changing the face of medicine, which is why, in the book, I talk about the fact that this is not just about marrow transplantation, but it’s also about this revolution in cell therapy.

FA: Well, of course, other people might see it differently, but looking at it through the lens of bone marrow transplant, that’s the way I see it.