ASH Oral History: Eugene Cronkite
ASH provides the following oral history for historical purposes. The opinions expressed by the interviewees are not necessarily those of ASH, nor does ASH endorse or make claim as to the accuracy of any of the information included here. This oral history also is not intended as medical advice; you should always seek advice from a qualified health provider for your individual medical needs.
The following oral history memoir is the result of two tape-recorded interviews with Dr. Eugene Cronkite, conducted by Madeline Marget on February 6 and 7, 1989. Also included is an addendum to the interviews written by Dr. Cronkite. In 1989 Dr. Cronkite reviewed the transcript and made corrections and emendations. The reader should bear in mind that the following oral history is a verbatim transcript of spoken, rather than written, prose.
Q: Let's start Dr. Cronkite with talking about your early life and how it may have influenced your choices.
Cronkite: Well I was born in Los Angeles, California. My grandparents were from New England and we were brought up in a proper New England manner. And this required that we go to Sunday school. My brother and I became somewhat suspicious about some of the stories in the Bible, particularly the one of the whale swallowing Jonah. And we had to check in the Encyclopedia Britannica about what kind of food whales had, and we realized that most of the whales have sieves that they just filter out the small plankton and small fish and so on. It would be totally impractical to swallow a human being, but we were told in no uncertain terms that there are many things that one accepts on faith, and I think that was a very early reason to separate ourselves from any formal religious activity.
Later as an undergraduate, I was tremendously impressed by Professor Bennett M. Allen, Professor of Biology at UCLA, who had learned how to dissect out one or two cells in a developing tadpole that would prevent its metamorphosis. In other words the cells that were being taken out were the precursors of the thyroid gland and if the thyroid extract, or dry thyroid glands were given to the animals, they would then metamorphose.
I had, for reasons that are unclear today, decided to study geology and mineralogy and then shifted to chemistry. This was in the middle of the Great Depression. When I learned that the maximum income, at that time, for a graduate in chemistry was in the order of $45-$50 a month, I decided to do something else. My brother, who was already at Stanford University as assistant professor in Anatomy, suggested that I apply to Stanford Medical School. All which I did, and one of those funny things; when being interviewed by the admissions committee, the first individual who interviewed me was a professor of medicine, and he was in his little laboratory with an evaporating dish and sand in it, Bunsen burner under it, stirring something. The only question he asked me, he said, "Mr. Cronkite, what am I doing?" And since I had some mineralogy and geology," I said, "You're determining the nature of some mineral you picked up." He said, "Oh, fine. We'll admit you to medical school." And I was admitted.
Medical school in those days, was simply, this was in the '30s, was simply pre-antibiotic, pre any of the things that we have today for use in medicine. The main thing to do was to diagnose individuals and either they lived by the grace of God, certainly not by anything we could have done by and large. The day that sulfonamide came in and suddenly. people who would ordinarily die from various diseases were living, was one of the most dramatic things that I've ever experienced up to that time or since then: that diseases that normally 80-90% mortality, particularly in the older population, suddenly nearly 100% were surviving. The entire treatment of venereal disease, particularly gonorrhea, completely changed. During this period of time, actually if I recall correctly when I was a junior or senior medical student, a Professor [Arthur Leonard] Bloomfield, the chairman of the Department of Medicine, called me in and asked me if I would like to articulate in a study that he would like to have done, which would be a repetition of what Dr. [William] Castle had done earlier in Boston. And it seemed very interesting to me and he explained it to me. Mainly it was a matter of taking normal gastric juice, incubating it with liver or hamburger, and then administering this to an individual with pernicious anemia. And I was told that as soon as there was a patient with pernicious anemia, I would be notified, that I was to get the hamburger and gastric juice. It occurred to me when it was time to come to do this study, that where was I going to get the gastric juice? I asked permission to see the professor, who was a very formal man.
Q: Do you recall his name, Dr. Cronkite?
Cronkite: Bloomfield. Arthur Leonard Bloomfield, a very famous clinician. I went in to see him and said, "Where do I get the gastric juice?" And he looked at me as if I were the most stupid human being in the world. And he said, "It's simple. You put a tube down in your stomach and muck it out." Which I thought, goodness gracious, I had never done anything like that before so I asked the resident in medicine, Marcus Krupp, "How do I get the gastric juice?" And he said, "There's no problem on that. I'll put the tube down your stomach for you, but remember to come in fasting." Which I did. And we incubated the hamburger with the gastric juice and then it was administered to a patient with pernicious anemia. And sure enough the same things happened in San Francisco that happened in Boston. It made the professor happy and I think it was one of the reasons he finally selected me as one of the interns in the medical department.
At about this time, the professor became interested in a publication from Johns Hopkins on the effect of extracts of the spleen upon granulocyte counts in the rabbit. Excuse me, of platelet counts in the rabbit. And he asked me if I would like to see if these studies that were done by [C.P.] Rose and somebody else at Hopkins, I've forgotten now. And when the first spleen was taken out from the patient with idiopathic thrombocytopenic purpura, I followed the instructions from the work at Johns Hopkins, made the extracts, injected them into the rabbit, and at about this time I did one of the things that happens to, I guess, almost all young men. I'd fallen in love with a young woman who was actually assistant supervisor of ophthalmic nursing. I was given a small broom closet in which we kept some rabbits, and she would come down with me with her nose going more like the rabbit's nose-- a sort of impossible environment for a surgical nurse, but she put up with it-- and did the platelet count, and that turned out to be the first publication that I have on the effect of platelet extracts, or spleen extracts upon platelet count. And the work from Johns Hopkins was more or less confirmed.
The rest of my training in medicine was actually truncated by World War II. After two years, about a year and a half actually, after Pearl Harbor was bombed by the Japanese, as a young individual, I felt very uncomfortable not being in uniform and volunteered for the United States Navy. Primarily because, having been in ROTC and CMTC, the Civilian Military Training Corp, I couldn't conceive of going to war with the Army. If you have to go to war, you might as well do it in the Navy where there's good food and white sheets to sleep in.
The time in the Navy was very interesting during World War II. There was never any question about what the necessity of being there, so far as the sick and injured were concerned. But at the same time, several opportunities arose to have certain investigative opportunities. Having had training exclusively in internal medicine with no experience in surgery, the Navy thought I would be a menace if I were assigned to the Marine Corp or Ships Medical Officer. Then they sent me to the Naval Operating Base Hospital in Norfolk, Virginia, for training in surgery. I was very fortunate. The Chief of Surgery there was J. Montgomery Deaver, who was one of the professors of surgery from the University of Pennsylvania, Chief of Surgery of the Lankenau Hospital. And the Chief of Medicine was William McCann, professor of medicine from the University of Rochester. So that I was put into what was really, although a Naval Hospital, was an academic atmosphere. I was the only person under training there, and I sort of split my time between medicine and surgery and had really unexcelled opportunity for training of a type that one could really not get, I think, in an academic institution.
Q: Can you tell us Dr. Cronkite what was different about the training from that which you have received in an academic institution?
Cronkite: That is a little bit difficult to define. I think it was primarily because I was the only person at that time under training there. And the professors that were in the Navy, I guess, felt that they had to train somebody. And I was trained literally 24 hours a day, every day, and it was --Plus the fact there was not only the injuries coming in from the Atlantic fleet, ordinary injuries of people in training in the military service. But the thing that gave us an opportunity to do a little bit of research resulted from the sinking of a German submarine off of Norfolk, Virginia. With the damage, they had to surface and the crew was captured. They'd had very serious injuries, burns, all sorts of traumatic injuries. Some of them were burned so severely that there was very little skin available for grafting by the ordinary split technique and sewing graphs in. And it occurred to me, since fibrinogen had become available as a result of the plasma processing that was going on, that if one could take little bits of skin in the denuded areas and stick it on using fibrinogen and thrombin as a glue, that it might be worthwhile. That was done and it did, in fact, work. Unfortunately, what we did not know at that time is that the plasma or products of plasma that came from pooled plasma was contaminated with hepatitis virus which we didn't even know existed at that time. So most of the individuals that were given this also developed hepatitis, which was an unfortunate event.
After that I went to sea aboard the USS Sylvania, that ship right back there, as a medical officer, and did the sort of things that a medical officer does. A few traumatic injuries, every time you go into port, venereal disease, respiratory infections and otherwise, a few days back out at sea again. It was just dull and boring. There was just nothing to do except read and the library aboard ship is not a very exciting thing. Actually, duty on the USS Sylvania followed duty in North Carolina, Cherry Point Marine Corps Air Station with the 3rd Marine Air Wing.
At the end of World War II - I left one thing out. My first duty station in the Navy was the Naval Medical Center in Bethesda, Maryland, and after indoctrination, which struck me as sort of silly-- we were losing ships every day and medical officers were needed-- a group of us had been sent there to learn how to become proper officers in the Navy. It seemed like a nation losing a war that it was a tremendous waste of time to try to indoctrinate individuals in how you're supposed to behave as a naval officer, and how your wife was supposed to behave and so on. But that's the way it was. The Navy was very slow in adjusting to what the realities were.
I was assigned then to the American Red Cross to develop blood banks, not blood banks but mobile blood transfusion units that traveled around Virginia and Maryland collecting blood for plasma, since at that time the technique for preserving blood had not been developed to the extent that blood could be shipped. At this first duty with the Red Cross, I made acquaintances with Captain Lloyd Newhauser and Eugene Lozner. Lozner had his training in medicine at Harvard and then Boston City Hospital with Dr. Castle and others. He was an assistant to Captain Newhauser in developing the plasma program for the Navy. After this, I had regular duties in one place or another, and lo and behold in the latter part of 1945, the ship that I was on came to Port Hueneme, California and we picked up chains, anchors and buoys. And everybody wondered what in the hell was going on. The Captain of the ship didn't know and went then from Port Hueneme, California to Hawaii. When we left Hawaii, out in the Pacific, these secret orders were opened, and Captain Forbes Bryce with whom I had become good friends, invited me to his cabin, and said we're taking the buoys, chains and anchors to Bikini to moor the first target ships for the nuclear bomb tests at Bikini.
Cronkite: Yes. Forbes Orville Bryce; a good Irish Bostonian. And went out there, and that was sort of an interesting experience because we were the only ship, the first and only ship to enter the Bikini Lagoon. There were no maps for it and the Captain did not trust the fathometers so he issued an order that nobody understood except, fortunately, one bosnn's mate, "Man the chains" and I wondered what the heck that meant. There are two little platforms off the bridge and a seaman is supposed to get up there and just like on the Mississippi River, throw the lead weights like Mark Twain, so that they actually measured the depth as we went into the lagoon. It has nothing to do with research in medicine but it just popped into my mind.
And then orders came for me to make a medical survey of the Marshallese that were at Bikini. There was somewhat of a language barrier. There was no English spoken but I did make a trivial survey, did blood tests and so on. And then the natives were moved from there.
And about this time, another set of orders came in, "Do not disturb the flora and fauna but clear up the debris that the natives have left." And the Captain told me to do it. I took my hospital corpsmen ashore, knowing nothing about what happens when coconuts are aflame. We decided to burn the latrines and some of the other things down. Until you've seen exploding coconuts-- when they exploded then the fire started to spread. From the ship they could see that something unexpected was happening on Bikini, and our signalman signaled back that we needed help to try to put the fire out because we were supposed to protect everything for reasons that we were not aware of. And fortunately they brought the pumps ashore and fire hoses. It was finally put out. But the captain was wondering whether there'd be a court of inquiry as to the damage that was done. About that time, another ship came in with Sea Bees to put in a camp on Bikini for the personnel and they were sort of pleased at what had been burned down, they didn't have to take care of. So one of those fortuitous things. I then received orders to report immediately to the Naval Medical Research Institute in Bethesda, Maryland. When you're out in the pacific, an area where there are no flying fields and so on, you just can't report immediately. And it took me about two weeks to get to Bethesda, Maryland.
When I arrived in San Francisco, my wife met me and she said, "Oh, you're going to be the hematologist for Operation crossroad." I didn't know what Operation Crossroads was. I said, "How in the heck do you know?" She said, "Well, Mrs. Lozner called me and told me." This is what's called in the Navy "the wife line."
When I got to Bethesda, I was ushered into the commanding officer's office and he told everybody that was about that we had very secret orders. We were going to participate in the upcoming atomic bomb tests. I fortunately kept my mouth shut. I didn't let the cat out of the bag, but I already knew what I was going to do. But it was all explained to me. This hot, super secret.
Q: How much did you know about the upcoming atomic bomb?
Cronkite: I didn't know a thing about it. My wife knew more about it than I did. Lozner is the guy that I met first in Bethesda with the American Red Cross. And he had become ill and would have been the hematologist for Operation Crossroads. And when he couldn't go, he was asked is there anybody in the Navy that could do it. And he suggested me, and they issued the orders. You know, suddenly you are the hematologist whether you're competent to do it or not.
Q: I'd like to back up a little bit Dr. Cronkite to how you became a hematologist. Hematology then was not a specialty.
Cronkite: No it wasn't. It was a matter of being interested in it. At that time, in 1946, hematology was really not identified, recognized, sub-specialty in medicine. How did I become a hematologist? I guess I just became one. Grew like topsy into it.
Q: But by 1946 you so identified yourself?
Cronkite: Yeah. I was interested in it. I had this experience: two things that Professor Bloomfield had gotten me into, and during the Navy, it was a routine practice of medicine, ordinary things, and it was obviously not for me. And actually I practiced medicine part-time for six months, and it just drove me out of my mind. Unless you had really acute diseases and so on in which you could possibly do something, it just wasn't-- it certainly wasn't the thing for me. I would have gone completely batty with the ordinary practice of medicine.
So I guess the answer to your question about how did I become a hematologist, I became a hematologist by fiat. A set of orders from the United States Navy said "Thou shalt be the hematologist for Operations Crossroads." And then when I began to learn a little bit about what was expected of me, I realized I better --Of course in those days, when I went to school, undergraduate physics was required for entrance into medicine, but the physics we had then was mechanics. It was nothing. Mechanics and electricity and a little bit about magnetism, but nothing was taught about nuclear energy. It hadn't really been developed to the extent yet where it got into textbooks in undergraduate teaching. So I had to learn a lot about physics, and I'm still trying to learn enough about physics to pursue the things that we're still doing.
Well Operation Crossroads brought me into contact with Shields Warren who was professor of pathology at Harvard, and a Captain in the Medical Corp in the United States Naval Reserve, and a real bonafide Yankee. He was the scientific director for Operation Crossroads, and a series of animals-- goats, pigs, rats, guinea pigs, were selected for exposure to the air drop and also for the underwater shot to explore the relative effects of ionizing radiation thermal burns and blasts.
I guess the most generous thing that could be said about it is, yes exposure of living things to nuclear bombs is disastrous. There wasn't enough known about the distances, estimates of radiation and so on, so things were done in a way that nearly, from a scientific standpoint was really poorly interpretable. But we did learn, along with what was already in the literature, that there were major causes of death after exposure to large amounts of radiation. There were 1) infection due to granulocytopenia, 2) hemorrhage due to the thrombopenia, or at least as a clinician, it seemed to me and my associates that the reason the animals became very susceptible to infection was because of the granulocytopenia, diminution of granulocytes - the white blood cells that phacyocytize bacteria. And the reason they bled is because of the deficiency of platelets.
However, this was not the concept of others, namely-- and this maybe one of these things that should not be made available-- J. Garrott Allen and Leon Jacobson at the University of Chicago -- J. Garrott Allen was a surgeon at the University of Chicago and later became professor of surgery at Stanford University, and Leon Jacobson who was assistant professor of medicine at the University of Chicago. They did some studies that became internationally accepted in which dogs had been given fatal doses of radiation. The blood became incoagulable. They did look at platelets but they concluded that the cause of incoagulable blood and the hemorrhage was because of a heparinemia. Heparin being a substance that is an anti-coagulant product of particles in mast cells in the body. As a matter of fact, I had spent a few days with the University of Chicago before going out to Bikini to learn how to do their tests, all of which were negative in the animals that bled severely.
When it came back to the Naval Medical Research Institute, I kept worrying about the problem of ascribing radiation hemorrhage to heparinemia. Because if this were true, there are two substances that would have therapeutic value. One is toluidine blue and the other is protamine which will inactivate heparin. As a matter of fact, there were plans to stock-pile protamine by the Navy. There was what was called the Annual Tripartite meetings of England, Canada, and the United States, of how would you plan for certain things in warfare. And the only part that I was ever brought into was the question of how would one plan for the care of casualties in the event of nuclear warfare. And since the Allen-Jacobson work was accepted, there was serious thought being given to stock-piling protamine and toluidine blue.
It seemed to me that we ought to do some further studies. We tried to repeat the stuff at the Naval Medical Research Institute. We couldn't repeat what Allen and Jacobson did. And then I came across a Danish monograph from about 1920-21 something like that, Fabricius-Moeller, who ascribed bleeding in radiated guinea pigs as being correlated with the diminution in platelet count in the animals. It seemed then the next thing to do was to work out methods for separating platelets and to give platelet suspensions to irradiated animals and see what happened. And George Brecher, at the National Institutes of Health, and I had already begun to collaborate on other aspects of radiation injury. In talking to various people, a fellow George G.H.
Dillard at the National Institutes of Health, an associate of George Brecher collaborated on platelet separation.
Cronkite: It should be possible to separate out platelets, quickly and easily. And in fact, using sodium EDTA-- I can never remember the chemical terminology. EDTA is the anti-coagulant -- and with non-wetable surfaces, very careful handling of the blood in drawing it, that one ought to sediment out the red cells and have a concentrated suspension of platelets in plasma and then by centrifugation of concentrate platelets to a small volume. Well we did this and it worked well in dogs and in rats. There was no problem in getting concentrated suspensions of platelets. At the same time, it appeared necessary to have an accurate method of counting platelets. And Brecher and I worked out a phase microscopy method for counting platelets. That was much superior to the indirect methods that were in use up to this time. Also simultaneously a guy in Switzerland (Feissly), whose name I've forgotten, also developed a technique of counting platelets with phase microscopy.
So we had an accurate method of counting platelets, and found out one could relatively quickly get concentrates of platelets. So the next thing to do is get enough of them, and get enough dogs in order to do the study, because it was going to take a lot of donors. We convinced the people at NIH and the Navy to support a blood donor colony of dogs. We used American Foxhounds. By this time, Larry Young [Lawrence E. Young], and [Dr. John R.] O'Brien, at the University of Rochester, had worked out a method of blood-typing in dogs.
We used their method of typing so we had a colony of, I think it was 100 American Foxhounds, for the donors. These were selected because they're relatively uniform. They had relative similarity in blood groups. They were large animals so that one could take 250-300 milliliter blood out of them without any harm. And we used other American Foxhounds for the recipient. After fatal radiation of 600 RAD, *that is uniformly fatal, animals were dying between about 10 and 20 days after radiation with massive hemorrhage, Purpuric hemorrhage, big hemorrhages in the brain, heart, gastrointestinal tract.
We then made suspensions of platelets from the donor colony, and injected them into animals at regular intervals so that they never became thrombopenic, or at least not as thrombopenic as the non-platelet transfused animals. And the animals then died from infection without hemorrhage. This seemed to be conclusive evidence that by keeping the platelet counts up, the animals didn't get hemorrhage. They died then from fatal infections. So we wondered if we now concentrated granulocytes and gave granulocyte transfusions, would this prevent the infections. The answer is yes. Granulocyte transfusions did result in the transfused granulocytes migrating out into areas of infection. They controlled the infections to a limited extent, but the animals, even though they were typed as much as we could...
