George Santos, founder of Johns Hopkins University Bone Marrow Transplantation Program, pioneered many of the innovations used in bone marrow transplantation that are relevant today—but he didn’t get nearly as much credit as others working in the field.
E. Donnall Thomas, another early pioneer of bone marrow transplantation who conducted research out of Fred Hutchinson Cancer Research Center, shared the 1990 Nobel Prize in Medicine with Joseph E. Murray “for their discoveries concerning organ and cell transplantation in the treatment of human disease.”
“Much of what we’re currently doing in bone marrow transplant internationally was developed by George,” Richard J. Jones, professor of oncology and medicine, director of the Bone Marrow Transplantation Program, and co-director, Hematologic Malignancies Program, at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said on the Cancer History Project podcast.
Previously on the podcast, Fred Appelbaum, executive vice president, professor in the Clinical Research Division, and Metcalfe Family/Frederick Appelbaum Endowed Chair in Cancer Research at Fred Hutchinson Cancer Center, presented an overview of Thomas’s contributions to the field of Bone Marrow Transplantation.
Appelbaum is the author of “Living Medicine: Don Thomas, Marrow Transplantation, and the Cell Therapy Revolution.” After reading The Cancer History Project’s conversation with Appelbaum, Jerome Yates, emeritus professor of oncology at Roswell Park Comprehensive Cancer, wrote a letter to the editor that called attention to Santos’s contributions to the field.
“[Santos] had quite a chip on his shoulder regarding Seattle and Donnall Thomas,” Jones said. “George felt that he was doing a lot of the innovations that were moving the field, like, he in fact did the first conditioned matched sibling allogeneic transplant.”
Santos was responsible for a lot of the firsts in the field of bone marrow transplantation, Jones said.
“Nobody would argue that he did the first studies with cyclophosphamide. Nobody would argue that he did the first studies with busulfan,” he said. “He developed these two drugs, which are now some of the major drugs, if not the major two drugs used in the field. He did the first non-myeloablative transplants.”
In the 1960s, Santos and Albert H. Owens, one of the founders of the field of medical oncology, conducted mouse studies using Cytoxan (cyclophosphamide).
“George and Al actually found out that cyclophosphamide in their hands was the best drug for both getting the transplant in and preventing graft-versus-host disease,” Jones said. “When I started here, cyclophosphamide was the major drug we were using for the transplant and after the transplant to prevent graft-versus-host disease.
“If you now go forward about 55 years or so, cyclophosphamide has now been basically accepted by the community as the best way of preventing graft-versus-host disease,” Jones said.
Researchers at Hopkins continued the work with cyclophosphamide that began with Santos and Owens.
“We figured out how it worked, why it worked, and that you could in fact give it at high doses after the transplant,” he said. “This work started back in the 1960s with George and Al, and continued here at Hopkins over the last half of a century by many people.”
In a recent study published in The New England Journal of Medicine, the use of post-transplant cyclophosphamide, also known as PTcy, proved to be more effective than the standard of care treatment of calcineurin inhibitor plus methotrexate in patients undergoing allogeneic hematopoietic stem-cell transplantation, Jones said.
“The development of post-transplant cyclophosphamide is probably one of the major advances in bone marrow transplant ever. And certainly the clinical use of it in this millennium,” he said. “That work was started by George and Al Owens again in the 1960s here at Hopkins, in animals. And it took over 50 years.”
What did the field of bone marrow transplantation look like back when Santos and Owens conducted their research? At Hopkins, BMT and cancer researchers were driven far away from Hopkins’s main medical campus.
“He and Al Owens were actually farmed out to a city hospital called Baltimore City Hospital that’s about five miles east of the Hopkins main medical campus,” Jones said. “And that’s where they did all the original laboratory research and clinical research.”
Department chairs did not look fondly upon cancer researchers.
“Using radiation and animal models and transplanting cells between human beings was not thought to be hard science,” he said. “In fact, I think it’s fair to say that all cancer research at the time was not thought to be hard science.”
When Hopkins received NCI-designation in 1973, NIH mandated that the cancer center move its cancer research operation back to the main medical campus.
“That was not viewed to be great by the rest of the medical school at the time,” Jones said. “And it became a little bit of a problematic area throughout the cancer center. And in fact, oncology became a department at Hopkins. In most places, it’s a division under a department of medicine, largely because they had to hire people, and other departments wouldn’t let them hire into their departments. So, the dean just made it a full department in Hopkins.”
When Jones began as a fellow at Hopkins in the 1980s, he recalls Santos holding court at a dinner one evening while speaking between cigarettes.