...they developed anti-bodies against the granulocytes and after a few transfusions, they were no longer successful. So though it was a good idea, it was ---It showed that separated transfused granulocytes would behave like the animals own granulocytes. Unfortunately there were histo-incompatibilities resulting in immunologic reactions so that it didn't work very well.
Well about this time, I presented this data at the annual meeting of the Federation meetings, and a very prominent pathologist, an American Pathologist Jacob Furth--
Q: When was this, Dr. Cronkite?
Cronkite: 1950 roughly. I could get this out of my references. About 1950 because I was still in the Navy. Dr. Furth was chairman of the session in which I presented this, and it was a humiliating experience. He just said, after I gave my presentation, "There is no substance to what Dr. Cronkite has presented because we have demonstrated that radiation hemorrhage is due to injuries of the capillaries, to the capillary
Endothelium." You'd have to know Dr. Furth in person, a very positive individual. He was an Austrian Jew and really a truly remarkable human being, as you will see in a little bit. But he wouldn't listen to me; And I went back, and of course the story went around the military service, which is a closed thing, that Cronkite had really blown it now. And the Commanding officer got me in and wanted to know how could I make such a fool of myself. It never occurred to anyone that Brecher and I might be correct. That never occurred to them.
But I must admit for a while there I was really shaken by it and I was wondering what to do. And one day we got a telephone call from Dr. Furth. And he said, "Dr. Cronkite, I've been thinking about the presentation. There's a possibility you might be correct." I said, "Well sir, I'm reasonably confident that I'm correct. I know that George Brecher and I are convinced we're correct." And he said, "Well that's why I called. I want you to come down to Oak Ridge. I've already collected the dogs for the platelet transfusions. I've had a surgeon at work developing a technique of cannulating the thoracic duct. And if you're correct, all we have to do is give platelet transfusions and the blood lymph is coming out, and it will stop." I said, "I believe it but Dr. Furth, I'm a Naval Officer, I just can't get up and go anyplace." Well he said, "Who could authorize you to go?" Well I said, "The Surgeon General's office." "What's his phone number?" So I gave it to him. And about an hour or so later the Admiral's aide called and "Who the hell is Jacob Furth? He wants you to come down right away and the Surgeon General won't say yes or no until he knows who he is." So I explained to him. And in the meantime, he had been after George Brecher. And Brecher was a Public Health Service officer. "I can't just get up and go. I've got to get authorization." And again through the Surgeon General, the Public Health Service Office, ultimately an amazing thing took place in just a few days. I guess it was the next day. We had orders for us to go to Oak Ridge. We went down there and Furth had all these donor animals lined up. He had a couple of dogs that were thoracic-duct cannulated. Bloody lymph was coming out of the cannulae. When you go into somebody else's laboratory and you try to do things that you do regularly yourself, you get nervous. Something almost always is going to happen that things just won't work. That's the nature of the beast. But everything worked perfectly. I bled the dogs. George Brecher and I prepared the platelet suspensions. Usually they're a little bit pink when we were doing them at Bethesda, and this time they were perfectly white, beautiful suspensions. We never made such good suspensions before. We went into the surgical suite. I gave the serum, about 100 cc serum platelet concentrate, to George and he gave it to Dr. Furth. Dr. Furth gave it to me. Who's going to inject this? So it came down to me -George Brecher had vision in only one eye, no binocular vision, I injected and boom like that. Here was the most dramatic thing I've ever seen. Cherry red lymph coming out and within 10-15 minutes, you could see it begin to get light pink and suddenly it was colorless. And Furth says, "You're right."
So at the next Federation meeting, I was going to present something else again. Furth again was the chairman. And he said, "Sit down, Cronkite. I'm going to tell them." So that was --
[END OF SIDE ONE, TAPE ONE, BEGINNING OF SIDE TWO, TAPE ONE]
Cronkite: When I start thinking about some of these things, they're a mixture of a young person being thoroughly crushed. Or I shouldn't say person, persons. George Brecher and I were thoroughly crushed for a moment but when you tangle with a guy like Jacob Furth, his innate intellectual honesty and desire to know the truth was finally surfaced. As he thought about it, maybe something was wrong, and then he felt it was his obligation to correct it, which he did.
Well today, of course as you know, platelet transfusions are used daily in individuals that need platelets and under chemotherapy or extensive radiation therapy, or candidates for bone marrow transplantation.
Q: How has the antibody problem been overcome? Am I jumping too far ahead?
Q: I may be jumping too far ahead.
Cronkite: The antibody question. Now with very few exceptions, I have not been concerned with platelet transfusions in human beings. To answer your question directly, it hasn't really been solved. There are platelet antigens. There are leukocyte antigens. The roll of lymphocytes being contaminating. You never get rid of all the nasty little lymphocytes that are really immunogenic. So the objective now, with platelet transfusions or red cell transfusions, to try to avoid allogeneic immunization, the suspension of platelets or washed red cells are exposed to about 2000 RAD-radiation to kill all the lymphocytes in there, and to avoid it. And this is helpful but it doesn't really --When one does all the things that can be done today, the probability of allogeneic sensitization is diminished but not abolished. It still remains a problem. It's not a major problem but it still remains a problem. So where were we?
Q: We're in 1950. You're still in the Navy.
Cronkite: Yes. So it's still before 1954. In the early 50's Egon Lorenz at the National Cancer Institute had discovered that in the guinea pig and in inbred mice that if one were to give the fatally irradiated animal a suspension of bone marrow, that the amount of radiation they would tolerate was greatly increased. In other words, this was the first successful demonstration of the value of bone marrow transplantation. That was in the mouse and the guinea pig by Egon, Lorenz and Delta Uphoff. And then with Charles Congdon at Oak Ridge National Laboratory, they did some quantitative studies in the pathology and so on. It was a very clear cut demonstration that fatal irradiation or fatal aplasia of the bone marrow could be corrected by a bone marrow transplant.
Q: Where was the marrow transplanted from?
Cronkite: From other animals. In the mice, I forgot what strain of mouse they used, but they used genetically identical mice so it would be like an identical twin so there would be no immunological reaction. And then they went on with that to work with unrelated animals. And so on. Then there was a - Everybody all over the world got interested in this because the obvious thing that if you could do it in animals maybe it could be done in human beings, too.
Cronkite: Uphoff, Delta. The third person was Charles Congdon. Dr. Lorenz was very interested in trying to-- it was about the time the clinical center was in construction or early operation at the National Institutes of Health, and he and I had had some discussions about the possibility of developing a human transplant program at the National Institute of Health. About this time, actually March 1, 1954, the change of wind resulted in the deposition of fall-out on a large number of Marshallese in the Bikini Atoll: Rongerik, Ailinginae and Uterik. And the Atomic Energy Commission was unable to get a team together of physicians from the civilian community through the contract groups; because of problems--- Well I don't know why. They just couldn't. Admiral [Louis] Strauss was Chairman of the Atomic Energy Commission at that time. The Army and Air Force couldn't come up with a team to go out there. And when the Surgeon General of the Navy was asked, he said, "Sure, we'll do it." And it was around about 8:00 in the morning, if I recall correctly, about the 2nd or 3rd of March, I was down in the laboratory autopsying some animals when the chief master at arms came down and told me that I was wanted instantly in the Commanding Officer's office. "I can't go up there now. I'm all bloody." "I was told to bring you up instantly." Okay, so I hate like hell to go up to the commanding officer's office looking like a butcher, but I did. He agreed that I couldn't go into the Surgeon General's office. Then I had to change my clothes. A car was waiting for me and took me down to the Surgeon General's office, and there was John Bugher, Director of the Division of Biology and Medicine, AEC, and Shields Warren, who was then ex-director of the Division of Biology and Medicine, and Admiral Strauss. He was Chairman of the Atomic Energy Commission, under Eisenhower. And fortunately, I had had what was called Q Clearance for studies that we'd done in Nevada, the bomb tests, and also out in the Pacific, the first nuclear bomb test. And the situation was explained to me. A large number of human beings had been exposed to fallout. They did not know the magnitude of it. Plus some American servicemen that were on the Island of Rongerik, and that my job was to organize a team to be ready to leave in 48 hours, which was simple enough to do, because we had been on many field tests, and I knew the individuals who were cleared that would be allowed out into the area, and the ones that would work and so on, and the ones that were clinically very good.
At that time, actually working with me at Naval Medical Research Institute was Ray Shulman, who is now head of a Division of National Institutes of Health. He was a very good clinician. And I called Richard Studley Farr, who was in the regular Navy, but was working on his PhD at Cal Tech, who is a darn good hematologist. And he said, "Well, I can't be disturbed. I'm working on my PhD." I said, "Well, I'm sorry. You're an officer in the regular Navy and you will be at Hamilton Air Force Base outside of Sacramento, California by such and such a time. And if you're not there, I would suggest you be prepared for Federal Marshall to come and pick you up and trot you off to federal prison someplace for court martial. And if you don't believe me, I suggest you get hold of an attorney right away and discuss it with him." Well he called back in a couple of hours and he said, "I'll be there. " [Laughter]
The only reason I tell you this is why when it began to come through to me, that you could have-- During the war, I never objected to any orders I got or anything I did, although I had a wonderful time at the Naval Medical Research Institute. You got complete support in everything you wanted to do both, equipment, money, personnel. But it sunk through to me that at anytime you're subject to getting a series of orders that is just going to disrupt your personal life, and I made up my mind instantly as soon as this thing was over, I was going to resign from the Navy. We went out there and taking care of the Marshallese, and worrying about how serious it was. We didn't know much about the dose relationships in human beings. The usual hematologic studies were done and hematologically we were trying to make our minds up whether anything should be done. We decided that watching and waiting was the best thing, which turned out that we were correct. We could have been wrong, or it could have been a disaster but it turned out we weren't wrong. And that is one of the largest studies, it's the only study of the effects of fallout on human beings. And it's still being studied in many respects, so far as long term effects are concerned. Actually, the program was transferred to Brookhaven after I left the Navy and then I turned it over to some other people; Dr. Robert Allen Conard who did the long-term follow-up on the Marshallese. And he did a magnificent job of follow-up and it was taken over by William Adams who is here in this department now and is following the Marshallese group for long-term studies. But I actually got ahead of myself.
I mentioned earlier about Egon Lorenz and our sort of aborted discussions of the possibility of developing a human transplant program at the clinical center at NIH. When I came back from Marshall Islands, I went to him seriously and I said, "I've made up my mind. I'm going to resign from the Navy."
Cronkite: So I talked seriously then with Dr. Lorenz about the possibility of getting a job at the National Cancer Institute and developing a clinical unit, which I was very excited about doing, though I had no real notions how one would go about it; Nor I guess at that time did anybody else. I was given an offer at the National Cancer Institute. I accepted it. My resignation was finally accepted by the Navy contingent upon going into the Naval Reserve. It was to be effective October 1, 1954 and sometime during the summer I got a call from the director of the National Cancer Institute, Rodney Heller. He wanted to speak to me about the appointment. I went over there and wondered what --Heller was an admiral in the Public Health Service, two stars in the Public Health Service. He was a very confident guy. He'd done excellent work in cancer research and so on, and was a very good administrator. But he started out, and he said, "I understand from my friends in the Navy that you're a trouble-maker." Well I said, "That's news to me." He said, "Yup, that's what they tell me." "Well sir would you mind explaining to me what you mean by trouble-maker." "Well you give your seniors a bad time." I said, "I've always felt it was an individual's responsibility to express one's opinion or notions about any subject but when my seniors insist on something, I'm a good naval officer. I go ahead and do it providing it doesn't conflict with my ethical concepts. And that's very clearly specified in naval law and so on. So far as medical officers are concerned, nobody can make you do something that you don't think is ethical and proper." He says, "Well they convinced me you're a trouble-maker." And I'm wondering, "Well what does this mean?" He says, "It means that we're withdrawing the job offer to you." "In other words, you mean I'm fired before I'm hired?" He said, "Yes."
At this time I was wondering what the hell I was going to do. As a Naval officer, you just made enough in those days to get along. You couldn't put any money away. I had a wife and a daughter. I wondered what the hell am I going to do now. And just by sheer chance, I met Shields Warren and he had known I was leaving the Navy. I told him I was going to the National Cancer Institute and then when I met him and told him that I'd been fired before I was hired. He said, "Well you know there is a possibility at Brookhaven National Laboratory. They've been wanting somebody that knows about human radiation biology, and I'll suggest your name to the director there, Dr. Farr," which he did. Shortly thereafter, Farr met me in Washington. I think it was one of the most unsuccessful interviews I've ever had with anybody. I couldn't understand what he was talking about. I am certain that I was totally incomprehensible, but a few weeks later I got a written offer to come here to Brookhaven as a senior scientist. Want to guess what a senior scientist got in 1954?
Q: Tell us.
Cronkite: 12,000 bucks which was substantially less than the actual take-home pay that I got in the Navy. But at least it was an income. The other amusing thing that happened about that time. There was one other thing I still had to do for the Navy. And to save my soul, I cannot remember why, but I had to make another trip to Europe on behalf of the Navy. I first flew by Naval Air Transportation Service to London. And when I arrived in London, the London newspapers said -Oh I left something out- When I left Bethesda in a station wagon with wife, daughter and her dog, the dog and my daughter were sick all the damn way. It was a mess. I got up here and put them in an apartment. I think my wife was acutely unhappy about it because it reminded her of WWII in what we used to call Splinterville in various places we'd been. And I took off and went to Europe.
When I landed in London-- it wasn't a straight flight then. We went to Newfoundland, to St. John's, to Iceland, to London. So it took two days to get there in a beat-up, old Naval Air Transport plane. The headlines said, "Hurricane" - I can't remember the name of the hurricane now - "Goes Over The Center of- the eye goes over the center-- of Famed Atomic Energy Research Laboratory -Brookhaven National Laboratory. Fells Steeple of North Church -the Site From Which the Infamous Paul Revere Started His Ride." [Laughter] I think I've got the words pretty much correct. Then I tried to get on the telephone to see what happened. The British said, "Well if you call back in about a week, maybe we can get a call through to the States. You're only one of thousands of people wanting to know what's happened in New England and New York."
So that's how I started. I came on a one year contract and immediately started looking for a job elsewhere. But here it is 34 years later, I'm still here.
Q: Why did you immediately start looking for a job elsewhere? Because of the pay?
Cronkite: Oh, well the pay was ridiculous, and because what I was supposed to do, the mission as it were, was to have a program in human radiation biology, and I couldn't conceive of how one could have a program when it was ethically not acceptable to do anything. You could study a little bit in people under radiation therapy. But there was just no way you could study human beings ethically. It was just -- One doesn't like to be given a mission in which one can't do it - period. Unless there was something like the fallout accident.
It looks pretty decent now, but the medical department was not in this building. It was in the old Army hospital, and it was miserable conditions. The animal facilities were atrocious. There wasn't anything that was good about it, whereas everything at the Naval Medical Research Institute was avant garde equipment wise, facilities, everything. This place was the pits really.
Actually, I had been offered a professorship in physiology at Jefferson Medical College. I told the chairman of the medical department, gave him a copy of my written offer, and shortly thereafter I was given permanent tenure here and a substantial increase in pay. All the things I complained about as being second rate, were put into motion to correct. So 34 years later I'm still here. Well where does one go from here? When I arrived here, shortly thereafter, the head of the division of experimental pathology was Jack Godwin, a very fine Southern gentleman. He was an absolutely outstanding, surgical pathologist. Got his training at Memorial Hospital. But he really was not an experimentalist. And I was impatient to get things going. He didn't understand what I wanted to do. I didn't understand why he didn't like what I wanted to do. But he was a perfect Southern gentleman. We were very good friends, but we just couldn't see eye to eye.
Q: What did you want to do?
Cronkite: What did I want to do? I wanted to develop a program on radiation effects in animals. I wanted to test. There was no argument. We knew by that time from what happened to the Japanese exposed to the bombs at Hiroshima and Nagasaki, that there'd be incidence of diverse types of tumors and increased incidence of leukemia, thyroid tumors. Now we now that any organ in the body could develop a tumor.
The Marshallese had something unique. They had a large number of skin burns from the fallout that was in contact with their skin. And I wondered whether there would be any additivity of the radiation effects from the beta emissions on the skin and the whole body irradiation. So we wanted to set up a study in rats that would be given approximately the same amount of whole body irradiation as the Marshallese received, plus localized skin burns.
And we did set it up and it turned out that there was nothing to that but the animals did develop a very large number of mammary adenomas and adenocarcinomas that subsequently was turned over to Claire Shellabarger in this department, who exploited the system, and he became one of the world's specialists on experimental radiation mammary carcinogenesis.
One thing I left out. It goes back to-- which I think is relatively amusing. In 1946 the National Institutes of Health-- I guess it would be after the war, so it'd be '46-- Decided that there should be a wide basis of support in biomedical research and set up a program for extramural support in many different research areas.
Cronkite: -- which was the beginning of the extramural research program. Another program in cardiovascular disease. There is a hematology, immunology, infectious diseases. I've forgotten all of them. And the hematology study section-- or for all of the study sections-- the Army, Navy, Air Force and Veterans Administration, was asked to appoint one of their individuals to be a member. And these were originally to be voting members of the study sections, and I was appointed by the Surgeon General of the Navy as the Navy Representative. And I was on the study section up until I resigned from the Navy, effective October 1, 1954.
This association was tremendously important to me, not only giving me contact with what the thinking was and what people wanted to do in hematologic research both clinical and basic, cellular and molecular, but not much molecular, in 1946. But I had an opportunity to meet - Originally we met four times a year. The first study section was William Castle, Charles Doan. Castle was professor of medicine at Harvard. Doan, professor of medicine at Ohio State. Edwin J. Cohn, University professor of biochemistry at Harvard. Kenneth M. Brinkhous who was then professor of pathology at Iowa but now professor of pathology at the University of North Carolina. The NIH representative was George Brecher. The executive secretary was Kenneth Endicott. The professor of surgery from the University of Washington, Seattle, whose name eludes me now (Harkins), but had done a lot of work in transfusion problems.
But the important thing was that every time there was to be --Today all meetings are in Washington. But there was plenty of money in those days. They would meet in different places in the United States: Boston, Columbus, Ohio; Seattle, Washington.
Dr. Castle, in those days, I don't know whether he ever got over it, had a morbid fear of airplanes and would always go by train. And then I would find out what train he was going to be on, because to spend a few hours, if you're going across the country, three days in those times, listening to Castle and so on was just a completely invaluable education.
And the same with Doan, hated airplanes. They just hated them. He was the original chairman. Max Wintrobe was on it too. Doan and Castle hated airplanes. Castle would not, in those days, go on an airplane at all. It just gave another opportunity for a free education from the best that existed in the United States at that time.
Edwin Cohn. Castle was fantastic. Always a perfect gentlemen. Edwin Cohn was truly one of the great American biochemists, protein chemist particularly. To try to say something nice about the man though is very difficult. He was a miserable son of a bitch. Any way of saying it-- he was a four pie revolting son of a bitch. It was just unbelievable what a dictator this guy was. Completely ruthless with human beings. He was on the study section. From time to time things would come up in which he was trying to use the study section to get tremendous support, financial support, literally millions of dollars, for an idea he had of having a mobile unit that would go around the country with all of the chemical processing equipment in it, so that literally at one end of this big truck a human being put his arm out, be bled, the centrifuges would separate out the red cells, platelets and so on. Buckets here. Plasma in this bucket and then it would go out down through the thing and at the end would come albumin and fibrinogen and everything. It was a beautiful engineering thing but the money that would go into it, and why it was necessary to have a truck going around the United States doing this never seemed to make any sense to me. It certainly didn't make any sense to my friend George Brecher.
Endicott as a executive secretary, he didn't like it. He said personally, after a couple of drinks, that he thought it was bad but publicly he couldn't say anything because of the position that he was in.
Brecher and I were giving him [Cohn] a bad time and might possibly have been able to influence the vote of the study section and go against this thing. Unbelievable. Right in the meeting he got on the telephone in front of us and he called, of all people, General George Marshall, who was at that time Secretary of State. And he says, "There's a Naval Officer and a Public Health Service Officer that's giving me a bad time." And he gave our names and said, "I want you to take care of them." And apparently he went with the circles that were if you're a university professor from Harvard you talked to people like General Marshall. Maybe they played bridge together or something. I don't know.
Sure enough back down through channels came the ''Why are you giving Professor Cohn a bad time?" [Laughter]
Association is a bad thing. You start talking about one thing and then you suddenly remember something else in the past. My first association with Cohn actually was 1942 when I was first in the Navy. When I was the junior, junior officer when I was assigned to the Red Cross: Captain Newhouser, Lieutenant Commander Eugene Lozner and myself. We were Naval officers then. We were just collecting blood and all sorts of funny things. All happened as a result of that which I may think of in the moment. I'd heard there was another guy in the Army Colonel Kendrick, John Kendrick, and John Elliot who was a funny character, represented the Army in this thing. So there was to be a meeting of the scientific directorate: Max Strumia from the University of Pennsylvania, Leandro M. Tocantins from Jefferson Medical College and Director of the Cardeza Foundation [of Hematological Research], Edwin Cohn and a couple other people whose names I've forgotten. I said, "Gee this will be great. I can sit in the back and listen to the great men talk." And the next thing I know the meeting was convened. All the great men came in. I was standing dutifully by the door of the blood donor center at 23rd and C Street, Washington, DC. They all went into the room and in came this man with pearl gray gloves, cane, a boller, gray spats, an overcoat with fur around the collar. He saw me. Took his cane, gloves, hat, overcoat, handed it to me, walked into the conference room, closed the door. "What the hell is going on." The only thing I could do. I hung it up and I said, "Gosh I guess if the door's closed I'm not allowed in there." So I was bitching to the nurses and the hospital corpsmen about it. They were trying to convince me that I should go ahead and walk in, but since I wasn't invited and there is certain protocol that junior officers are, like children. They should be seen and not heard.
So that left me with a bad feeling about Professor Edwin J. Cohn to begin with. Then this thing that I already told you happened in the study section. Before that though, there was another amusing thing that happened.
When we met in the Mayflower Hotel one time, and Cohn invited everybody up to his suite, and had hors d'oeuvres and drinks and so on. And you assumed the great man was going to pay the bill, but when it came the time, it was split up among those who were there. And after he had a couple of drinks, he said, "Cronkite I've met you somewhere's before." "Yes Dr. Cohn you did. I was the doorman at the blood donor center in Washington, DC who hung up your coat, cane, pearl gray gloves, etc." "Ah yes, I remember that."
A very funny thing is when he got into these arguments, or was trying to impose his will upon people, he would develop a very severe case of acute asthma. And he carried a bottle of adrenalin with him and a dirty syringe. And when he had one of these attacks, he'd tap me on the shoulder, "Cronkite, come on." We went out. He took out this bottle of adrenalin that should be water clear and it turned sort of pink, this dirty syringe. And he says, "Give me an injection." I thought, "My God. I can't do this. This violates everything I know about--"
Q: Dr. Cohn's eccentricities.
Cronkite: His asthma,
Q: His injections?
Cronkite: -- Contaminated -- His only reaction was to the thing is, "Yes I know you doctors are always concerned about sterility and so on. It always takes care of my asthma and I've never got an infection yet." So, okay where to go now?
Q: I'd like to bring you back to the cumulative effects of radiation. It seems interesting to me. You said with the rats, the skin burns didn't add up. Did that lead to other kinds of research?
Cronkite: I guess one of the earliest cancers that was induced by radiation was skin cancer. But this was in radiotherapists and physicists who were totally unaware of the harmful effects of radiation, who would develop ulcerations, and there'd be chronic infection. And they did develop cancer on their hands primarily. And it was disastrous in some of the early pioneers in radiation physics, and in early parts of radiation therapy, where they had to have amputations and they'd get metastases and be killed by the cancer.
Now in animals, radiation of the skin in the absence of ulceration, there was no skin cancer. So there was the feeling that not only the radiation but also chronic inflammation was required for cutaneous cancer. This was borne out in part by people who had had severe skin burns from heat, flames, hot objects that did not get skin graphs and had chronic inflammation. Some of them would develop cancer also. So the primary thing was believed to be the chronic inflammation as a result of the ulceration and chronic infection and so on.
Well the question that I was addressing was when you -- Now the Marshallese had very extensive skin burns from contact of the fallout on their skin. This is the tropics. The skin is warm. The material stuck to their skin, and they got very substantial burns, all of which healed completely. There was no chronic ulceration. It took a few weeks for the healing to take place but there were no ulcerations.
So the question I was asking is, would total body irradiation disturb the metabolism in some way. Today it's a stupid question to ask. It wasn't a stupid question in 1954. Would there be some perturbation of metabolic processes, so that the cells in the skin that had been injured but recovered at least so far as covering the area, would they now be promoted into cancer? Now there is some evidence from Berenbaum in Israel who had shown that if one irradiates skin to a certain extent, or treats it with a chemical carcinogen such as di-methylanthracine at a subulcerating level or a level that will not in itself produce a cancer. But you then treat it with a substance, croton oil was a crude thing that was used. A hell of a good cathartic. This then would promote the injury which by itself on the skin was not adequate to produce a cancer -- would make the cancer. And this is how Berenbaum got his notions of initiation if something happens to the cells, now known clearly that it's a rearrangement of some change in DNA. And if you now force the cells to divide by an irritant as croton oil was -
[END OF SIDE TWO, TAPE ONE, BEGINNING OF SIDE ONE, TAPE TWO]
Cronkite: You've got to remind me, where was I?
Q: You were making the association between--
Cronkite: Oh yes. The use of DMBA, Dimethylbenzanthracine, in a sub-cancergenic dose to the skin, followed up by croton oil, or an extract of croton oil, phorbollester, which is an irritant, resulted in a cancer. And this resulted in the concept that is now widely accepted of initiation being a change taking place in the DNA that will not be expressed as a cancer unless the cells are stimulated repeatedly to divide, as they will be with inflammation. It could be just mechanical inflammation, probably, producing a callous. So what else about the cancer project do you want to--
Q: I was interested in, I guess, the double hit with the radiation, struck me--
Cronkite: It is a very interesting thing. Number one, there is only one human population that is large enough and yet when you start analyzing the data, it is really not as large as one would like it to be. The Japanese that were exposed in Hiroshima and Nagasaki had a single exposure. The exposure to radiation took place in a fraction of a second. And thereafter, a series of things -- Well the acute effects that happened in the Japanese is exactly like what we observed in animals later, that Shouse and Warren observed in the early 1920's in the studies on dogs. There was no mystery so far as the acute effects of radiation was concerned. There had been a few scattered studies in animals; Some by Jacob Furth that I had mentioned earlier, that were pretty good evidence that one could anticipate an increased incidence of leukemia in the Japanese.
Cronkite: 1 1/2 years after the individuals were exposed to radiation at Hiroshima and Nagasaki there was a perceptible increase in the incidence of chronic granulocytic and acute meloblastic leukemia in the exposed individuals compared to those who had not been exposed to significant amounts of radiation in either the cities, or to the Japanese population at large.
The increase in incidence peaked at about 7 1/2 years after exposure, and by 15 years after exposure was nearly back to the expected incidence. Today it depends upon how one argues or does the statistics. There may or may not be a slightly increased incidence in the exposed populations.
Next thyroid tumors made their appearance. Both benign and malignant thyroid tumors. Then increased incidence of carcinoma of the breast, gastrointestinal tract, possibly salivary gland, genital urinary tracts, and I don't remember all the -- But the thing that's important to know is that the latency between the instantaneous exposure at which the injury to DNA took place, either by strand breakage of DNA with reassembly of the chromosomes was showing trends of what was going on. When one chromosome, they're broken, and the chromosomes rejoined with parts of other chromosomes. Translocation is the right word. Or deletions by a chunk being broken off and not rejoining any other chromosome and just lost, so that the genetic information on that piece of the chromosome is lost to that cell and it's progeny. All of this took place, injury in a second. The diseases did not make their appearance until 18 months in the case of leukemia, 5 or 6 years for thyroid disease, for breast 15-20. So it takes a long time for the initiation to be promoted to a diagnosable tumor. And during that period of time the factors that are involved are probably concerned with the metabolic changes that take place with aging, with inflammatory things in the gastrointestinal tract, prostrate and other glands. God knows what they are but they are, of course, tremendously important. Because if you could stop the promotion you would stop the, you would prevent the development of cancer after chemical and radiation injury. Now the notion a lot of people have, particularly environmentalists and people who are trying to oppose nuclear power, is they act or speak as if there was an epidemic of cancer in Hiroshima and Nagasaki. These people were exposed to a very large amount of radiation. There was not an epidemic. The total number of excess cases of leukemia in this population of which there was close to 200,000 exposed was only 200 cases all together. And there was no detectable increase in the incidence after exposure to people to less than 50 rad. It doesn't say there isn't anything there but it is statistically not detectable. One would need a population of several million to detect it, if you don't make these assumptions that are made of linear no threshold. And to try to answer the question that people like Ralph Nader, [Jeremy] Rifkin who are saying that 10 millirem exposure in a nuclear power plant will increase the incidence of leukemia, in order to determine that you would need more, statistically to determine it, you would need more than the population of the entire world. I mean it's one of these number games. If you start out with a premise that it's harmful, that you've got to have zero risk, then you can juggle the numbers and say this is what happens. But this is simply irrational. It's irrational primarily because whether one likes it or not, fossil fuels are limited. They should be conserved for the generations unborn. Once they're gone, they're gone. It's hopeless. Nuclear power is nearly clean power and though fissionable material is also finite, it will go for years and years and years, for hundreds of years, if not thousands of years. Whereas fossil fuel at the rate it's being used now will probably be gone in a 100 years. So humanity needs nuclear power. Even if were harmful. Even if one had to occasionally put up with a Chernobyl, which one does not have to put up with, it would be the only way to go. There isn't any-- hydroelectric power, maybe you could get another 10% in the United States. And you know what happens if somebody tries to build a dam some place, the ecologists say no this is going to ruin the --which it will do. So you can't build anymore dams. You try to build a -- what was it? Con Edison had a -- somewhere's up the Hudson River. They were going to pump water at slack times up to the top of a mountain someplace when electricity would be available, and then, when they needed it for peak uses, they'd let the water come down and they're making--their own hydroelectric. The ecologists and environmentalists shot that down. I have no use for some of the commercial concerns for various reasons, but boy, poor old Con- Edison what they put up with in New York is unbelievable. They're a lousy corporation. Long Island Light, I think, is a lousy corporation.
Cronkite: They can't produce the electricity people want. There's no way they can. Anything they try to do, they get shot down. I've diverted, got onto a favorite subject that has nothing to do with my own research. But it just confuses me as to how the Ralph Naders and the Rifkins and a lot of other people can so influence public opinion to the detriment of the welfare of the United States of America, and why the French are able to get away with building reactors. 75% of their electric power now, is nuclear generated. And it will be 100%. In Japan where they always talk about radiation as being terrible for obvious reasons, they will be 100% in nuclear power by the turn of the century. They don't bother to-they pay no attention to environmentalists there. They just go ahead and do it. They have to. What is Japan going to do if they don't have nuclear power. If somebody decides to turn off the oil, or the Chinese decide not to sell them coal anymore, they're destitute. Okay one should stay off of that subject.
Q: It's a good subject. One strain I'd like to introduce into your thinking, or into your speaking, I'm sure it's already in your thinking, is the changes in biology itself particularly since the discovery of DNA. When you differentiated between molecular and basic cellular and clinical scientists, it seems to me that that's a real, not only turning point, but on-going point of interest.
Cronkite: What I have to do is put it into focus of what I know most about. And that comes right down to cellular hematology. Back in the last century the act of cell division was discovered in small organisms, when the microscope was developed. Of course, it was originally developed in Holland by Anton Van Leeuwenhoek, and don't ask me to spell Van Leeuwenhoek. Even though my name used to be of a different spelling of a Dutch name, I cannot spell Van Leeuwenhoek. Made the first microscope and identified sperm and red cells and little things floating around in water that nobody knew existed there, but they were obviously alive because they were moving. And then the resolution and power of microscopes increased so that one could look at living tissue of different types, and going from things that you could see them, like sand dollars or something else, dividing. Then you'd see at different times, and one would fix them with formalin or with alcohol, and then when they're fixed and then stained with various things, you could see what --Then the same things were observed in mammalian tissue. And you're getting two cells where there was one. And there was nothing wrong with the thought processes of people there, that if you're producing cells and they came up, Virchow [Rudolf] in Germany and some other Germans and also French and British who's names I've forgotten--accurately and logically said that cell division in mammalian tissue means that cells at the same rate they're being produced must be dying or you would begin to get tumors. It was self-evident. This was simple logic. And then the argument began, how long do cells live? And there were all sorts of notions about the life span of cells that were in no relationship to what is known to be reality now, until two very remarkable women scientists: Winifred Ashby, who's British born and educated and couldn't make it in England, came to the United States and was a clinical pathologist at Mayo clinic. She developed a notion based on immunological differences in human red cells: the MN antigens, in which M cells can be identified by making antibodies as can N cells, but for reasons that are too complicated to go into-- I never really have understood certain aspects of immunology-- You can transfuse M cells into an N individual without getting a transfusion reaction. And when you do that, and if you have antibodies made elsewhere against M cells then you make a suspension of blood cells at different time intervals from an individual who has been given M who is an N. And by differential agglutination, the M cells now are agglutinated by the antibody and each time you do this, you can find out they're disappearing from the blood. Naturally Winifred Ashby did this in I've forgotten how many, and she came out with the notion that the human red blood cell lives, has a mean lifespan of 120 days. Now this was totally unacceptable to the pundits of that time for reasons, looking at the old literature, I don't understand why nobody accepted her work. It might be that she was female. It might be that it would just --They weren't prepared that a red cell is going to live 120 days, because simple calculations that anybody could do if red cells lived 120 days it means that 2 x 10 raised to the 11th power red cells are being produced per day. And that's a big enough number to make a nuclear physicist pay attention, or an astronomer. That's a hell of big number. And I think that was the thing that just sort of made the pathologists of the day say no that's not possible. You can't make that many cells a day, so her number's wrong.
Q: When was this, Dr. Cronkite?
Cronkite: Her paper was published 1920-21. There were two papers. Then later in the 20's Florence Sabin, with some other simple observations on granulocytes in the blood deduced the life span of granulocytes and it came out that they lived less than a day. Again nobody paid any attention to it. Although what she did was absolutely 100% logical but it came up with a huge number, too. So that things went along until World War II and with the use of radioactive isotopes, chromium 51, labeling of red cells by Joseph Ross and Emerson, and by carbon 14 labeled glycine by Shemin and Rittenberg.
Q: Do you know Emerson's first name?
Cronkite: No I don't remember his name. He was in Boston. Joseph Ross was in Boston and later went to UCLA, [David] Shemin and [David] Rittenberg were biochemists and with carbon 14, labeled glycine amino acid, which is precursor of hemoglobin, they came up with a notion that if give a single pulse of carbon 14 labeled or N-15, actually what they used because it was before the radioactive isotope was available-- but the stable isotope and then by chemical techniques they would be able to determine the specific activity of the N-15 in hemoglobin with time. They came out with exactly the same curve that Winifred Ashby had in 1920-21. And chromium 51 is another technique. Iron 59 labeling of hemoglobin is another one. They all came out with the same answer with the appropriate mathematical corrections. So at least something now was pinned down in respect into two cells, or one cell rather-- the red cell. A very amusing thing happened actually in 1948. I guess it was. The National Research Council convened a meeting of all of the individuals concerned with red cell life span, preservation of red cells, in the National Academy in Washington DC, to see where they stood, because the lifespan of the red cell and how you preserve it and whether you influence the lifespan determines directly how much blood has to be available for military purposes and civilian uses, and ordinary things. It's a very critical thing. And I was there representing the Navy at the meeting, and sitting over in the corner was a plump lady who I'll never forget had a big floppy purple hat on. I kept looking at her and what in the hell-- She said nothing. She just sat there all through the meeting and smiling. And after Shemin had presented his stuff and Irving London had presented their stuff and [ ] Ebert from Duke had gone all through the mathematical interpretation of data, the chairman of the Medical and Research Committee, professor of pathology from Yale, who's name eludes me for the moment (Windernitz) but a very amusing little man, said, "Dr. Ashby, you heard all of the data presented today about the lifespan of the red cell. And you've been very quiet. Would you like to comment on something?" And she sort of giggled. And she said, "Oh yes, it's nice to know that all these fine scientists have shown that I was correct in 1921." That's all she had to say.
So Florence Sabin. I never met Florence Sabin. She was a protégé of Dr. Doan at Ohio State, or maybe he was one of her protégés. I don't really know. But she had deduced the lifespan of the granulocyte as being somewhat less than one day. And also she was a very remarkable woman. When she retired, she went back to her home in Colorado and became the public health officer in Denver. She was very much concerned about the incidence of venereal disease and that it was higher in Denver than it was elsewhere. It shouldn't have been. There was no reason for it to be unless there was some organized pattern of prostitution and so on. She began to look into it. She realized and identified where the brothels were and brought it up to the mayor and police chief and so on. Is there something you can do about this? No. No, nothing we can do about it. She thought more about it. She was one tough lady obviously. She decided to go look into who owned the property. She found out it was owned by the mayor and the police chief. After some article in the, I forgot the name of the Denver paper, about the honorable mayor owns so many brothels and the police chief owns so many, of course, they were instantly closed up and that solved the problem.
The time when DNA, its properties and labeling it, became very important was in 1955-56. Various chemists worked out methods. They knew that the purines and the pyrimidines with their sugar along with phosphate constituted DNA. A lot about the structure of DNA, chemical structure of DNA was known. But they didn't know how to put it all together. And they didn't know what the sequence was. But one very important thing was that difference between DNA and RNA is DNA has thymidine and thymidine only goes into DNA. It does not go into any other molecule in the body.
Q: Dr. Cronkite you've done work with thymidine is that right?
Cronkite: I'm leading up to it. Actually when I came to this department I was still very much interested in platelets and so a matter of fact, Theodore Liedner, whose name you've seen here, came from Germany to work with me on platelets and radiation hemorrhage and one thing or another. And about this time Walter Hughes who was a biochemist in this department got the notion that if you could put tritium onto thymidine in a non- exchangeable position, that then you could do two things. One clearly, you could tag DNA in cells when they replicate DNA and follow their progeny by radiochemical or audio radiographic procedures. The other thing you might do, if you could get it selectively into malignant cells, you might have a therapeutic agent. When he put tritium on the methyl group of thymidine and showed it was non-exchangeable, he came to me-- he had somebody in his family that had died from acute leukemia. And like so many chemists and physicists, they get a notion they're going to cure cancer. Commendable idea but it hasn't happened yet. Could I use this in the treatment of leukemia? I said, Well, that's one big jump. We've got to find out a little bit more about where it goes, what it might do to normal tissues and so on. And in the biology department, which is right across the way there, there was a man at that time Henry Quastler, as near a genius as anybody I've ever known. And they had done a little bit of work, Taylor and Woods and Hughes, with a very small amount of tritiated thymidine had demonstratives, in plants that you could label chromosomes, you could see that one chromatid was labeled, the other chromatid was not labeled.