“He was very engaging,” Jones said. “Many people thought he was crazy, and in many ways he was. But he was also very insightful.”
Santos’s passion for his research was apparent in the way that he spoke.
“He was unbelievably committed to this emerging field of transplant,” Jones said. “He would just talk about treating patients with doses of radiation and chemotherapy that would kill them if they didn’t have this transplant. And most people knew about graft-versus-host disease by this time, and scared people, and he was just so committed and sure that this was going to work.”
Santos was also close with his patients—the wall behind his desk was covered in their photos.
“Bone marrow transplants are a little bit different than many other cancer treatments because the patients remain at the transplant center for several months back then, maybe even longer,” he said. “Bone marrow transplant doctors see their patients every day. So, in many ways, the relationships they develop are incredibly close. You get to know them very well. You get to know their families.”
He left behind a book in which he wrote down the name of all of his patients. When he retired in 1994, the number of patients stood at 1,936.
At the time, researchers at major hubs for bone marrow transplant studies like the Hutch, Hopkins, and Memorial Sloan Kettering, worked in their own silos, Jones said.
“It allowed people to innovate, develop different approaches, and figure out the one that worked the best,” he said. “We’ve become much more collaborative in the field over the last 20 years, basically through the development of an NIH-funded grant called the Bone Marrow Transplant Clinical Transplant Network. And I think we’re, as a group, figuring out which of these approaches work the best.”
Thomas and Santos might be considered friendly rivals, Jones said.
“There’s sort of a joke that says if you get 10 bone marrow transplanters in the room and talk about how to treat a patient, you’ll get 10 different ideas of how to move forward,” Jones said. “They were both trying to develop an area and they both were sure it was going to work. I think George and Don had the utmost respect for one another.”
Jones spoke with Alexandria Carolan, associate editor with the Cancer History Project.
Transcript
Richard J. Jones: Actually, the mid 1950s. I think it was ’54.
Around the time of the Korean War, and if you were drafted as a physician, you could apply for working in research labs instead of being shipped off to Korea.
And he did that and got assigned to the Naval Research Lab in San Francisco. These physicians were actually called Yellow Berets, which is an interesting categorization. And as I think you and Fred [Appelbaum] discussed—a lot of the research related to bone marrow transplantation was funded by the government looking for potential treatments for radiation sickness.
That’s, I think, how Dr. Thomas got much of his original funding. George was assigned to a laboratory doing exactly the same thing, looking at bone marrow transplant as a potential cure or treatment of radiation sickness. Now, it’s never going to work that way, despite several tries at it for lots of different reasons. But what grew out of that was the fact that you could cure leukemia and mice with this approach, and it went on from there.
So, he was a resident here at Johns Hopkins. And he was recruited back by Al Owens, who was the first director of the cancer center at Hopkins. It wasn’t an official cancer center then—to actually start a bone marrow transplant program in the late fifties, early sixties, because it was just at that point becoming an interesting topic.
So, George and Al did the first research in cancer at Johns Hopkins in the sixties, basically related to bone marrow transplant in different areas.
RJ: So, when Hopkins was doing it, there were probably three places doing transplants. Seattle—where E. Donnall Thomas moved from Cooperstown, New York, and [Memorial] Sloan Kettering with Robert A. Good, and Hopkins. There was some research going on in Europe as well related to bone marrow transplant. But those were probably the three places where it was going on.
RJ: Oh, because of the government funding for looking for ways to treat radiation sickness and the data that came out of animal models showed that you could actually cure leukemia and lymphomas with a bone marrow transplant. So, what George’s original work was in mice and rats trying to develop the platform that would work for a transplant.
RJ: Yeah, so animal models are all artificial, and they just give you a look into biology to help you translate the findings into humans. Donnall Thomas and most people were working with total body irradiation as the part of the transplant that would help cure the leukemia.
It worked pretty well in animal models, but when it was translated into humans, the way that radiation was being given at the time was too toxic. It was given as one dose. The mice could tolerate this one dose often, but humans couldn’t.
When George got to Hopkins, there was no radiation source that he could use to treat his animals with total body irradiation. So, he had to innovate and find another way of treating animals prior to the bone marrow transplant. And he basically took every anti-cancer agent that was available at the time, and there were eight to 12 depending at the time.
And he found that a drug called Cytoxan was the one that looked the most like total body irradiation. It had a very strong anti-cancer activity, and it suppressed the animal’s immune system to allow the new transplant to take.
So, George’s original studies were all using cyclophosphamide in rats and mice, whereas Dr. Thomas and others were using radiation.
And I think Jerry Yates probably contacted you because these innovations that George did, probably, today, have a lot more relevance to bone marrow transplant than some of the things that were being done at other places.