Q: Who was Taylor, Dr. Cronkite?
Cronkite: J. Herbert Taylor. He was professor of biology, I think, at Columbia, and then later went to Florida State. And this was the first demonstration that, of course chromatids had been known by the structure of chromosomes and so on, but that this precursor of DNA was incorporated only into one of the chromatids and when they divided, you could then sometimes get an-- after the first division you could see a little radioactivity in the other one. And if you paired these things up, you could see where there was radioactivity. there; that would not be any reactivity in the one that was originally. So there was an exchange of genetic materials between chromatids. And this was a major development. Oh there are many more sophisticated techniques today that look at what goes on, but that was a major development in biology.
Henry Quastler and I discussed whether it would be possible and how much would we need to try to-- A little bit was known about thymidine pools and total concentration and so on. How much of a radioactive material would you have to put into an animal in order to label cells. We made all sorts of calculations and we came to the conclusion that there just wasn't enough available to do anything. So both of us being biologists decided what little bit Hughes had we would inject a little bit into one, or all that was available, into one newborn mouse. And then 24 hours later we killed the animal and made sections of the tissues for audioradiographic study. And lo and behold, the cells were just absolutely loaded with radioactivity. If we had been really-- If we had not been biologists, we would have probably said it's hopeless. But being biologists you never say no until you do it and find out what the hell happens. And it worked. But going from about a 1 gram newborn mouse to the whole mouse, to get to larger animals as human beings, became a production problem that could not be handled by Hughes here. The biggest producer of purines and pyrimidines, I guess in the world, was Schwartz chemical company. They made their money from producing yeast for the brewing industry in the United States. As you know, beer drinkers get very upset if they have a favorite beer and its flavor changes, they get very unhappy. In contrast to wine drinkers, who always want something different and more exciting to the pallet. But to a beer drinker, it must be the same. And the Schwartz Chemical Company had developed for decades a technique of making yeast so that it would always be the same; get rid of mutants and so on, so that when they gave it to the brewers their beer would always have the same flavor.
Yeast is just loaded with-- The fraction of the yeast cell that is DNA and RNA is really enormous. And they had all of this stuff left over and they were chemists too. Mr. Schwartz was really a chemist but I guess he didn't too well. He didn't like the income and went from teaching chemistry or something into his grandfather's business. He would separate all of the things out from the yeast. They had "tons", literally of adenine, guanine, thymidine, and it was put up to him-- The guy was a chemist and he talked to Dr. Hughes, what was involved in setting up a commercial production of radioactive thymidine. Thymidine they had by the "tons". And they worked it out, a technique of making large amounts of it and they gave all the original stuff to us for nothing. And that's how we started it. We did a little work in mice. A little work in dogs to see that we had a good appreciation of how much you would have to give of a material to give a specific activity to label cells. The chairman of the department here at that time, Lee Farr, who was a pediatrician, said "Why are you fooling around with animals when you ought to be able to get appropriate clinical material and find out what happens with the migration patterns of granulocytes in human beings, the time that it takes from labeling in the bone marrow to that it appears in the peripheral blood." The more I thought about it, the better it sounded to me. Our first patient was [omitted], a comatose patient with glioblastoma multiform, a brain tumor. He had been operated on and he was unconscious.
It was a hopeless situation. Actually, he had become an economic burden on the family, and his wife had wondered whether we could take care of him here. All the clinical research that had ever been done here was at no cost to anyone and she had heard about it. And we proposed to her that this study be done. And that there's absolutely no way in which it would be of any benefit to him. The benefit if any would accrue to getting new knowledge about behavior of human cells, which may or may not be of use to other people. It would be too early to make such a prediction. And she agreed to it. And on December 8th, because that was my daughter's birthday I remember, we injected [the patient] with tritiated thymidine and then at regular intervals made bone marrow aspirations of blood samples and prepared these for autoradiography. And we saw the labeled cells in the bone marrow and the myelocytes to determine the fraction that were in DNA synthesis, and we could measure the time that it took to go from the terminal myelocyte division to the metamyelocyte to the band cell, to the segmented granulocyte inside the peripheral blood, the appearance in the blood. This was terribly exciting at the time.
Cronkite: Yes, '56. It had just started. No one had ever had any idea of how long it took to go through this storage compartment in the bone marrow. It was known it was there. With infections it gets dumped out into the circulation and so on. But how long it moves through. We were able to determine what the cycle time was of the precursor cells by watching the --You'd label the cell in DNA synthesis. The label is present. What isn't incorporated in DNA is degraded very rapidly and then one could watch the movement from DNA synthesis into G2 which is a post-DNA synthesis rest period when the cells are tetraploid at twice the amount of DNA in them. And you can see them into mitosis, prophase, metaphase, anaphase, telophase. You could see then that two daughter cells that had on an average half of the intensity of label as the original cells. And it was really very exciting to see this, and you could see then how long it took before they appeared in the blood, and then one could get a crude guess by looking at an average grain. You had to count little silver grains over the cells and it just drove you crazy, the microscopy that had to be done. And then using the highest-- say that the grain count varied from three or four grains over a granulocyte to 35-40, and let's say you'd get a threshold of 30 and say now we'll just look how long do those cells that have 30 or more grains in. it last, then you'd get an estimate of a lifespan in the blood. And it was a very crude estimate, a very large statistical error. But it was something on the order of 12 hours. And then about this time other people had developed the technique of labeling granulocytes in the peripheral blood with the DFP 32 radioactive material, and they'd take the blood out, label it with DFP 32, separated the cells, and re-inject it in the same individual and then watch the disappearance of the radioactivity. And it came out to be a single exponential half-time in the blood of about 7 hours and the mean lifespan in the blood of about 12 hours. Our crude estimates were about the same, but this was a very precise technique and could be done in lots of people. They did it in Wintrobe's group, Alvin Mauer, Maxwell Wintrobe, John Athens, and other people out there in Utah. I can't remember all of their names. They did this on 100 prisoners or so on the Utah state prison and had a very, very precise estimate of the lifespan of the granulocyte in the peripheral blood. And then by calculating from their numbers and calculating back, we could estimate all sorts of things that had never been known before. None of this work would have ever been accomplished if it hadn't been for Dr. Fliedner, who's responsible for doing the studies. I don't have the patience to sit hour after hour at the microscope counting these little tiny black dots. I mean it was an absolutely tour de force that Ted Fleinder did, sitting day after day, of course. Of course being a German, they love precision; they love accuracy and so on, and he'd do it. But how he could do it, I don't know. He was in here at the laboratory at 4 o'clock in the morning every day. In those days, I used to come in at four too but not to look through the microscope. I guarantee you that. And then we went to looking at people with leukemia and so on. And learned a lot of things. We were able to correct some of the misconceptions about the nature of leukemic cells and the rates of turnover. They don't turnover as rapidly as everybody thought they did. They are relatively long lived. And a defect in just one or interference with the steady state proliferation so that the birthrate is somewhat greater than the death rate and you have a slowly expanding population of cells. We did this with multiple myeloma and chronic granulocytic leukemia, and chronic lymphocytic leukemia. And after our first publication or two, we had a little tiny hospital here and a small staff, well all over the world people picked up the technique. Japan, big clinical centers here in the United States, particularly Sloan Kettering. Mauer then had become chief of pediatric hematology at Cincinnati General Hospital, and his associate Beatrice Lampkin. And they did an absolutely outstanding --They had this tremendous amount of clinical material coming through. We had to give up those studies because there was no way in the world we could compete with what was going on in Japan or the big clinical centers here in the United States and in Europe.
Q: How much of the clinical care did you do yourself, Dr. Cronkite, if any?
Cronkite: All of it. Well no. Young people.
Q: But you did in fact care for the patients?
Cronkite: Oh yeh, everyday. Every single day I was in there with patients and anytime anything went wrong, anything went wrong at all, the nurses were instructed to call me at home and I would come in instantly. You see who actually does the work is the young people who are with you, but I supervised every bit of it. And when you get into clinical research, you ask yourself everyday about the ethical aspects of it and so on. Well clinical research today I think would forbid --I shouldn't say forbid. It would be very difficult. When we did these studies, or initiated them, in the late 195O's--
[END OF SIDE ONE, TAPE TWO, BEGINNING OF SIDE TWO, TAPE TWO]
Cronkite: --the individual and the different organs by whatever radioactive isotope may be used. There were no committees like now, the Clinical Investigative Research Committees that consist of not only scientists but physicians, lawyers, maybe a housewife, school teachers on it. Committees now would have great difficulty, I think, in authorizing what we did then because you always come up against --There's a certain uncertainty that we knew that we weren't going to do any acute damage to anyone. That was certain. But to say can you be absolutely certain there isn't going to be any long term injury, that's damn difficult, almost impossible. If somebody were to discover digitalis or penicillin today, both of which can kill people, you would have one hell of a time getting it through the Food and Drug Administration, let alone through your own committees, because you know these are dangerous drugs, but they're life savers.
Q: How long did these studies go on here at Brookhaven?
Cronkite: I'd say about 1963 was about the last of the ones-- These are long term studies. The time that it take to study the material, the serial sampling, the exposure to the photographic emulsions and so on are all time consuming. And you know you've done something the first of the month, and it may be three months from now before you start looking at it through the microscope. It's not the way to do research if you can avoid it. I would say about 1962 we decided what we wanted and did to with Horton Johnson, a few studies on solid tumors. But again it was-- here when you get an occasional patient referred from the community, to try to compete with Sloan Kettering Memorial Hospital or any of the big medical centers, it was just ridiculous so we went onto other things.
Q: Do you want to start now with what you went onto or do you want to wait?
Cronkite: I think I've had enough.
[END OF SIDE TWO, TAPE TWO, END OF SESSION]
February 7, 1989
Q: Can you tell me something of your history with the ASH, and your understanding of it in relation to other professional societies to which you belong, and its development?
Cronkite: The American Society of Hematology as I recall was a creation of William Dameshek who was a very distinguished clinical hematologist in Boston's Tufts medical center --New England Medical Center. Bill Dameshek was a very forceful individual.
Cronkite: Rightly or wrongly Dr. Dameshek made enemies of very prominent people in American hematology, such as William Castle, Maxwell Wintrobe, Charles [Austin] Doan, Carl [Vernon] Moore, who were in the immediate post-war period, the prominent academic hematologists in the United States. Dameshek did not ask their counsel. With financial support of Henry Stratton, the publisher of Stratton Publishers, he went ahead and organized the American Society of Hematology, according to his own desires.
I'm a charter member of the American Society of Hematology. Castle I don't believe ever became a member. And I don't believe Carl Moore ever became a member. Max Wintrobe was asked to join the American Society of Hematology by Louis Wassermann, professor of medicine hematology at Mt. Sinai University with the carrot put out that he would see to it that he would become president of the American Society. The Society was run for, I can't remember for how many years, in a very dictatorial fashion by Dameshek and his, I guess one could say, cronies.
One summer day I received a telephone call from Dr. Wassermann from his farm in Connecticut. I'd been working out in my garden. It was a weekend. And he said, "Gene, how would you like to be president of the American Society of Hematology." I said, "If you can swing it, O.K." He said, "OK, it's settled. If you want to be, we'll make it." And lo and behold I was sole candidate for president and elected. There were no democratic procedures at all in the American Society of Hematology originally. I was followed as president by George Brecher who was also a charter member of the American Society, I believe. And then Wintrobe followed him, and I've forgotten who all the other presidents are. But ultimately the Society became democratized and all officers are now, at least two are up, and they're truly elected. Perhaps it's my paranoia, I suspect that there is some selections in the nominating committee that if you're not amongst the people that are in the establishment of that time, there's not much a chance of being on the ballot unless a lot of your friends voted. But as I recall, anybody can be nominated if "n" number of individuals, and I forget what that is, write in to nominate an individual.
The American Society of Hematology originally was primary a research organization. As hematology became a sub-specialty of internal medicine, there was a growing number of individuals in the society who wished to use the society for, should I say crass economic purposes, they were trying to get the Society to have a lobbyist in Washington. When I was president, I was violently opposed to changing the Society from a basically clinical research, basic cellular hematology, coagulation, biochemistry and things related to blood one way or another, to primarily an educational and clinical organization. Well it was a fruitless opposition because individuals for pecuniary reasons that wanted it to change, saw to it it changed. Then under the jurisdiction of my friend George Brecher, the Society did find a man to represent them in Washington in Congress and so on. I forget the individual's name. He's still represents the Society. I must admit that in retrospect, I was probably wrong. The American Society has become not only a research society, a very strong clinical society, an exceptionally good educational body that fulfills the needs of individuals in continuing medical education. I know so far as my own continuing medical education is concerned, I look forward to the educational program that takes place every Saturday and Sunday mornings on the beginnings of the annual meetings of the Annual Society of Hematology. And the Society fulfills several responsibilities now -education, research, a place for young people to meet the established individuals. At times, the annual meetings sometimes like a mob scene. There just simply cannot be, at least I don't believe there can be, as many hematologists as there are members of the American Society of Hematology. So that's about all I can think of in respect to the history of the Society. It has gone from an organization run by Dameshek and his friends to a fully democratized organization which fulfills a real need in American medicine, both at the clinical level and in research and education.
Q: Why don't you tell us something about some of your other colleagues, Dr. Cronkite? You talked about Dr. Fliedner and Dr. Brecher. I'm wondering about Dr. Stohlman.
Cronkite: Well I chose not yesterday to bring something up.
Cronkite: In 1942, as I mentioned yesterday, in part, the dean of the school of medicine at Stanford and the professor of medicine, shortly after Pearl Harbor, when it was obvious they had to start making arrangements for continuing medical education and running the clinical services when a large number of individuals would have to go into the military service, I was chosen to be the chief resident in medicine. I was obviously highly complimented to have Professor [Arthur Leonard] Bloomfield and Dr. Chandler, the dean...
Q: Dr. Chandler's first name, Dr. Cronkite?
Cronkite: Loren Chandler. He was a professor of surgery and dean at the school of medicine.
Q: Dr. Bloomfield's first name?
Cronkite: Arthur, Arthur Leonard Bloomfield, always known as the Professor, and which he certainly was. He was really my role model. My only ambition in medical school after I saw how the different professors acted was to become a professor of medicine someplace. And accordingly I was tremendously pleased to have the professor of medicine and the dean have confidence in me, and offer the residency in medicine which would have prevented me -- I would not then have been eligible for military duty through the draft. I thought about it for a day and decided it would be the wrong thing to do. I had enough training to be a physician in military service. I turned down the offer and voluntarily went into the Navy. I have never regretted that decision, but after WWII, I went back to Stanford University and asked the Professor what the opportunities were of coming back and continuing my medical training and so on with the objective, hopefully, of becoming a professor of medicine sometime. I was offered an instructorship in medicine. Believe it or not $1800 a year. I was commander in the United States Navy at that time with about $9,000 income with essentially no taxes. All the individuals had stayed out of military service were now assistant Professors. Their careers were established. And to put it-- Why I was really burned up. You do what you think is morally the right thing to do, and you suffer for it. It really just burned me up no end. Although I had so much respect for Bloomfield I didn't tell him what I thought about the way I was being treated. I really thought that four years in the military service, with all the medical experience I had, was certainly equivalent to a couple of years in a hospital, but they thought otherwise. Particularly since a good part of that time had been with Professor McCann whom I mentioned yesterday and Professor [J. Montgomery] Deaver. So I stayed in the Navy. I personally dislike sitting very long at the microscope, and there were some problems coming up in radiation effects in which really a highly skilled histologist, pathologist, was needed. I went to my friend Kenneth Endicott who was then head of the hematopathology at the one of the National Institutes of Health. I've forgotten what it was called. National Institute of Arthritis Metabolic Diseases, I think. And he said, "I have a fellow coming from Mayo Clinic, a Czechoslovakian a European who escaped from the Nazi's and so on and finished his training at Mayo Clinic, and we'll give him the job of working with you." And this was my introduction to George Brecher. Well number one nobody gives George Brecher--just tells him what to do; it doesn't work that way. But after sitting down and discussing the problems with him, he began to see the possibilities, both for the practical applied and basic science, and a collaboration began which still continues today. After about three or four years, Fred Stohlman who is a graduate of Georgetown University and then went to Boston City Hospital for training-- Fred was a huge man. He was about, close to 7 feet and absolutely enormous with a gravelly voice, actually one of the gentlest human beings I've ever come across. My wife thought the world of him and just loved when we go someplace where there was dancing because she said he was the best dancer with whom she ever danced, and I was next to being the worst. But Fred was a remarkable individual. His father was an attorney in Washington, DC, and they expected Fred to finish his training at Boston City, come back and be a society physician. Well he did come back and he was at Georgetown for a little while, and he became very unhappy in just the straight practice of medicine, and he was looking for a position that was of more intellectual challenge to him. And at that time George Brecher had a position open and Fred took it as whatever the lowest level of Public Health Service Officer there was at that time. This was a terrible disappointment to the Stohlman family because they expected him to be a society physician in Washington, DC. Well after several years Fred went up quite rapidly. He became very well recognized with George Brecher in investigations on the control of erythropoiesis, on the physiology of erythropoietin -- the hormone that regulates the rate of production of red cells.
During this period of time we had difficulties getting things published. The editorial boards of journals were then dominated, and are still to a large extent, dominated by academic medicine. And it's difficult to verbalize what I'm thinking because it's an indictment, in part, of the attitudes of professors. To be very specific, I mentioned yesterday, the--
Cronkite: --about the work that [J.] Garrett Allen and Leon Jacobson had done saying that heparanemia is a cause of radiation hemorrhage and that both in the field tests in Bikini, we were unable to confirm it and other tests, studies, at the Naval Medical Research Institute, we were unable to confirm it. I submitted a paper to Journal Laboratory of Clinical Medicine, in which the editor at that time was Carl Moore, and the review that came back rejecting the paper said that it has already been established by very well known investigators at the University of Chicago, namely J. Garrett Allen and Leon Jacobson, that heparinemia is the cause, and the subject is closed, and this is not publishable. I was really burned up about that.
I had made acquaintance with George LeRoy who had been in the Army, had been in academic medicine before World War II, and was on the initial team that went into Hiroshima and Nagasaki for the study of the Japanese in the early phases. And at someplace we were out together, had a couple of drinks, and I told George about being rejected. I thought it was simply a matter of the professors looking at something coming from a military laboratory that refutes the work that is done in a major American university, and their minds were closed, and they couldn't accept that a commander in the Navy with some enlisted men in the Navy could possibly do reliable research. At least that was my feeling. George is a very considerate, thoughtful individual. He said, "Well, if you're right, and if you can arrange for me to come down, I'll bring a technician, and we'll repeat these studies. And if you convince me in the laboratory that you're right and they're wrong then we can submit a paper in which I would be an author, and I'll be a professor of medicine from the University of Illinois." He later became professor of medicine at Chicago. Well to make a long story short, when it was resubmitted with a professor's name on it, it was instantly accepted. Well this made George mad and made Fred Stohlman mad, and I was mad, and we called ourselves the "subculture in medicine." Sort of a joke between the three of us. Later we admitted another individual to the subculture, namely Shirley Ebbe. When Fred went to St. Elizabeth's Hospital in Boston as director of the research laboratories there, his junior associate first was Shirley Ebbe, who had been trained by Dameshek and Tony Pisciotta, a heck of a good clinician and very bright young woman, and became a specialist in platelets, regulation of platelet production, megakaryocyte behavior, etc. She's now at Donner Laboratory, Lawrence Berkeley Laboratory, University of California and continuing very fundamental research on the factors that regulate the production of platelets. Well, where am I?