And cyclophosphamide, now, is the number one drug used in bone marrow transplant to both get the graft in and to prevent the major complication of the transplant graft-versus-host disease, or GVHD. And this was all developed in the sixties by George and his boss, Albert Owens Jr., working in animal models.
Just like Don Thomas was working mostly in dogs to develop their platform for transplant, George was working in mice and rats and was translating what he found in those animal models to the humans.
RJ: He did his first allogeneic transplant in March of 1968, and actually in Don Thomas’s lecture for his Nobel Prize, he said that the matched sibling allogeneic transplant was done by Bob Good in November of 1968.
George had actually done two matched sibling allogeneic transplants in 1968, but one in March, and one in October. He did them before Donnall Thomas, where everybody else was using TBI, total body irradiation, he was using high-dose Cytoxan as the conditioning regimen before the transplant.
RJ: So, all the original transplants done throughout the world had two major problems. One is, they were treating end stage cancer. Even if the transplant itself was successful in getting the graft in, the patients ultimately relapsed.
The other major problem was this thing called graft-versus-host disease, because when you put a new immune system into somebody, unless it’s an identical twin, which has the exact same biology as the donor recipient, there are reactions that occur where the new immune system will attack not only the cancer, which you want it to do, but the patient’s normal cells. These were the things that they had to work out to get transplants to take and to work.
After Donnall Thomas figured out how to give total body irradiation—and to do that, you had to do something called fractionation—meaning you don’t give it all as one dose, you give it as multiple doses over several days.
And then he added cyclophosphamide to that, which he actually learned from George, and that helped with controlling the disease. And for the first time we were seeing cures with bone marrow transplant.
George eventually added a drug called busulfan, which is perhaps the second most commonly used drug and bone marrow transplant—and so he developed the regimen called BuCy. And when I started, the two major conditioning regimens for transplant were Cy/TBI developed in Seattle, but using George’s cyclophosphamide, and BuCy developed in Baltimore.
RJ: I mean, it was a very small field. There would be meetings, national meetings where they would get to know each other. And although bone marrow transplant has become a huge international area now, back then there were only a handful of people.
So, they met at meetings, they read each other’s papers. I think, where Don Thomas first heard about this, he invited George out to give a talk in Seattle, and in probably the late sixties or early 1970s.
RJ: It was a small cadre of people and George was a prominent member of it.
RJ: I can tell you that here at Hopkins, it was not accepted. All cancer research, particularly George’s research in bone marrow transplant, was considered sort of pseudoscience.
He and Al Owens were actually farmed out to a city hospital called Baltimore City Hospital that’s about five miles east of the Hopkins main medical campus. And that’s where they did all the original laboratory research and clinical research.
RJ: Well, the major players were the department chairs, and using radiation and animal models and transplanting cells between human beings was not thought to be hard science. In fact, I think it’s fair to say that all cancer research at the time was not thought to be hard science.
It was looked at as throwing poisonous drugs at animals and people and seeing how it works. An interesting part of the story is that George and Al put in a NCI grant when Nixon started his war on cancer. One of the major parts of it was to give out NCI designation to centers around the country to help them move the treatment of cancer forward.
And Hopkins got one of these first designated cancer center grants in ’74 or ’75. And in that grant, they were told by the NIH that they had to move their cancer operation back to the main campus so that they were going to be working more within the major aspects of the Johns Hopkins Medical School.
That was not viewed as great by the rest of the medical school at the time. And it became a little bit of a problematic area throughout the cancer center. And in fact, oncology became a department at Hopkins. In most places, it’s a division under a department of medicine, largely because they had to hire people, and other departments wouldn’t let them hire into their departments. So, the dean just made it a full department in Hopkins.
RJ: They were able to build a cancer center building that opened up in 1976, I believe, here on the main campus, which is where I started in 1984 when I got here.
RJ: So, there are two aspects of transplant as I was telling you. One is conditioning therapy before the transplant that would allow the transplant to take. And then there was treatment after the transplant to try to lessen the severity of graft-versus-host disease.
I won’t say prevent it, because it turns out that graft-versus-host disease is a double-edged sword. It’s the major thing that cures cancer as part of an allogeneic transplant, but it’s also the major toxicity of the transplant because of the harm that this can do to normal tissues.
In addition to the leukemia, George and Al actually found out that cyclophosphamide in their hands was the best drug for both getting the transplant in and preventing graft-versus-host disease. When I started here, cyclophosphamide was the major drug we were using for the transplant and after the transplant to prevent graft-versus-host disease.
If you now go forward about 55 years or so, cyclophosphamide has now been basically accepted by the community as the best way of preventing graft-versus-host disease.