Q: You're still with Fred Stohlman.
Cronkite: Well Fred Stohlman left NIH, went to St. Elizabeth's Hospital as director of research and chief of medicine, and developed a very fine unit there. And his predecessor, an Italian whose name alludes me right now, had established a system of bringing young fellows from Italy to work with him. Unfortunately he-- it's difficult for me to explain this-- had a condition of these Italian fellows that would be paid by the Public Health Service, was that they would pay a certain amount of the money to the boss to get them over here. Well when Cardinal [Richard] Cushing heard about this, Cardinal Cushing instantly fired this man, and that was how the job became open and Fred Stohlman was selected for it. But the flow of Italian fellows continued, and they're all bright young men. Things were very poor in Italy at the time and their educational research institutions they were still rebuilding after the war. I've forgotten how many, but all of these young people who came to work with Fred for two years, returned to Italy and they are leaders in hematology in Italy today, and internationally known for many their thinking. You mentioned your interest in bone marrow transplantation. Guido Lucarelli is now chief of hematology in Pessaro, Italy. I don't remember the name of the institution. But he has very successfully developed bone marrow transplantation for children with thalassemia major. That's not 100% successful, and I forget what percent, but a substantial percentage of these children that would otherwise have a miserable death probably by the time they're 10-15 years of age or even earlier, are now treated by massive radiation chemotherapy to eradicate their own hemapoiesis and then transplanted with-- hopefully when available, and fortunately Italians have a lot of children so usually siblings are available that are thalassemia minor but will produce red cells that have a normal life span, in contrast to the thalassemia major which is a disastrous disease.
Fred became very prominent in the American Society of Hematology organizing symposia at all the annual meetings, also the International Society of Hematology. At the meeting in Jerusalem, Fred was one of the stars there: the work that he presented at the symposia that he'd organized. We remember so vividly, we went to a reception at one of the Israeli hematologists the last evening, and then I sat up a long night just reminiscing with Fred and his wife in the King David Hotel. And they tried to get me to change my plans to come with them to Italy. They were going to a symposium on the Isle of Capri, on erythropoiesis. I decided not to do it because my mother was living with us at that time, and was not too well, and I thought I ought to get home as quickly as possible, which was a very fortunate thing because the Arab terrorists had put a bomb on the plane in Athens, when the plane went to Athens. Maybe the bomb might have been put on in Israel, but it's unlikely. But it exploded over the Ionian Sea, and everybody was lost on it. It was a tremendous loss to medicine.
George Brecher resisted leaving the National Institutes of Health. He was a little annoyed, more than a little annoyed, at the holier than thou attitude of the professors, but finally he was made an offer to organize a department of laboratory medicine at the University of California, San Francisco. And he made conditions to stay at NIH. I've forgotten what all the conditions were but one was obviously to be promoted to the next higher - -He already was internationally known for the excellent department that he built at NIH. The thing they came through with -- The only offer they made to him, it made him so damn mad, that I think he would have gone anyplace. They decided to give him a reserved parking place. So he went to the University of California and developed the first academic department of laboratory medicine which became a model for laboratory medicine in several medical schools in the United States.
George is emeritus professor now and works at Donner Laboratory, Lawrence Berkeley Laboratory, University of California, Berkeley. And actually George and I are still doing some work together. He does some of the work in Berkeley, and we do some of it here. And in the last couple of years we've had two, three publications.
Now you can obviously detect that the three of us had our problems with American academic medicine, and intensely resented being looked at as second class citizens because you're not a professor in one of the major universities. I don't think [William] Castle ever felt that way. But I can guarantee you that Wintrobe and Doan, and Carl Moore, Isadore Ravdin. He was professor of surgery at the University of Pennsylvania, a very distinguished guy in medicine. Edwin Cohn I mentioned yesterday. Kenneth Brinkhous didn't feel that way. Kenneth Brinkhous, I told him of problems that I had once and he said, "Why don't you, when you have something to publish again, why don't you send it to me, and I'll go over it and tell you whether I think it's something that ought to be published or not," which he did. And he was tremendously helpful.
Well I think that everybody who gets into research would like to go up the academic ladder and would like to ultimately become a professor someplace. I had several offers. I was offered the chair of physiology and director of the Cardeza Foundation at Jefferson Medical College. And then I'd get to think, do I really want to be part of the academic community or not, and I declined it. I was offered the chair of anatomy at Vanderbilt University, declined it. I was offered the chair, not chair, but the dean of a school of human biology that was going to be developed by the University of Wisconsin in Green Bay, Wisconsin. And that was a very attractive thing, to do something that had never been done before in the United States, probably not in the entire world. But I guess the thing that turned me off there since I was coming from California and I don't really like cold weather, I was there the first week of September, and one of the mornings I got up walking around, the puddles of water were frozen. And I said, oh this is no place to live. But there was one very interesting thing they offered along with a really nice salary, and many opportunities in developing it, is that you got season tickets to the Green Bay Packer's games.
But later I was offered the chair of medicine at Stony Brook. And that I turned down, and that was the biggest mistake I ever made. I should have taken that, but somehow or another every time I'd get to thinking about going to the university, I childishly, when people would ask me, how did you get trained to be a hematologist, I said I trained myself, which was essentially what happened. And I was proud of that, and if you join them, then you're part of them, you can't resent it anymore, I guess. It was childish as could be, but that's what I did. And you can imagine that my wife thought I was absolutely nuts. How she tolerated these things for almost 50 years is beyond me, but she has always been extremely supportive of anything I wanted to do, and listened to all the trials and tribulations without a murmur of any complaint.
Was there something else that you had?
Q: Well I was wondering from this too, Dr. Cronkite, about the people you trained.
Cronkite: OK. The first individual, whom I mentioned yesterday, was Richard Studley Farr. He was a product of the University of Chicago. It looks like all of my troubles always somehow or another associate with the University of Chicago. He had to, like thousands of young men had to, take their obligatory duty in the military service. He was able because Dr. Bloom, professor of anatomy at Chicago.
Q: Do you know his first name?
Cronkite: That's his textbook up there. It's William Bloom definitely. Well, Bloom. William Bloom had arranged for him, when he came on duty in the Navy, to come to the Naval Medical Research Institute. He caused me more headaches than any human being. He thought that since my training, number one, was all in internal medicine-- I had no research training whatsoever-- he didn't want to do the things that we had to do so far as the Navy, though we had lots of latitude of doing other things, and plenty of support to do it. He arranged actually, talked the research executive; a captain in the Navy, I was a commander, into taking some of our technicians and I was not even allowed to know what the heck he was doing. It turned out it wasn't worth a damn. And it gave me a big laugh. And he decided to go into the regular Navy, primarily because you get a big pay raise, $250 extra a month, if you're in the regular Navy instead of the Reserve. And he was a very bright guy. There was no argument about that. He was working in Cal Tech on his PhD. And I mentioned yesterday how he disliked the notion of being tapped for military duty, obligatory military duty on a mission in the Pacific, which he did admirably. There was no argument about that. He was the first. He has never really, for reasons --One of the things that I don't understand at all is that some individuals who may not be terribly bright, become extremely productive. Other individuals who are extremely bright, have tremendous breadth of knowledge, but somehow or another just don't accomplish much. And Farr was one of those.
The next guy was Dr. Shulman, Nahum Raphael Shulman. He had worked with Henri Tagnon at Sloan Kettering and came on obligatory duty in the Navy. He was very cooperative. He recognized the problems with which we were confronted, and so on that had to be done, and he was able also to do some of the things that he wanted to do, and they were very productive. And he was responsible, primarily, for the clinical observations on the Marshallese.
The next individual was Dudley Pennington Jackson who came on obligatory duty in the Navy from Johns Hopkins. He had finished most of his training there in internal medicine, hematology with [C.] Lockard Conley. And he was again, a very bright, self-propelled individual. But recognized the need --He was a major participant in our studies in heparinemia and later on in platelet transfusions, and so on. He was first class. He went back to Hopkins for a while after he left the Navy. One morning he walked out --He lived in --Are you familiar with Baltimore? Well they have these row houses where they're right up to the sidewalk. He went out of their little apartment and there was a cadaver laying at their front door that had been shot up. And he and his wife decided they ought to get out of Baltimore. And he took a job as, I guess, associate professor of medicine at Georgetown and been there ever since, and has been pretty darn productive, clinical investigator, and has developed a fine department at Georgetown.
Cronkite: Dr. Iwai has been here for many years and he feels that my wife and I should eat proper Japanese food about once a month, so on this Thursday evening we're his guests at a Japanese restaurant. He's never figured out that my wife hates Japanese food.
Q: I hope she likes the company.
Cronkite: I love it. We think so highly of him, she wouldn't under any circumstance do anything that would offend. She will dutifully push some of this stuff down her gullet, and hate every moment of it. I'm a gardener as I told you before, and I raise every year, daikon. Do you know what daikon is?
Q: I've seen it on menus.
Cronkite: Well daikon is a white radish and the Japanese use it in everything. So I supply him with-- all summer long he gets daikon, and about once a month we get Japanese food. Some new Japanese restaurant in Suffolk County. Okay lets --
Q: Dr. Jackson?
Cronkite: Let's see who else was at the Naval Medical Research Institute. Yes, about this time --
Q: What time is this now, Dr. Cronkite?
Cronkite: '52-'53. March 1, '54 is when the thermonuclear bomb was exploded at Bikini, and individuals were exposed to fallout, and I organized a team, as I mentioned yesterday, and which included Farr and Shulman. And then I resigned from the Navy after that. I was psychologically unable to face the thing that as long as one is in the military service, you are subject to change of orders at anytime, which maybe makes sense, and it may be at the whim of somebody because they just decide you ought to be elsewhere.
So I came to Brookhaven in the Division of Experimental Pathology, and I mentioned that we were testing the hypothesis as whether whole body radiation plus beta burns to the skin would allow healing, or whether this would be carcinogenic and it wasn't.
I received a letter from Captain James English who was in the dental corp in the United States Navy and the representative of the Office of Naval Research in London, as to whether, I would consider the possibility of a young German who was familiar with our work on platelets and radiation hemorrhage and so on, who wanted to work with me. I said, "Of course, we'll consider it." And it turned out that this young fellow from Heidelburg was Theodore Fliedner. And he arrived, I guess it was October, '56. I can't remember right now. Yes, '56. And we started to work on some problems of radiation injury to capillaries, platelets and so on. As I mentioned yesterday, Dr. Hughes developed tritiated thymidine, and we immediately changed our track and exploited its use in the labeling of DNA, etc., as much as possible, both in the basic cellular hematology and clinical hematology.
We were still continuing to participate in the nuclear bomb tests in Nevada. And I had the job of organizing for Civil Defense a program evaluating the effectiveness of underground shelters as protection against blasts and protection against radiation. And in these tests there was a participation of UCLA of people doing the dosimetry and one young man, Donald Paglia, struck me as being, not only bright, but a hard worker and so on. I offered him a job to come here as a technician, which he accepted. And it became so evident that Don was very bright, conscientious. He just had a bachelor's degree in biology, chemistry, and it was a waste of talent, but he was --His father was Italian and his mother was Mexican, and it was sort of a cultural thing in the family, that the idea you would go ahead and get further education was sort of frowned on.
[END OF SIDE ONE, TAPE ONE, BEGINNING OF SIDE TWO, TAPE ONE]
Cronkite: But we talked, and we decided that he should apply to medical school, which he did and much to his surprise, he was admitted to the new medical school at UCLA. Graduated there. Had his training, went back to UCLA, finished his training in pathology, and is now professor of surgical pathology at UCLA, and one of the leading artists in American medicine. He was chosen to be the artist for NASA on one of their tests. And his pictures are hanging in the Smithsonian, or not at the Smithsonian, in the National Aeronautic Space Museum in Washington. That's one of his very earlier pictures. That's crab nebula in case you don't recognize it. But he doesn't do any of that kind of painting any more. He does things that one can recognize; cable cars in San Francisco and so on.
Then Fliedner worked here for two years, went back to Hiedelberg, and realized that if he was going to go any place in German medicine that he would have to get training in clinical medicine. He applied to work with Wintrobe. Wintrobe called me, "Looks like a bright young man. That he has good credentials," but he said, "I'm Jewish and I just can't bring myself to having a German in my department." And because of his age, he had to have been a member of the Hitler Youth. Every young man and woman was. Well not man, everyone from 8 years of age or so on, was part of the Hitler Jugend. It was just the system. He applied with Carl Moore with of the Washington University, St. Louis. And Moore accepted him. He had two years training in clinical medicine there, and then came back here and worked for another year, and then he became associated with Ludwig Heilmeyer, who was a very famous professor of medicine in Germany, a hematologist who had done very outstanding work in iron metabolism in various hematologic disorders. And Fliedner had been aware that the European community or Euratom, was developing programs in biomedical research in the various sponsoring countries, Italy, France, Germany, Belgium, Holland. Fliedner proposed that they have an institute of hematology at the University of Freiburg. And it was accepted and made as a part of the University in the department of medicine, as a free standing institute at the department of medicine at Freiburg. And in 1965-66, I went to Freiburg as visiting professor of medicine for a year and worked in this institute. Fliedner was one of these fellows that were not only bright, but hard-working, extremely hard-working. A short day for him would be a 12 hour work day. And with organizational capabilities. He just had that capability. Whatever it was it made no difference how complex the research protocol may be written up for a certain purpose, he would have it all out where everybody knew at every minute what you were supposed to do and all planned ahead of time. A really magnificent organizational capability. Probably the reason that the German army was so damned effective. An amusing thing was that while I was there, he had developed an association with Lucarelli who had worked with Stohlman as I mentioned earlier. They were interested in developing fetal liver transplantation.
Q: When was this?
Cronkite: 1965 or '66. I went there in August of '65 and came home in August of '66. And there was a big program in which Fliedner had the facilities, the animals and so on, to have a lot of pregnant animals so that one could have the fetuses and so on. Lucarelli was invited to come. And he was a co-equal investigator on it. And I'll never forget how it was. Everybody had everything. You going to sit here, and this is what you're going to do at 10 o'clock. They'd start harvesting the fetuses or livers would be taken out by this technician, and somebody would grind them up and the cells would be counted. Started killing the animals. Lots of them were not pregnant. Lucarelli in his Italian voice said, "Professor Fliedner, everybody got their instructions but you didn't give those males the instructions on what they were supposed to do." Well it could have fractured me. Fliedner was absolutely taken back, how anyone would say that out in front of all the technicians and so on. He was still a German, and he didn't see anything funny about it. I thought it was riotously funny. And I always like to tell it every time I can.
Well Fliedner --Heilmeyer died. Well, I have to back up a moment.
Heilmeyer decided that they should have a medical university in Germany that would be truly avant garde and introduce things that were new, not done in Germany, and would diverge from the Humbolt educational tradition. The state of Baden-Wurtenberg supported this idea to develop a medical university at the city of Uhlm which is the birth place of Albert Einstein. They originally wanted to call it the Einstein University of Medicine, but it was decided it was probably better not to in view of the history and so on, all too recent history.
Well Fliedner went there as a professor of physiology and later a professor of occupational medicine. And he went up the academic ladder and he became rector or president of the university in 1970, I've forgotten. And was reelected for rector again, and again he'd shown his organizational ability of just developing an university that has the flavor of classical German type of education, plus a self-standing research institute, plus multiple professorships in each department, something that had never been known in classical Germany. There was one professor, Herr Geheimrat Professor, and that was it. And everybody, all the young people, were just waiting for the professor to die. And they lived under this horrible system, knowing that only one of them was going to make it. And then they'd be downtrodden the rest of their life if they don't make it. But Fliedner had seen and appreciated what went on in the United States and has to a certain extent been able to break the system, and it's beginning to crumble in other places in Germany.
OK, Ludwig Feinendegen was about the same age as Fliedner. He had his education at the University at Cologne. And of course, when he finished his education in medicine, Germany was still in a shambles and rebuilding everything. He came to the United States. He had some sort of scholarship. I've forgotten what it was. He was at a hospital in New Jersey, and then got into St. Luke's Hospital in New York City, and finished his training in internal medicine. He had had training in biochemistry before he left Germany, in addition to his medical education. And somehow or other he heard about the medical department at Brookhaven and came out to visit to see if there was any possibility of working here, and actually my associate J Victor Bond was able to get him into it. He was so much interested in clinical medicine. He was interested in the things that Bond wanted him to do. But he was also wanted the contact in clinical medicine, and he was very well trained in it.
Cronkite: Bond. Victor Bond. He's still here in the department. Actually what I should mention that I've omitted, not a deliberate omission, an accidental omission.
When I came to Brookhaven, a condition of my coming here was that I would be able to bring one or more individuals in with whom I knew I could work by past experience, and who would complement the study. And one of them was Dr. Bond who had gotten his MD during World War II at the University of California, San Francisco, and then got a PhD at the University of California, Berkeley after the war, in biophysics. And I made it a condition that he be given an offer, which he was, and he accepted it, and he's been here ever since. And he went up to chairman of the medical department, and then associate director of life sciences. Three years ago he had to have a triple by-pass and gave up the associate director, but he's in the department as a senior scientist, and we still work together.
Feinendegen was an excellent clinician and did a lot of very fine work in the early days on trying to understand-- Well, number one) what is the turnover rates of RNA and DNA in different cellular systems. Using the labeling techniques with thymidine, tritiated thymidine, tritiated cytosine, and other radio-labeled purines and pyrimidines, and he made some very fundamental observations. The nucleolus was the center inside the nucleus for synthesis of ribonucleic acid. And then the ribonucleic acid, you could see the radioactive labeling first in the nucleolus and then it would spread out of the cell as you do serial samples into the cytoplasm. This was a real major development at that time in utilizing the techniques that had become available to study ribonucleic acid or RNA and DNA metabolism function.
After, I guess he was here for four years, he wanted to go back to Germany but the condition at that time, was if he went back, he would have to enter a program in some German university, which is a very prolonged difficult thing, to get his dozent, which is sort of like getting a PhD in a way. But it's required to get ahead in academic circles. He'd been in the United States too long and this idea of conforming to something that no longer made any sense to him, he just said no. And he got a job with the Euratom in Brussels and wrote a book on tritium; its use in biology and medicine, and then went to the Curie Institute in Paris for a while.
Then the German counterpart of this department had been developed at the Kernforschunganlage Julich. And the institute of medicine there, the director had patterned it right after this department. And he had quit for ill health, and it was open. With great reservations on the part of the German academic community from which the committee came to make the selection, even though Feinendegen had never gotten his dozent, the job was offered to him and he took it, and he's done an outstanding job as director of the Kernforschunganlage.
Another guy that came here was Sven Killman. He was from the University of Copenhagen, Denmark. Actually, he wanted to work with George Brecher at NIH. And I told you how I was fired before I was hired there. Well George had been told that he would have a position open. It was offered to Killman. When Killman and his wife were almost on the ship, on the way to the United States, they retracted the job that George had and he called me. And he said, "I've got a terrible embarrassing situation on what to do with Sven Killman." So he told me about it, and told me a little bit about him. He had met Killman in Europe. George is a polylinguist. He spoke French, German and Czech. He understands Polish and Russian. On top of which he probably knows the English language better than anyone whom I've ever known. And he and Killman had communicated in German. So I said, "Well, George, if you swear up and down. It's a good thing I happen to have a position open. And I haven't interviewed anybody yet. No commitments are made, but for God's sake get me his CV and one thing or another, so the director here won't think I'm playing games." Dr. Farr although American born, he also had all of the characteristics of a Herr Geheimrat German professor.
So Sven came here. And he was number one a clinician. And he was the major moving force in taking care of all of our patients that were here for-- I guess he was here for three years. The initial studies on using tritiated thymidine and looking at cell proliferation, and multiple myeloma, acute myeloblastic leukemia, chronic granulocytic leukemia, would never had been done without Sven Killman.
We wrote a series of three papers published in Blood on an analysis of how one analyzes the kinetics of cell proliferation in principle and in hemopoietic cell proliferation. And they were classical papers at the time. Of course nobody's really interested in that sort of thing anymore. That's not true. As a matter of fact, the molecular biology in the recombinant DNA technique and these substances now being used in clinical medicine, require going back to do the old stuff that we had to do to find out really how these substances are acting. And I know I'm diverting you a little bit.
Q: No this is good, please continue.
Cronkite: But Michael Dexter who is head of the experimental hematology at the University of Manchester in England has been doing outstanding work in very modern application of cell culture in vitro studies, to look at the properties of proclivities of various cell types in normal disease states. And they started using the recombinant molecular hemopoietic regulators that are now available. The things that are present in microgram amounts in the body, are now available. Grams of it, literally buckets of it are available from recombinant DNA technology.
Q: These are the so-called growth factors?
Cronkite: Growth factors. But GM-CSF, G-CSF, M-CSF, erythropoietin, IL-1,2,3,4,5. I guess we're up to 6, maybe seven interferon and so on. All of these things are available. It was tremendous labor that people --I read the things over and I thought, a lot of these things I would have liked to have made myself, but when I saw the labor that was involved. The gallons of urine, the gallons of plasma, the gallons, I mean gallons, not just two or three, I mean hundreds of gallons, if not thousands of gallons of tissue culture media that would have to be processed to isolate a microgram of these things and, you know, a millionth of a gram; and then you start working on that for biological properties, and chemical structure and so on. But the recombinant DNA technology became available; they got a microgram of the stuff and then there off to the bases. You could know a little bit about the structure, you get a good idea about what the gene has to look like and either synthesize the gene or take it out of the cells, chop it up with all these enzymes that are now available, and pretty soon you have a clone of E. coli or yeast . Primarily E. coli or yeast. Sometimes mammalian cell cultures. That just grinds the stuff out in buckets full of it. It's just mind boggling. But Michael Dexter wrote me and said, "I've come across some" --I've known Michael Dexter for many years. It's just one of these things. What has been done in the past is forgotten and with young people coming into research the computerized-- medical literature is computerized, goes back --Well everything goes back at least five years. Certain things go back 10 years. Some 15 years. Anything that was done 15 years ago, a young person coming along, unless you tell them about it, or show it to them, or they happen to read it in an old textbook, will never even know it existed because they're computer oriented. They could sit at that thing, pump it out and get this hoard of, like some of the stuff I have over there. I use computer printouts too. You ask for references on, say recombinant hemopoietic factors, say GM-CSF, and you want to know what's going on with it in the last year or two, you'd get several hundred, maybe a thousand things in languages you can't read, and may or may not be any good. But Dexter realized that they had to look at what was actually happening in the kinetics of cell proliferation, and had some young fellow in England start looking at the literature. And they came across my name and found out that all of the studies in the kinetics in normal human beings, or people with normal hemapoiesis; they weren't normal human beings. He wrote me and asked me if I'd like to collaborate with him and do the autoradiagraphy and so on. I assured him that he was doing the right thing but I certainly, at this stage in life, had no intention of sitting down at a microscope and counting little black grains over cells again. And that they must have somebody in England that would love to do that. And I just received a letter from him last week. They've completed their studies on the influence of GM-CSF and GC-SF, and have asked me if I would consider submitting it for review for publication in the proceedings National Academy of Sciences which I'd be glad to do. I'm just waiting for the manuscript now.
Anything that was done 15 years ago, unless you point it out, and give it to the young person, he will never know that it existed. This is not a criticism. It's a criticism of a computerization. Because it costs too damn much money to have somebody go back when you look at the enormous amount of literature that exists. Of course it's going up exponentially now. More and more is being produced and to try to get back, it's just too costly to do it.
So Feinendegen, Killman. Killman went back after three years here, I believe, to Denmark and became professor of hematology, University of Copenhagen. He and his wife, Nicole Mueller-Berat -she's a French scientist. Her first husband was a Dutchman -are editors of Leukemia. It's a very prominent journal now in hematology. It publishes stuff in both clinical and in basic science studies on the nature of leukemic cells, the genetic defects that lead to leukemia, etc. Peter Reizenstein came from the Karolinska Institute in Sweden. Extremely bright guy and somewhat difficult personality, but he was quite productive. He was here for a couple of years. Went back and he is now, I don't know whether he ever made it to professor at Karolinska or as associate professor there, but he's been very productive.
Pierre Stryckmans came from the University of Brussels, Belgium. A very quiet, unassuming, hard working individual, and made some major contributions in the cell cycle, in kinetics of hematopoiesis and also in the aging of the red cell, and it seems trivial, changes in volume and so on as cell age. But it was really quite important because it gave one an idea, if you were interested at looking at young red cells versus old red cells, to see what the difference is. Because when cells get to be 120 days of age phagocytes grab a hold of them and take them out of circulation. His studies made it possible in principal to study all that biochemistry in old cells compared to the new cells. And other people exploited this. He is now professor of hematology, I don't know what he is. Yes, he's professor of medicine hematology oncology actually at the Institut Bordet in Brussels and has a very excellent research program going.
Jose Ramos from Peru, a bright guy, hard working, also contributed significantly but clinically he couldn't qualify. His training was too lousy from the University of Lima, but he did a lot of very nice work when he was here. He went back to Peru and we've never heard from him since then. Feinendegen, Strykmans, Killman, Fliedner, Hans Cottier, from Bern, Switzerland. He was in the department of pathology there. After our first publication on the utilization of tritiated thymidine in the study of cell proliferation, I got a letter from the director of the Institute of Pathology in Bern, Switzerland, saying that a young man in his department, Dr. Cottier, had asked him to invite me to come to Switzerland and give a lecture, and visit; which I did. And I was very much impressed by Cottier and he wanted to come to the United States and work with us. We didn't have the funds right then to bring him but it turned out that his wife owned the big Swiss watch company, so there was no problem, they came anyway. We did give him something, but it was embarrassing. He had a job at a very small fraction of what he was making in Switzerland. Compared to the other European countries, what they got here in terms of dollars, was an enormous income for them but not for Cottier. But he did superb work on lymphopoiesis, the labeling of lymphocytes, working out the cycle time in animals, and he also participated in the clinical program and after a couple of years here he went back to Switzerland as professor, director of the Institute of Pathology from which he just retired last year.
Around about this time I had another notion that one could investigate the properties of lymphocytes by taking advantage of the fact that they, at least a certain fraction of them, are very radiosensitive. Now one of the classical techniques for studying red cells is bleeding. It's very simple. You take blood out. Throw it away. The animal becomes anemic and then you can watch what happens in the bone marrow production, utilization of iron, one thing or another. And I reasoned that if one could kill lymphocytes in the circulating blood, by circulating the blood through an extravascular shunt, through a radiation field, that one would be able to kill the lymphocytes. They would be taken out of the circulation and it would be analogous to bleeding for studying erythropoiesis. This was a simple enough notion, but technically it was exceedingly difficult to actually do. We tried it in dogs and it was totally unsuccessful. We tried it on swine, rabbits. Technically you just couldn't get the blood flowing through an extracorporial shunt in a radiation field without clotting.
About that time there was a veterinarian from the University of Minnesota working here, Ole Nilsen, and he said, "You're wasting your time with all those animals." He said, "This will work. I'll guarantee you it will work if you do it on cattle." Cattle, my God. I didn't know anything-- And he said, "Don't worry about it. It will work on cattle." "My God, how do you handle those beasties." He said, "Don't worry." And I didn't agree one way or another. He wasn't actually a part of it. He was our staff veterinary. And one day a couple of calves showed up, and when I saw the volume of urine and feces they produced and how strong they were, I thought, how can we do it. Well to make a long, long story short. Ole was a veterinarian and he knew how to handle big animals. Get her down under local anaesthetic and it was very easy to put a shunt into it. They have veins, my god their jugular veins are that big around, and we could get tubes in and pump the blood around, and it worked. And this was a development of extracorporeal radiation of the blood for studying lymphopoiesis. Cottier did all the histology on that and did a magnificent job and along with Jansen from South Africa.
Cronkite: Yes, Jansen. Chris Jansen who was an extremely talented fellow. Hard worker. I think most of the work we did on extraporadiation of the blood of the cattle, extracorporeal radiation of the lymph, cannulating the thoracic duct was made possible by Jansen. He was pretty darn good. He had a good pair of mitts in doing surgery.
About this time also, we had an unanticipated addition to the group, Kanti Rai, who was from India and come to the United States and was at one of the New York hospitals and training in pediatrics and then went to work with Arthur Sawitsky, and he was about ready to go back to India and Arthur Sawitsky whom I'd known suggested that there might be some possibility for him to work out here. And he came out. I had been told by many people to be very cautious about bringing Indians into the research group. That they would be very bright and have all sorts of ideas but that had an objection to doing anything with their hands. They liked to tell a technician, if somebody else would do everything. Having been warned about this, I remember the first thing I asked Dr. Rai, I said, "If you are to come and work with us, we work with big animals. We have the clinical work and you're going to have to get your hands dirty." And he said, "That doesn't bother me at a1l." Then I had to level with him, I've been told and I believe it's true, that a large fraction of Indians that come to this country are high caste and the idea of doing technical work or anything that verges on labor is just socially unacceptable to them." And he said, "Oh that's right." He says, "I come from that class but it's not unacceptable to me." And as a matter of fact, his family was, not Maharajah, but major domo to a Maharajah, somewhere in India, north of Dehli. Well he turned out to be, he and Chris Jansen, who of course--the South Africans in south Africa have no use for people with any color in their skin, but it was really interesting to see how well--.
Cronkite: this south African and this Indian got along just extremely well and.1 would come in at 4 o'clock in the morning, because a lot of this stuff, when these things were going around the clock, and people had-- and in the pile of straw I'd go back out where our large animal facility was and see Jansen and Rai sound asleep in the straw. They were there all night with an alarm clock set to get up and do things. So it was sort of an exciting business.
Q: When was this Dr. Cronkite? About what date is this?
Cronkite: It was in the mid-sixties, I think.
Cronkite: But anyways it was so successful in depleting animals of lymphocytes, we learned a lot about the rates of repletion and the factors that would influence the repletion of lymphocyte pools in the body. It seemed like the next thing we had to do to see if there was, if we could obtain animals, calves with leukemia. And we were able to do this. There was a program at the University of Pennsylvania, School of Veterinary Medicine, on bovine leukemia, and they supplied some animals for us, and we did extracoporeal radiation of the blood in these animals with leukemia. We'd get dramatic changes and the counts coming down. The lymph nodes get smaller and so on. So it seemed like we ought to consider this in patients but in order to do this you really had to have a properly trained surgeon to do it, and Rai said that he had a classmate of his that had gone from India to England, who was just finishing his training in surgery and would like the idea of coming to the United States for a year or so to see what research is like. He had only clinical training and this was Arjun Chanana. He came here on a two-year appointment and has been here ever since. He is now chairman of this department. He had had seven years training in surgery in England. He could do anything with his hands. Ask him if it was possible to do this and he'd think about it, look at a couple of cadavers, work it out --you know, he had charmed hands. It always worked. So we wrote up the proposal for studying this extracorporeal radiation of the blood in human beings with chronic lymphocytic leukemia that were refractory to treatment. And it was approved. By this time we had begun to get a little bit more-- American Medicine had become a little bit more sophisticated in how one entered into clinical research. That horrible thing that happened at Sloan Kettering where somebody, whose name is just as well I don't remember, had transplanted cancer from cells from one patient into another patient. Of course they didn't grow, but it was something that just shouldn't have been done, and it really shook up the medical community. And that was the beginning, along with some other things that had happened, of more and more regulation from the National Institute of Health. And the Atomic Energy Commission, required that all of their facilities abide by the regulations promulgated by the National Institutes of Health. So that was the beginning of having clinical investigative research committee with a multidisciplinary background of the membership. It was approved and we started it. It was really remarkable that 1) the shunts didn't clot; 2) we had no infection in individuals that are very susceptible to infections; 3) in these individuals that had become refractory to chemotherapy the counts went down, the spleen got smaller, the lymph nodes got smaller. Some of the individuals transfusion requirements disappeared. The platelets came up. They were better off. All patients did not respond, and we progressed from those who had been refractory to chemotherapy to those that had no chemotherapy. Some of the remissions --You never get a total remission in chronic lymphocytic leukemia. That's never been attained by any method but people's counts would come down and be down for months and months, and some of them for two-three years before they started to come back up and the lymph nodes began to grow again. So it looked like it might be feasible to do this in a larger scale. We went in for a NIH grant to expand this. We all were going to do this in collaboration with William Moloney who is professor of hematology, Harvard at Peter Bent Brigham and with Sam Hellman who is radiotherapist---
[END OF SIDE TWO, TAPE ONE, BEGINNING OF SIDE ONE, TAPE TWO]
Cronkite: [radiotherapist at the Joint Center for Radiatrion Therapy]. Whole body irradiation was set up. Well this was the time when funds were beginning to become a little restricted and while the proposal was approved, it was not funded. So extracorporeal radiation died a natural death. Whether it should have died a natural death, whether it will someday be reactivated is something one never knows. There are some reasons to think it should be. The policy now in treatment of cancer in general prior to chemotherapy is to debulk tumors as much as possible, so you reduce the number of tumor cells, so the smaller the number cells remaining the greater the probability of having that lucky as yet unattainable kill of the last tumor cell. And one certainly in chronic lymphocytic leukemia, acute meloblastic leukemia can drastically reduce the burden of tumor cells in individuals, and then initiate chemotherapy. So from time to time, I'm wondering whether somebody will ever reactivate this. As of the moment, it's obviously dead.
During this period of time we had the study on chronic lymphocytic leukemia. Pradeep Chandra, Indian, who had his training in internal medicine/hematology, between Montefiore Hospital and the Long Island Jewish Hospital, again with Arthur Sawitsky, proposed that we offer him a position, which I did. He was a major participant in the clinical studies with extracorporeal radiation. Did some excellent work and developed another facility we have which is an unique facility here, our whole body counter, that counts very low levels of radioactivity. He came across in the literature that chronic lymphocytic leukemia cells have a higher concentration of potassium than other cells. And a certain fraction of the potassium in the world, potassium 40, is radioactive and everybody has radioactive potassium in their body. And this is detectable by measuring the radioactivity in this whole body counter. You can put anybody in it and you can determine very precisely the amount of potassium 40 they have. So the operational notion was that one would be able to measure directly the diminution in the tumor cell mass, in chronic lymphocytic leukemia by determining potassium 40 before commencing chemotherapy or extracorporeal radiation of the blood, or radiation therapy, and then measure it at time intervals afterwards. It turned out it worked beautifully. You could see-- with the mathematical treatment of the data, one could actually say how many pounds of tumor cells were eliminated. And then the most interesting thing was one could then observe, with time, after cessation of treatment whole body potassium, potassium 40, content. And you could see it beginning to come up before there was ever any indication, clinically; that the disease was recurring. So it was a very useful thing, I believe. And it isn't used today, and I think it would be very useful. The very simple reason it's not used, these whole body counters, I guess to duplicate the one we have would probably be close to a million dollars now. Who has a million dollars to put up? We have the only one of this type in the world, actually, the one right here. It cost a quarter of a million dollars, originally. And now it would be at least a million dollars to build another one. It would be very useful in maybe a number of things, but no way is there going to be any repetition of these -building of other whole body counters, given the financial condition of the United States Government.
Chanana, Rai, Jansen, Ramos. Giuseppe Moccia and Marilyn E. Miller and Helen Garnett. I lump them all together, and Kenichi Harigaya because they worked closely together.
Marilyn Miller was one of Fred Stohlman's friends, and she was not only a superb clinician she was one of those people that had ideas. She'd take a single idea, design a simple experiment, to answer it. There was nothing complicated about it. She never got confused with masses of data and confounding things. She could always formulate a simple little question, and after Stohlman's death, actually before his death, I'd asked her if she'd be interested in coming here, and she was unmarried and said she would like the idea of being in a place where there was purely research and a minimum amount of clinical responsibility. And it was a very productive relationship. Kenichi Harigaya wrote me from Japan that he would like very much to come here and work for awhile in America, see what it was like in the United States. He was also a very talented individual, hard worker. My goodness he was a hard worker. Also he and Marilyn got along extremely well because they always would ask a simple question and come up with a simple approach to answering the question. And they were always questions that were pertinent and important.
About this time I got a letter from Helen Garnett who was professor of biology at the University of Witwatersrand in Johannesburg, South Africa. And she said that she would like to have a sabbatical here to learn about hemopoietic cell culture, how to study kinetics of cell proliferation in order to pursue the things in which she was interested in, which is mainly she was interested in the Epstein-Barr Virus, and the cytomegalovirus that causes these horrible diseases in people with immunological suppression, AIDS; people on extensive chemotherapy. She was a PhD, not a physician. Harigaya was a pathologist in Japan. Marilyn Miller was a physician, oncologist, hematologist, internal medicine.
Helen arrived, and it was really a great-- Everybody couldn't do everything they wanted to do at the same time, but these three people were able to work together, and then obviously somebody had to make the decisions and that was left up to me as to what was going to be done with the facilities we had. And it was always done in a very pleasant but competitive atmosphere; whose study got done first. But all three of them were such compulsive workers, before I knew it and without my approval, sometimes two or three things would be going on simultaneously. But it mainly made no difference because they worked like hell and they got the work done and very, very productive.
About this time financial difficulties hit this place. The Office of Management and Budget in about '76-'77 decided that the Environmental Protection Agency should have a program in basic research, basic cellular research. And the way to do this was to transfer research from the Department of Energy. The Atomic Energy Commission was abolished by Carter or Nixon. I can't remember now, and replaced by the Energy Research and Development Administration which was a disaster, because they decided radiation was no problem. We had to study the harmful effects of the products of fossil fuels. And then-- it was Carter-- it was before Carter those things happened. Then Carter abolished the ERDA, the acronym for it, and formed the Department of Energy which was an absolute bloody disaster for research. It might have been good for other things, politically or perhaps economically. But for research it was an absolute disaster because it politicized the entire thing, and rather than having qualified people that knew science head of different things. For example the first head of the Biology Division on the Department of Energy was Ruth Clausen who knew nothing about research. She was president of the League of Women Voters. She was a big, tough woman, but she was given a job by Mr. Carter for which she was totally unqualified. She tried hard but you don't suddenly learn the administration of science when you've been a politician. And it was an absolute disaster and it hasn't improved ever since then.
But in the great wisdom of the Office of Management and Budget, they said the simplest way to give EPA a basic research program to undergird their regulatory function, is to transfer it from the Department of Energy. And they transferred 14 million dollars of research from the Department of Energy, of which a million dollars of it was my research.