There was just a New England Journal of Medicine article, actually, that compared post-transplant cyclophosphamide, or PTCy is what we currently call it—PTCy—to the prior standard, which was cyclosporine and or tacrolimus and methotrexate, and PTCy had better results.
But this work started back in the 1960s with George and Al, and continuing here at Hopkins over the last half of a century by many people.
George and Al had it all figured out in mice, it turns out, but they were scared of cyclophosphamide. It was a chemotherapy agent that was being used at high doses before the transplant. The only thing that really worked in mice was high doses after the transplant, but they couldn’t understand how you could successfully give a drug at high doses after a transplant.
And so, when they took it into the humans, they took it in low doses and that didn’t work for preventing graft-versus-host disease. And then cyclosporine came on the horizon and that became the major drug for preventing graft-versus-host disease. But we continued to work with cyclophosphamide, many of us here at Hopkins in the lab, and we figured out how it worked, why it worked, and that you could in fact give it at high doses after the transplant.
And I think it’s fair to say, and I’m obviously a little bit biased, but the development of post-transplant cyclophosphamide is probably one of the major advances in bone marrow transplant ever.
And certainly the clinical use of it in this millennium. It allows us now to do mismatched transplants, which was one of the major problems with transplant. Prior to the post-transplant side, the only way you could successfully do a transplant because of graft-versus-host disease was to use closely matched donors.
And it was, you’ve probably heard, difficult to find a close match for many patients, particularly patients of certain racial and ethnic groups like African-Americans and Hispanics, for lots of reasons.
Post-transplant Cy now allows us to do mismatched transplants using half-matched family members and half-matched unrelated donors so that now everybody who needs a bone marrow transplant can have it.
RJ: And that work was started by George and Al Owens again in the 1960s here at Hopkins, in animals. And it took over 50 years. I’ve written a few thought pieces about this, about the history of how it got developed and why it took so long to become standard of care, but it is now standard of care.
RJ: I’m not sure we ever know how we get into something. Often, it just seems to happen. I can tell you that it was probably generated by two things. One is, my dad was diagnosed with chronic myeloid leukemia, or CML, in 1970 when I was in college.
Today, CML is a little bit like hypertension, and very few people die of it because of the advances that have happened, including bone marrow transplant. But when I was really getting into medicine, bone marrow transplant was becoming the treatment of choice for CML, and the only thing that actually could cure it.
And number two was an article Don Thomas wrote in 1975 when I was in medical school, and it was in The New England Journal of Medicine, and it was sort of a summary of this newly developing field of bone marrow transplant. So, when I went looking for my fellowship, I wanted to go to a place that did bone marrow transplant. And there weren’t a lot at the time, and it was either, basically, you went to Sloan Kettering, University of Minnesota, Seattle, UCLA or Johns Hopkins. And I’m a northeast boy from Pennsylvania. So, Johns Hopkins made a lot of sense.
And George was quite an interesting individual. They had a dinner for the new fellows early right before we started. George was sitting at one of the tables and basically held court. And he was very engaging. Many people thought he was crazy, and in many ways he was. But he was also very insightful. And I would say that much of what we’re currently doing in bone marrow transplant internationally was developed by George.
RJ: I mean, he chain-smoked. He would talk between cigarettes. He was unbelievably committed to this emerging field of transplant. He would just talk about treating patients with doses of radiation and chemotherapy that would kill them if they didn’t have this transplant. And most people knew about graft-versus-host disease by this time, and scared people, and he was just so committed and sure that this was going to work.
I can tell you one other story about him. He had quite a chip on his shoulder regarding Seattle and Donnall Thomas. They were the industrial revolution of bone marrow transplant. I mean, they were doing hundreds of bone marrow transplants by the nineties, when Hopkins was doing 150—they were doing 700 or 800.
Most people in the field who trained internationally went to Seattle to learn about it. But, I think George felt that he was doing a lot of the innovations that were moving the field, like, he in fact did the first conditioned matched sibling allogeneic transplant. He developed cyclophosphamide that everybody was using. His group developed busulfan that everybody was using.
When the Nobel Prize came out, he actually intimated this to me, that he was disappointed because he thought he should share that prize with Donnall Thomas, and several people in the field have told me that that was their feeling through the years because of his impact that persists to this day. And again, I’m biased, as I said, but I think the post-transplant side has been the major advance in this millennium in transplant and started by he and Al Owens in the 1960s.
RJ: Well, there’s sort of a joke that says if you get 10 bone marrow transplanters in the room and talk about how to treat a patient, you’ll get 10 different ideas of how to move forward. They were both trying to develop an area that they both were sure it was going to work. I think George and Don had the utmost respect for one another.