Well the fellow that was responsible for this was delighted. I happened to know him. He was a pretty good radiobiologist. And he was delighted to get this money. And he said, "Everything will be the same. You just continue doing everything you do and we'll support it." If that was the case, as much as I thought it was a horrible thing, if it's going to be that way, maybe it's good. After about three years, this guy retired. Another character showed up. He says, "I don't understand why we're supporting a basic research program." And I said, "It was given to you. It was taken out of the Department of Energy and given to you so it undergirds--." "Nah, it doesn't make any sense. You have to figure out within six months a program that meets our programmatic needs, regulatory needs and so on, or we'll just terminate it." And I, Holy Cow! They can't do things like that to you, but they can.
So I thought about it a little while and did some reading, and a major potential hazard to the public is the inhalation of benzene. The Environmental Protection Agency had taken lead out of gasoline, or was taking it out progressively. They still haven't gotten it all out. But Americans still want high powered automobiles and you got to have anti-knock, and the petroleum producers couldn't put lead in it any more, had to take it out. So the lead came out. There are other anti-knock compounds that are toxic, and they decided not to use those because they would get knocked out. So they said they could change the temperature in the distillation columns and get gasoline with an increasing amount of benzene in it. Benzene has anti-knock properties. Benzene is one of the things that is unequivocally a carcinogenic agent in human beings, and there's no argument about it, so I proposed a research program on the toxicity of benzene. And they said, "Ah, great." And that went along and this is where Harigaya comes in. He came and we outlined a program that I had for studying the toxicity of benzene in tissues culture, and trying to work out a method for a rapid assay for the leukemogenesis and then you could do all the dose effect things and so on.
While our tissue cultures were going along, he noticed one day that there was an area in one of the cultures where the cells were piling up abnormally. And being curious, he mucked these out, and he suspended them, sub-cultured them, and then we began to look at them cytologically. And it looked like cells that were described by Michael Dexter in his development of the long term bone marrow culture system. So we took supernates from these to see if these cells were producing anything that would stimulate the amount of hemspoiesis. And sure enough they stimulated granulocytopoiesis, macrophage proliferation in culture. And Helen Garnett extended these things in some very nice studies that were published in the Proceedings of the National Academy of Sciences. That's one of the advantages of being a member of the National Academy of Sciences. If you want to publish something in a hurry as a member, there's no problem. You just contribute it. And it's possible that it could be junk because it's not subject to review, or wasn't subject to review in the past. Any member that --You know some people go bonkers as they get older, and some awful trash has been published in the Proceedings. But it makes it possible to have a fast publication providing you get it down to five pages. They have never published more than five pages of a given article.
The studies of Harigaya and Helen Garnett were the first studies showing that there is a cell line from the stroma of the bone marrow in which the genes for the production of GM-CSF and M-CSF were switched on by mechanisms for which we had no --I would have liked to have-- I would have been very happy had it been the result of the exposure to benzene, but it came from the control cultures and not the cultures that had come from animals that had been exposed to benzene.
And it would have been a great opportunity to pursue these things but the Environmental Protection Agency had no interest in going back to basic research. At about this time a guy came along and said, "We've written the regulations on benzene so we're not going to support your research anymore." Boom and it went to zero. Just like that. The Department of Energy felt very badly about this because after all they'd supported us. They'd supported me. We'd been very useful to them ever since the Atomic Energy Commission days. Anytime they had problems and so on, we busted our necks to solve the problems for them. How can I say it without sounding like a megalomaniac, I don't know. We were important to them and we were without support due to peculiar operations of the United States government that made no sense whatsoever.
Well they did put back some money in the pipeline and we were able to build it back up in relatively reasonable amounts. And about this time Tohru Inouye wrote me from Japan from the University of Yokohama saying that he would like to come and work. He was familiar with the work we had done, and I still continue to work with him, as a matter of fact. He was a pathologist but a very bright guy, an excellent mathematician. And we did a lot of work together and still continue to work together.
People have been here-- oh I left out Shinichi Okuyama. He worked here. A very hard worker but had great difficulties getting along with Chanana. And during this period of time-- I'm rambling now-- I was approaching 65 and I assumed that I was going to have to retire because the laboratory had a retirement policy of 65 years. In addition, I had become chairman of the department on July 1, 1967. In addition to running the research program and overall administrative problems with the department, some really brilliant things had really taken place in this department. George Cotzias had developed the treatment for Parkinson's Disease. Lou Dahl had shown unequivocally the role of salt in the development of hypertension, and worked out the genetics of it. And all of this under the support of the Atomic Energy Commission, ERDA, and then they were told they'd have to get support elsewhere. That it was no longer the type of things that they could support. We developed a big program in nuclear medicine with Harold Atkins, who is now professor of nuclear medicine at the State University of New York Stony Brook. So the department in general caused tremendous headaches, administrative headaches, because of changing policies. Atomic Energy Commission, ERDA, the Department of Energy and individuals who had been supportive for years, who were extremely productive, who were internationally known, were suddenly being threatened with zero support. And to their credit they went the NIH route and got support. And I also got NIH support.
I left out another Indian. Chikkapa. His first name Gundabatha. He was always called Chik. A very good clinician, a very hard worker; self-propelled individual. Contentious! My God he was contentious. Beat the hell out of me on the tennis court. Couldn't get along with anybody else but he would work 18 hours a day and by himself getting things done. He really was quite effective. He's now at medical school in Albany and in the VA Hospital there as chief of hematology. I think I've forgotten Moccia.
Moccia worked primarily with Marilyn Miller on problems of regulation of red cell production. And they did a lot of very seminal work that was the basis for understanding at the cellular level of what regulates red cell production. Marilyn did all the work on showing the role of acid base balance, the role of carbon dioxide, and understanding of what happens when one goes to high altitude or low oxygen tension.
Q: How do you spell Moccia, Dr. Cronkite?
Cronkite: Moccia. Giuseppe Moccia. Beppy was what he was called. He got along very well with Marilyn and they did some very effective work.
Q: What about your research on the stem cell? Is this all connected with that?
Cronkite: Yes it is. The stem cell is an illusive cell, the existence of which has been known since the turn of the century and before. There has to be a cell that self-renews itself; that is immature; its progeny can differentiate into any of the cell lines: erythrocytic, granulacytic, macrophages, megakaryocytic, eosinophilic, basophilic, B cells, B lymphocytes, T lymphocytes and all the sub-sets. The question of this stem cell was defined by [Alexander A.] Maximow, a Russian who published in Germany, and then later became professor of anatomy at the University of Chicago. We always come back to the University of Chicago somehow. A tremendously productive place but somehow or another I had troubles there. But he described without any evidence what had to be, and it had to be, and it has been shown to be.
Q: When did he do this?
Cronkite: 1900. Maximow, and William Bloom was his associate at the University of Chicago. It was clearly demonstrated. Then they did something that was impossible, but they did it anyways. They looked at smears and sections of bone marrow and said that cell is a pluripotent stem cell without any evidence whatsoever except this decided that's what it was. There had to be pluripotent stem cell. Of that there was no argument. And it had to have a capability. Its characteristics were clearly defined. I think it was 1901--that it had to self-renew itself retaining all of the genetic capacity to differentiate in any of the cell lines. And these cell lines had to have, because there were very small numbers of these things, had to amplify themselves by repeated cell divisions. And he decided to describe it as homoplastic and heteroplastic hemopoiesis. Nobody paid any attention to it.
Then there was a guy came along, Edwin [E.] Osgood, who was professor of medicine hematology, University of Oregon, Health Sciences, Portland. I think he probably, after Winnifred Ashby and Florence Sabin, first, I don't know what words to use --real thinker in hematology. Insomuch as it's possible in biology without basic understanding of things to learn a lot. He was a theoretician. He was an excellent mathematician. He formulated in mathematical terms how a stem cell would behave, how it would differentiate, the production and all the different permutations and combinations. He described them in mathematical terms, without any or little experimental basis. It just had to be that way. I was tremendously impressed by Edwin Osgood, visited him in Portland, and we became good friends. We used to communicate, and I had my ideas about how some of these things could be. They were a little different than his. And he had one thing that he believed in implicitly, and that is what he called an asymmetric mitosis, in which the daughter cells would upon completion of cell division have disparate potentials, but they both wouldn't have the same. That was somehow or other what we would describe now as saying the genes that are activated in one of the daughter cells would be different from the genes that are activated in the other daughter cells. Something of very fundamental importance and is now known to be the case, as I will mention in a moment. But a molecular basis for it was not at that time known or a cellular basis for it.
Now the problem with the stem cell is, nobody had seen it or described it but people like William Castle, certainly Fred Stohlman, George Brecher, including myself and I believe Carl Moore and Max Wintrobe, accepted without any doubt it had to be, but why can't we find it? Why can't we identify it; say, "This is a stem cell! It's got specific staining characteristics. The nucleus looks like this."
In 1960 [James E.] Till and [Ernest Armstrong] McCulloch at the Ontario Cancer Research Institute published a paper on functional ennumeration: not identification, a technique by which one could measure quantitatively the presence of a pluripotent stem cell. It's still not identified but you could measure. And it was a simple technique in the mouse. It still exists today. It also will work in the rat to a limited extent. It does not work in any other species. The technique is that you fatally irradiate a mouse which will never spontaneously recover. Earlier, the initial bone marrow transplantation work was done by Egon Lorenz showing bone marrow transplantation would save the lives of fatally irradiated mice. Till and McCulloch decided to inject bone marrow into fatally irradiated animals, and then at regular intervals afterwards, kill the animals and look at them to see what was happening. They were fully aware of what Egon Lorenz and Leon Jacobson and others, Charlie [Charles C.] Congdon, and Delta Uphoff, etc. had done. But they added to it by looking regularly at autopsied mice. First thing they saw starting around 7 days afterwards, you see bumps on the spleen. And then they started injecting smaller numbers of cells and then they would see that they would get the number of bumps that appeared on the spleen was proportionate to the number of cells injected up to the point where they were confluent and you couldn't count. They'd just run together. And they looked at these bumps histologically. They were erythropoietic, granulopoietic. Some were pure megakaryocytic colonies, little tiny ones. Others were mixed -erythropoietic, granulopoietic, megakaryocytopoietic, and so on. And then they worked out a technique with a chromosomal label that if all of the mitosis within a colony had the same chromosomal aberration then that colony had to come from one cell. It was all deduction, never identifying the cell. And they published the paper on the "Functional Assay on a Pluripotent Stem Cell." Still used today. And it's made possible the knowledge on the stem cell that exists. All based in the mouse, inferred to other species. The pluripotent stem cell is self-renewed. If they took colonies out and re-suspended the cells and re-injected them in other mice, they would get a certain number of colonies. They proved clonality of the chromosomal markers---
Q: --on the stem cell.
Cronkite: Oh yes. The Till and McCulloch assay.
Q: Could you spell McCulloch.
Cronkite: McCulloch. Ernest McCulloch and James Till. This was really a major, major development in hematology. It made it possible to study self-renewal, to study differentiation, factors that influenced it, and within a few months after their first publication in radiation research in 1960 or '61, I've forgotten when it was, people were doing this all over the world, because it was the first breakthrough in really beginning to understand how do you get from the unquestioned pluripotent stem cell to circulating granulocytes, red cells, platelets, etc., lymphocytes. They made a whole series of observations in rapid order showing the clonality. They could differentiate all those cell lines that if you subjected animals to hypoxia you could get predominantly erythrocytic colonies. If you gave excess red blood cell transfusion with a high hematocrits so that the animal had no need for further red cells you suppress erythropoiesis in the colonies so that one was beginning to be able then to look at the positive and negative feedback loops. While it was still not possible to get at the molecular basis of self-renewal or differentiation.
We became very much interested in the stem cell because of its obvious role in protection against radiation injury, which the Canadians demonstrated a lot about the radiosensitivity. We got into it measuring the radiosensitivity of the stem cell by two ways and also looking at different types of radiation so far as the relative effects. If you take a suspension of bone marrow, or irradiate the animal and then take out bone marrow after it had been given greater doses of radiation, the number of spleen colonies diminishes per number of cells injected. So you're killing stem cells and you can get a straight line as an exponential function. Very little shoulder. The shoulder is representation of the amount of repair, which means DNA repair. So you also have a way now to begin to quantitatively look at factors that may influence the repair, either prevent it or accentuate the repair process. We were interested in the relative effectiveness of different types of radiation: ionizing radiation, X-rays, or gamma rays, what was called LET radiation, low energy transfer, LET, that means as a photon goes through tissue that the Compton electrons that are knocked out of the orbits have a variable energy from maximum to near zero, and they're relatively far apart. Whereas alpha particles that comes from radon, plutonium, fast neutrons that will knock, hit a nucleus, and they'll have recoils and different particles will come out, have a much denser path of ionization in the tissue. So one could reason that if DNA is a target that then per erg deposited in the tissue, there should be a greater effect in damaging DNA from high LET radiation compared to low LET. Well that's true. They can get about twice the effectiveness. These are studies we did here with Bond and Carson.
Then when Inouye was here, he became very much interested in what happens, since we had to study benzene. At that time we were getting money for it. What happens to stem cells in animals that are exposed to benzene. There is no argument based on human studies that benzene produces an increased incidence of leukemia in human beings that are exposed to large amounts of it. Looking at the stem cells after animals were exposed to benzene, 400 parts per million, 6 hours a day, 5 days a week, trying to mimic a work week without going into overtime. The number of stem cells in the bone marrow precipitously dropped after one day of exposure and down to about 10% of the normal level. At the same time, the fraction the stem cells that were in DNA synthesis increased. Which means there was some mechanism that told a smaller number of cells present that -- I left another important person out, Ursula Reincke and Harold Burlington. There are some molecular mechanisms that switched on the genes responsible for DNA synthesis in a larger fraction of the cells that were surviving so that a smaller population of cells could produce a greater number of differentiated cells with a higher fraction of DNA synthesis than would happen if the fraction in DNA synthesis remained constant, which is about 10% normally. It went up to 50-60%. As soon as the exposure to benzene was stopped, boom, down it went to the normal level of roughly 10%. And then there was a very slow leisurely recovery of stem cells, back close to the normal levels but never quite back to it. And when they got back there was always a little increase in the fraction in DNA synthesis, which means there was some mechanism in the body that switched on the genes in cells that produced the proteins -- everything is regulated by proteins. So with a smaller number you would still be able to make the same number normally: blood counts, marrow cellularity, everything came back to normal. What this mechanism is is still unknown but it clearly established that it's there and some bright chemist one of these days, molecular biologist, will figure it out. Same thing occurs after exposure to radiation. There is a dose dependence in the diminution in numbers of stem cells. Very rapid exponential increase after exposure to radiation unless they die, and then increases to about 80% of normal. Greater fraction in DNA synthesis because they come back to normal cellularity etc.
Well we began to ask questions. Certainly benzene and radiation are leukemogenic agents. Another interesting thing. Even in working with a genetically pure strain of animals, everything so far as one can measure is genetically identical. It's like identical twins. It makes no difference what you do. So in a CBA/Ca mouse, spontaneous incidence of leukemia less that 1% (acute meloblastic leukemia). You can get it up to about 25-26%. Never any higher than that. But there's something that protects 75% of the animals. They have the same lesions and so on but they don't develop leukemia. That bugs me why they don't, but we asked the question, will the stem cells have a...
[END OF SIDE ONE, TAPE TWO, BEGINNING OF SIDE TWO, TAPE TWO.]
Cronkite: ...lesser mitotic capability. By this I mean if one exposes to radiation or to benzene and then waits weeks, months or even as in one of our studies, 270 days, and then takes the bone marrow out of those animals and determines the effectiveness of rescuing other animals from a fatal dose of radiation, will it take fewer cells in the age matched animals that had never been given radiation or been exposed to benzene. And the answer is it does take more cells from the treated mice. The stem cells are less effective in protecting. Which means that they have lesser residual mitotic capacity. That their capacity to divide has been reduced and when the pluripotent stem cell quits reproducing you have aplasia, aplastic anemia, boom, marrow failure and they'll die. And this is precisely what happens. The molecular mechanism of this is totally unknown. But we also asked the question, will the survival time of those protected by transplantation be shortened? I think this is rather important to human bone marrow transplantation. If you're interested in human bone marrow transplantation, you know that after the onslaught of fatal irradiation, extensive chemotherapy, people are really just clobbered. I mean all of the proliferative cellular systems are seriously injured. And then their hemopoiesis is reconstituted by cells from another individual that are never, unless you have an identical twin, they are never genetically identical. There will be some allogeneic incompatibilities.
But the question that was being asked was "Will the survival time after transplantation be a function of the number of the stem cells injected?" If you inject a lot, will they survive longer? If you inject a few, will the stem cells be forced to divide to maintain hemopoiesis and they'll run out of steam and the animals will die with marrow failure. The answer is yes and no. And this I'm writing up at the present time. If one gives in the mouse 10 raised to the 5th power or more bone marrow cells, the survival time of those that are rescued are the same. 105, 2 x 105, 106, 5 x 106, or 107 cells. The survival time is identical. If you give less than 105, the survival time is much shorter. And they do in fact die with marrow failure. But if you take the survival time of the animals that have been given fatal irradiation, rescued by 105 or more syngeneic bone marrow cells, compared to the survival of the animals that are never irradiated, there is a tremendous difference. Which means that the animal at large even though there is no marrow failure recognizes the prior damage to tissues in general from radiation, fatal radiation, and their life span is reduced by about 55-60% of the normal life span. How this applies to human beings nobody knows yet, because human studies haven't been going on long enough. Many individuals that were irradiated plus massive chemotherapy in their teens and rescued by bone marrow, are apparently in good health--Many of these kids are married, have children and everything else. But instead of having a mean life span of 70+ years, it may be something like 50 years. I've been dragging my feet a little bit on publishing this because, although you can't suppress information, once this sort of thing is known, part of the formula then in informed consent is to tell people, based on animal studies, that your life span may be reduced, if animal studies pertain to human beings, will be reduced. Instead of the mean life span of 73 years for males, 75 for females it will be reduced to 50 years. And gosh these people go through so much hell anyways to burden them with another bit of information that they're not going to live as long if they do survive, I think is unfortunate. I think we have to publish it anyways.
Where else are we?
Q: That actually was one of my questions, what you're working on now. And my two other most important questions before where you are entirely, are what you hope for. And just anything else you'd like to tell us.
Cronkite: I've been reflecting as to whether I didn't tell you things yesterday that I might mention today. I'll come back to that in a moment. What do I hope for?
When you get to be my age, you hope to have, to be able to live the way you'd like to live and when it's your time to go that it goes damn fast without the benefit of medical care. And that's the one thing. Now I come from a very long lived family. My mother died at 96. She'd probably still be alive today if -- she had a surgical problem if we could have gotten her into New York City or something. She had to be taken care of in a local hospital and it was a disaster. My father was 90. My Cronkite grandfather died in his sleep at 97. I had a great-grandfather who lived to 106. Both on my mother's and father's side, everybody lives. And fortunately they maintain their mental faculties and vision and hearing until it's time to die.
So one thing I think anybody begins to think about, you don't think of these things when you're younger, is when it's your time to go, make it fast without benefit of medical care which I think is disastrous at times. Elderly people that really would like to die and you don't let them die. It's a societal problem. I know there's not a damn thing in the world you can do about it. I carry along a statement in my wallet or my brief case requesting that extraordinary means not be taken to keep me alive. If I lose my apples let me go. There's no damn sense in living. That's one thing.
I still have a lot of things about which I'm curious. I have an NIH grant, 5-year grant, which I thought was a joke. NIH asked a year and a half ago, for proposals for studying the toxicity of AZT dideoxythymidine used in the treatment of AIDS. Well we have no AIDS patient. I've never seen an AIDS patient. But they said they'd like animal toxicity too on this drug which has never been properly evaluated. The homosexual community has been able to force it into clinical use. And I don't think anybody's really been harmed by it and it has been beneficial to a certain extent, but it does have a lot of toxicity.
I wrote up a program to look at one: does it have an effect on the stem cell. Will animals that are treated with AZT in the amounts that are given to patients, comparable amounts on a body weight basis, reduce the mitotic capacity of these cells, which I've already explained to you? Will animals, that are mice, kept on this for a prolonged period of time develop leukemia. And that's a five-year program that's been funded, that's going now.
It certainly has drastic effects on the stem cell. When we got the funds starting last first of October, we put animals on this, or gave them injections. Within 24 hours after an injection their stem cells plummet right down to very low levels. Whether it will have long term lasting I don't know, it probably won't. My prediction is it will not, for the following reason: 3' azido 3' deoxythymidine (AZT) is recognized to be beneficial for a retroviral disease of mice and people with AIDS. The retrovirus has reverse transcriptase, an enzyme which reads retrovirus RNA. This enzyme in the virus reads the messenger RNA and transcribes it into host DNA, and then the alpha-DNA polymerases, and probably other polymerases, take this part that has been transcribed from the messenger RNA and inserts it into the host genome. So the host genome now has the virus message in it, and this raises havoc with immunity and hemopoiesis. It's all well known by work that has been done clinically.
Since the alpha-DNA polymerase can handle AZT, they will insert it as thymidine in the chain elongation during DNA replication of stem cells and the azido group which is a triple nitrogen group hanging off of the sugar, blocks the phosphorylation so the elongation of the DNA chain stops. And if you can't get the phosphorous sugar link, it stops right at that point. So the cells that are in DNA synthesis, normal cells, nothing to do with the HIV virus, are stopped in DNA synthesis by the AZT.
But again, I have a conceptual problem of why stopping it should result in a drastic reduction in the number of stem cells present in the animal. It may be that they're there but the presence of the AZT in an incompleted DNA chain, makes it impossible for the cells in this assay system to produce the colonies that one counts.
Now if this were to be true, and we should know this in a couple of weeks, then by waiting for whatever the mechanisms may be, whether they're enzymes that now come along and chop out the AZT from the DNA of the normal cells, and then other enzymes which were there, the DNA polymerases will put in ordinary thymidine and the elongation will take place. Then in a period of time the number of stem cells should come back to normal. But they were just sort of in suspended animation. That we'll know --Three weeks from now we'll know the answer to that.
Dr. Bond and I have worked together for years and years on many things. I didn't mean to denigrate his role at all. He was a major participant in all of our studies on cell proliferation and so on. He had nothing to do with the extracorporeal radiation of the blood or our other clinical studies. He was a physician. He had just a Navy internship and then got his PhD and was not interested in clinical medicine. He's superb radiobiologist and has looked at human populations and the data from many non-mammalian systems, plants, tissue culture systems, to try to work out the basis, a rational basis for predicting what the effects would be from exposure of human populations to small amounts of radiation. Conceptually, he's developed a mathematical, physical concept, that's very plausible, very logical. It certainly applies to Tradescantia which is a little plant, very easily --You get a mutation with exposure to radiation. Instead of getting a blue flower, I forget what the botanists call it, you get a pink one -- that's the mutation. And these are easy to score. You can score thousands of them, and you can see what the effects of low level amounts of radiation, and different types of radiation. And the concept which he calls the Hit Size Effectiveness Function, is based primarily in Tradescantia, and chromosomal aberrations. To emphasize potential importance to carcinogenesis in man by radiation one needs to study radiation carcinogenesis in mice.
We got a contract with the National Cancer Institute, a five-year contract, that was seven years ago, and we're now writing up the data, in which we exposed animals to low LET radiation of protracted, fractionated single doses, to get an estimate of what is the degree of repair after different types of exposure. And trying to get things now that might be applicable to human population in society today. Nothing like the Japanese A-bomb survivors or patients with extensive radiotherapy. I can't say anything about the results. We're analyzing the data now.
He put in a big proposal to look at this with exposure to high LET radiation which has the merit that there's effectively no repair to high LET radiation. And there is a device at Columbia University which we use to produce neutron of varying energies that have a different pattern of deposition of energy so that there will be so many ion pairs produced per micron in the tissue. And you can vary this very precisely and that study was started two years ago. We have about 2200 hundred animals for that
Cronkite: The animals are just beginning to die with leukemia. I have been autopsying them, and I will do the histology on these animals as long as I maintain my mental faculties. This study should be completed -- All the animals should die within another three years. Oh no, four years. And hopefully this will be the last scientific thing to write up. But there is, since you asked what I'd like to do, there is another thing that I would like to do. And I wrote up last year. We have at the laboratory what's called Exploratory Research Program, Project rather, in which the director of the laboratory takes a certain fraction of money and sets it aside to give to people that have an idea, and they don't really care how zany it is. You know if you apply to NIH now, you have to have something that is considered proper or so on. If you have a wild idea, there is no way in God's world you're going to get supported, or you probably won't get supported through NIH. You might get supported through the National Science Foundation. But the National Laboratories like Brookhaven, Los Alamos, Oak Ridge, the directors all had discretionary funds. And they will support things to get the evidence that a zany idea may be worth pursuing.
Well I made a proposal on one that's based on-- of course the committee is primarily physicists, mathematicians, and engineers. I don't even think there is a biologist --well, the associate director for life sciences is on it. For many years it has been known in the mouse and rat that although the tail of these animals consists of bone marrow, there is no active hemopoiesis in it. And this is a peculiarity. And Charles Huggins, again we're back to the University of Chicago. He's a Nobel Laureate. He got the Nobel Prize, he's a surgeon actually, for administration of endocrines in the treatment of prostatic cancer and so on which is very effective. But he'd done other things. He had observed in the late 20's, early 30's, published in The Journal of Experimental Medicine that if you took the skin off the tail of a rat and then tucked the tail inside the peritoneal cavity so that it will just sort of stay there, the temperature is warmer now, it became after a few weeks, actively hematopoietic. And he said that temperature is what determined whether cells would proliferate in the bone marrow. And this has some, as in most mammals, particularly in human beings, in a baby in little swaddling clothes; all of the bones have active hemopoiesis in them. And as their extremities are exposed and so on, there is what is called a retreat of hemopoiesis. Goes from the toes and then up so there is nothing but fatty marrow in the legs by the time it's 6, 7 years of age. Nothing in the fingers. Nothing in the bones here. Maybe a little bit up in the humerus. And of course, the ribs, the sternum, vertebrae, skull and pelvis have the active hemopoiesis in an adult.
So actually I'd tumbled on this idea in the Navy about why there was no hemopoiesis. We did the same thing that Huggins did. And, did I mention this yesterday?
Cronkite: I was about ready to publish it. I was sort of excited about it. I happened to be thumbing through Experimental Medicine for some other purpose, and I popped open to a page and saw the "Initiation of Hemopoiesis in the Non-Hematopoietic Tail." When I read the thing he'd done, God, it must have been in the late 20's, and 30's he had done the same thing I'd been doing. Demonstrating that if you don't know the literature you make a fool out of yourself. So I filed the stuff. And I wrote on the letter, saying I would appreciate if you had a reprint. I got a nice letter back from him. This was before he got the Nobel Prize. He sent me a reprint. And he said, "This is the first time I've ever had a request for a reprint of this work." It's one of these things that I kept thinking about from time to time. Is could it really be temperature only? There is a study by [Lilian] Delmonte. I forget her first name now. Delmonte just like the canned goods. She's from that family. Worked at Sloan- Kettering and she observed that mice with mammary adenocarcinoma developed granulocytosis in the tail. That seems odd. Why should that be? And a lot of people started looking at the tail. A Chinese girl, [Minako Y.] Lee, in the University of Washington, Seattle, discovered extensive hemopoiesis in the tails of tumor bearing mice. In our studies on the toxicity of benzene, some of our animals started to develop mammary adenocarcinoma and sure enough they had a high white blood count. We looked at the tail. Sure enough there was hemopoiesis in the tail. We thought here is a God given opportunity to begin to look at this. What does this tumor produce that circulates to the tail and tells the stromal cells and either resident or transient stem cells to differentiate and produce primarily granulopoietic tissue.
We and others-- and this work we did with Burlington, and Ursula Reincke. We put these mammary adenocarcinoma cells into tissue culture. They grew avidly and we assayed the supernate from them. And the supernate from these tumor cells has tremendous amounts of the molecular regulators, and it will produce in vitro culture of granulocytes, macrophages, and mixed colonies. With time a strain, a sub-clone of the tumor developed that still produced a tremendous amount of molecular regulators in tissue culture. But the animal bearing this tumor when it's transplanted into him did not develop a granulocytosis. There has to be -- And other people in the mean time, Minako Lee in Seattle, and Japanese workers said the whole effect is due to the production of the granulocyte macrophage colony stimulating factor. But then we have a strain, of a sub-clone of our mammary adenocarcinoma that produces even more molecular regulators in tissue culture but does not produce a granulocytosis. Well Burlington and I wondered what the hell is going on here. We must be producing something else that instructs this marrow stroma to instruct transient or resident stem cells to differentiate in the tail. It occurred to me that a way to look at this would be to make adherent layers in culture from tail marrow, like Michael Dexter developed for normal bone marrow to grow in long-term marrow tissue culture. But to make the adherent layer that is required before you get any proliferation, self-renewal of stem cells, production of differentiated progenies, you had to have this adherent layer existing of cells that were fatty, fibroblasts, macrophages and so on which: produced the factors necessary for stem cells to self renew and more of them to differentiate in to granulopoiesis, erythropoiesis, etc. So the question was, will the stroma, adherent layer of the tail support hemopoiesis in tissue culture? If the answer is no, will supernatants from our cultures of the mammary adenocarcinoma switch on the genes in these cells to produce molecular regulators that will support hematopoiesis. And I proposed this as a wild idea. Number one of course, to a bunch of physicists and mathematicians, somebody's messing around with tails of a mouse and so on, and they thought it was all sort of gobbledy-gook. They asked a few questions and I convinced them it was worthwhile. And we were given money to initiate the study also effective last October and are in the process of looking at this.
Now it's not really, it may be that we'll learn nothing from our studies, but we also may learn, which would be of interest but no importance, that what the tumor is doing is producing interleukin 1 which is known to switch on endothelial cells, fibroblasts, T-Cells, macrophages, to produce GM-CSF. If that turns out to be the case, well then we will have answered how the tumors do this. It's not their production of GM-CSF but it is their production of IL-1 that switches on the cells of the tale to do it as a resident or transient stem cells were trapped and do their thing.
Or it may turn out that it's not IL-1, that it's some molecular regulator that has not as yet been identified. And if this be the case then we'll be in the position of trying to identify what it is, and within our limits of characterizing it to show that it is a very real thing. The antibodies for all these other factors are available, so if I neutralize anything else --These are all commercially available now. It's unbelievable what's available now. And if our supernates would switch this thing on after inactivating IL-3, GM-CSF, all this sort of thing, then weld have sound biological evidence that there is an unidentified molecular regulator. And this could be exciting. This is the worst type of wishful thinking for a scientist, but one who, is a physician, and has had to live through the horror of taking care of people with aplastic anemia, this could be the missing factor. You see IL-1 has been used in aplasia of the bone marrow and it's limited if any value, but something has happened so that the stroma of individuals that develop aplastic anemia is no longer able to support hematopoiesis. And it's wishful thinking, if you could say, "Ah, maybe we got in this system. Maybe or maybe we could fail completely."
But those are the things that I would like to still do, on top of playing tennis. We enjoy very much-- we have a place on the Chain of Lakes in Northeastern Wisconsin and my wife and I have decided that in part of May and June and September of every year, we'll go to Wisconsin and spend it with our daughter. Go fishing. It's a very lovely place but it's-- believe it or not, that part of Wisconsin is one of the more primitive parts of the United States. Wolves are there. Bear. You name it. Eagles, my God! Thousands of fish and it's beautiful. Before May it's too damn cold. After September it's too damn cold. I wouldn't go there then under any circumstances. And although we have a telephone there we can switch the bell off so if we don't want to be bothered, but if you had some reason to phone out, it's there. And I would still like to do some writing of different types. And I'm interested, very much interested in history of health things. Not only the history of science and hematology but I'm interested in the history of democratic processes. I've got a bug on Abraham Lincoln and the founding fathers of this country and how they got things started clearly in the right direction. But boy they were anything but --People talk about Jeffersonian democrats and that they really believed in the rights of --They believed in the rights of the males that were white and had money. No women, Blacks, nobody else had any rights. You know that is somewhat different from the French evolution. It fascinating to really think about as what goes on in the minds of people. They are long since dead but made a tremendous impact on the development of society.
There was one other thing that I thought that I left out. And this is clearly something that up until past the year 2000 --This really can be sealed? Who will see this sort of thing?
Q: Well, of course, I will have heard it. Ron Grele who is head of the office of oral history at Columbia will hear it, and a transcriber, whoever he or she may be, would type it. As far as I know those are the only people.
Cronkite: Why don't you turn it off for a moment and I'll tell you.
[END OF SIDE TWO, TAPE FOUR. END OF SESSION]
Addendum for American Association of Hematology Oral History Project
Paul Vincent, M.D., Ph.D. of Australia was referred to me by Leonard Lamerton, Ph.D., a distinguished British biophysicist. This was a fortunate referral since Vincent had extensive clinical experience in Australia and was just completing two years with the distinguished British hematologist, Dr. Dacie. With the exception of interpreting the Australian version of the English language, Dr. Vincent was not only a compassionate and skilled physician in general, but an excellent hematologist with a never ending flow of ideas worthy of research investment. He rapidly became versed in the terminology and methodology of studying the rates of cell proliferation. He made several contributions to an understanding of chronic granulocytic leukemia, the intravascular life span of granulocytes in the bovine and with the double labeling technique ascertained the duration of this cell cycle lymphocytes in the bovine. As most Australians, he was an excellent tennis player and thoroughly enjoyed a party, fishing, and searching for clams and oysters in the north shore of Long Island where they have become depleted. He still had an innate sense of where they would be lurking. In addition, his sense of humor was priceless.
Joseph Rubini, M.D. was a clinical hematologist with training in biochemistry. He made a very important contribution to the metabolism of tritiated thymidine that remains today a standard reference for those of us who use tritiated thymidine in human beings for the study of cell proliferation, an area that is reawakening in its importance because of the necessity to determine the influence of the availability of molecular regulators of hematopoiesis that are now produced by recombinant DNA technology.
Jean Laissue, M.D. was a Swiss pathologist sent by Dr. Cottier from the Institute of Pathology in Switzerland to work on problems of cell proliferation. In addition to his expertise in pathology, he brought a keen intellect with innovation into the study of the effects of varied DNA labeling agents upon the kinetics of cell proliferation. These studies performed in conjunction with Darrel Joe, D.V.M., Ph.D., of the Medical Department, are landmarks that are still used in the study of cell proliferation and its regulation. Dr. Laissue has now been promoted to Director, Institute of Pathology, University of Bern.
Victor Perman, D.V.M., and Dale Sorensen, D.V.M., veterinary pathologists from the University of Minnesota were brought to Brookhaven in a program developed with Dr. W.T.S. Thorpe, Dean of the School of Veterinary Medicine, University of Minnesota in which veterinarians would come for a two year period to Brookhaven overlapping a year to become immersed in our research program and also supervise the animal facilities in accordance with Federal Regulations. There was considerable contention in ideas about the management of potentially fatal radiation injury.
Drs. Perman and Sorensen were given the job of evaluating the effectiveness of antibiotics, platelet and red cell transfusions in the treatment of the potentially fatally irradiated dog. These studies in the early 1960's clearly established the value of antibiotics plus and red cell transfusions in increasing the survival rate of irradiated dogs.
Werner Boecher, M.D., University of Essen, West Germany was like all Germans an indefatigable worker. He had good ideas about research problems and was able to carry research to a logical conclusion, but was totally unable to put final work into an acceptable form for publication. He did, however, in conjunction with our earlier Danish collaborator, Dr. Sven Killman, make a notable contribution on the structure of granulocypoeisis. It was clearly demonstrated that myelocytes have long cycle time of about 54 hours with a large fraction of the cells being diploid. With a large fraction of myelocytes being diploid, it was logically assumed that there might be biological mechanism by which the myelocytes were accelerated through cell cycle in shorter time which would result in a larger fraction being in DNA synthesis and a smaller fraction diploid. This was put to the experimental test with Vaughn Larsen, another veterinarian from the University of Minnesota, and shown in fact to be the case. This important molecular observation now has a molecular basis, namely, that the recombinant G-CSF is able to put myelocytes into a more rapid cycle with a greater fraction in DNA synthesis, smaller fraction being diploid, and thus increase the rate of production of granulocytes when needed for fighting bacterial infection.
Emilie Gerard, M.D. was sent to work with us by the distinguished French hematologist, Professor Marcel Bessis. She brought a wonderful personality, bubbling with enthusiasm and spontaneity that made each day more pleasant. Despite her gallic nature, she was an extremely conscientious and hard worker. She made useful contributions on the nature of erythropoiesis utilizing diffusion chamber technique that withstood the test of time. In addition to her scientific contributions she is remembered for her description of American coffee as being nothing but "sock wash". She kept an espresso maker in the laboratory and always had a cup ready when one came into her lab.
Nicholas Odartchencho, M.D. was referred to me by Admiral Paul Bonnel, Medical Corp., French Navy as a promising young investigator who worked in the blood research laboratories of the French army. Dr. Odartchencho was half Russian and half French. He loved stories and immediately caught on to American humor. Although he brought a definite Gallic influence to our research group, which consisted of a Dane, a Swede, two Germans, and a Swiss, it was not divisive but made life more interesting and challenging for me as the leader. Odartchencho, bubbling with ideas, some of which were nonsense, but many of which basic knowledge of biology in medicine along with truly great imagination. He made excellent contributions on the kinetics of erythropoiesis and was the first to describe the various stages of megacaryocytes and their kinetics of proliferation from the diploid megacaryocyte to the polyploid megacaryocyte and its ultimate platelet production. This was an intitial important observation that became the basis for studies by others on the regulation of platelet production. He loved to race cars, was never caught by the Suffolk County Police, and with his wife Denise, loved fishing and always brought luck. Upon delivering our catch of fish into my backyard, he would direct his petite wife, Denise, to clean the fish and decide that we would sit and watch and drink a bottle of wine.
Lewis Schiffer, M.D. was omitted during the oral interview, since I found it difficult to talk or think about him after his tragic death by drowning in a lake in Colorado. Eugene Lozner, whom I mentioned earlier in the oral interview, communicated to me in the early 1960s that he had a young man who was finishing his training in internal medicine in hematology, who had expressed interest in research and had in fact shown an aptitude for it. He made an appointment possible for Dr. Schiffer at a ridiculously low income which he accepted. He in fact assumed the day-to-day supervision of in-patients and was my right hand in designing and carrying out clinical research. His contributions were seminal and many, designing a model for cell proliferation in chronic lymphocytic leukemia that stands today. He was instrumental in establishing the whole body counter as an accurate and simple way to measure iron absorption, blood loss, and vitamin B12 absorption.