There was not a lot of collaboration in those days because everybody was doing their own thing. And I’m not sure that would’ve been a good thing then because it allowed people to innovate, develop different approaches, and figure out the one that worked the best.
We’ve become much more collaborative in the field over the last 20 years, basically through the development of an NIH-funded grant called the Bone Marrow Transplant Clinical Transplant Network. And I think we’re, as a group, figuring out which of these approaches work the best. But back then they were—I would guess a term would be friendly rivals.
RJ: I think he probably attended the wedding of multiple of his patients. Bone marrow transplants are a little bit different than many other cancer treatments because the patients remain at the transplant center for several months back then, maybe even longer.
And although you may have a patient for many years as an oncologist, you don’t see them every day. Bone marrow transplant doctors see their patients every day. So in many ways, the relationships they develop are incredibly close. You get to know them very well. You get to know their families.
And I think George more than, or as much as many of us, really wanted to become very close to their patients and I think they appreciated it. And so he had his wall of pictures [of his patients] behind him. He kept a little chart on all the patients that went through transplant that he would fill in by hand. I actually still have it right here. I pulled it out.
RJ: Every patient that he had is listed in this now falling apart book.
RJ: So, he retired in 1994, and he put a number on every one of his patients. So, the last number that he has is 1,936.
RJ: Their age, their disease, their donor information, where they lived, how they were treated, what their outcome was. And he did it by hand himself. He had no data manager or research associate who did this for him. He kept this on his desk and filled it in for each of these patients.
I have a lot of his memorabilia in my office. That lamp is on his desk that you can see here.
RJ: There’s a picture of his microscope, his original bone marrow transplant harvest needles. I don’t have that picture, but I’m sure it’s somewhere.
And so the other aspect of George that I think is incredibly important, in addition to his innovative research, his love of patients, nursing, I mean—he was probably the biggest proponent of nursing in the early days and social work. He’s the one who got social work on every one of our oncology floors.
One of the things I remember him most for is pushing this concept of translational research. I’m sure you’re aware of the term. It actually stands for taking what we learn in the laboratory and moving it to the clinic.
And when I started here at Hopkins, nobody was using that term. It’s become sort of commonplace these days. But back then you were sort of pushed to either work in the clinic with patients or work in the lab with research. And George said, the only way we’re going to move science forward is to merge those things. And the best way to do it is to have people who worked both in the lab and the clinic.
So, bone marrow transplant and blood cancer research here at Hopkins was all built on people who were physician scientists who had a foot in the lab and a foot in the clinic. He used to call this process engineering, because he was an MIT graduate.
I never heard him use the term translational research, but I would use it after he would talk about it. And he’s the one that convinced me to work both in the lab, and in mice, and with Petri dishes, as well as work in the clinic to help translate those findings.
And I’ve written a few thought pieces, histories about the development of post-transplant-Cy now that it’s become a standard of care. And I think it’s the prime example of translational team science, taking what we learned in the lab and moving it to the clinic by an entire team of hundreds of people—because no one aspect of this could have been done by one person. And it’s happened over the last half of a century, more than half of a century.
RJ: Well, I mean, I just think, listing some of the firsts. Nobody would argue that he did the first studies with cyclophosphamide. Nobody would argue that he did the first studies with busulfan. He developed these two drugs, which are now some of the major drugs, if not the major two drugs used in the field. He did the first non-myeloablative transplants.
I was at a meeting having dinner with a group of people 25 years ago. So all the original transplants were called myeloablative. They used high doses of chemotherapy that were aimed at the leukemia for the lymphoma. And the transplant was thought to be a rescue for these high-doses of therapy, which also killed normal blood cells, because they were dividing.
We later learned that the major anti-tumor effect of an allogeneic transplant is not the drugs beforehand. It’s actually the new immune system of the donor. It’s sort of the first immunotherapy. We’ve learned a lot about immunotherapy, which is now the hottest topic in cancer—from bone marrow transplant.
They were arguing back then because nonmyeloablative transplants were being developed. They were much easier to do. They were cheaper. You could do them in older, less fit patients. Who did the first allogeneic transplant? And people talked about Israel, other people talked about MD Anderson. And I just stood up and said, George Santos did the first ones with high-dose Cytoxan.
And everybody said, “Yeah, you’re right. But he didn’t know he was doing a nonmyeloablative transplant.” So, he did the first non-myeloablative transplants. I think he was the first to use cyclosporine, which is one of our major graft-versus-host disease drugs. And I think his legacy is now post-transplant cyclophosphamide.
