ASH Oral History: James Tullis

Tullis: June 22, 1914.

Tullis: I first decided to become a physician when I was about seventeen years of age and had an accident while I was a junior in preparatory school at Western Reserve Academy in Hudson, Ohio. I was hospitalized for several months and had an opportunity to talk with the interns and watch the house officers, and was quite turned on by the experience and decided at that point I wanted to become a physician. My original premise was to be an orthopedic surgeon, because that's what I was being treated for, an injury of my back, but after I prepared for medical school I became so interested in biochemistry that I began to emphasize this.

While I was in medical school, I had a concept--which I've never been able fully to exploit, but which I've carried with me all through life--of seeing if one, through hypertonic and hypotonic changes outside the normal physiologic range, could influence the permeability of malignant cells in such a way they would rupture before, or at least have deranged functions, before normal cells, thinking that this would be a physical way that one might be able to differentiate the two, both diagnostically and therapeutically. So that while I was in medical school many years later, at Duke University, I took two terms off and did a project on the permeability effects of X-ray on Paramecium, where we could study the permeability of sodium and potassium exchange in radiated Paramecium, which are single-cell organisms, and easy to work with. My idea was then to carry these tools over to a study of blood cells.

Tullis: I don't think so. I enjoyed science always, but it was not, when I was a youngster, which is long before you were around, there was no emphasis on science education in schools at all, during my--well, my earliest days of school were in the 1920s and my later days in the 1930s, and at that time science was available for those -who were interested in it, but there was no public pressure, there was no enthusiasm about science. Indeed, if one said to his parents he was going to have a scientific career, he was looked at a little askance, as I was in my family. There had never been a physician. My father was a clergyman, my brother was a businessman, and no one had ever thought of science. So they thought I was just a little abnormal.

Tullis: I graduated in 1932.

Tullis: I had been there for several years, and my brother before me. It's a small preparatory school in a small New England-like community, out there in the Western Reserve. In fact, it's the oldest secondary school west of the Allegheny Mountains in the United States, and was founded in 1802. It's a very old, old school.

Tullis: Oh, they had science. We had a compulsory one or two years of physics, and one or two years of chemistry, just plain, ordinary chemistry, and mathematics, and so on. But, again, that was part of the curriculum, so one did it in order to get into college, but there was no obligatory emphasis on science.

Tullis: Rollins College in Winter Park, Florida, which is where I went, because as part of my illness--what had got me interested in science the year before--my family wanted me where I'd be in a benign climate. I think that I was sent down there so that I wouldn't get any infections.

Tullis: I beg your pardon?

Tullis: Superb. Rollins College--at the time I went to school, there were only two colleges that were getting themselves into new concepts of education. One was the University of Chicago under Robert Hutchins, and the other was Rollins College. These two schools set up curricula that were able to be tailored to the interests of the individual. He could go to school in as short a period of time or as long a period of time as he wanted, depending on how hard he wanted to work. And there were no interdepartmental barriers. One could take all science or all whatever and I enjoyed the school very much and got a good education because they had small classes. The largest class I had only had fifteen students in it. So one could get very direct interrelationships with his teachers. I remember my chemistry teachers there very well, both the organic chemistry teacher, Dr. Wise, who was a DuPont chemist who had been ill and had gone to Florida, as many people did in those days, for their health, and my faculty advisor, Dr. Sandstrom, who was the head of chemistry and influenced me a great deal. He was an M.I.T. graduate who had developed glomerulo-nephritis here in Boston, and his physicians had said: "If you have any more streptococcal infections, you'll get recurrence, so get out of this climate." So that he was there, and again, it was almost like having a close tutor all the way through.

Tullis: Yes. Very definitely. And then further emphasized when I was in medical school.

Tullis: Well, one had the standard courses, of course, in organic and qualitative analysis and quantitative analysis. We had one semester of physical chemistry. I wanted more, but that's all that was given at Rollins, and then a year of organic chemistry with heavy emphasis on laboratory. We spent almost half a day, three days a week, in the laboratory, as opposed to today, where it's more theoretical and less practical.

Tullis: Well, that really came more into my life in the 1940s and I'll just get to that in a few minutes if that's all right.

Tullis: Yes, I went straight to Duke from Rollins. My reason for going to Duke, again, was somewhat odd, because that was a new school. It isn't that I'm always looking for new things, but there had never been a scientist or a physician in my family and my father had a good fishing companion that he used to go to northern Canada with who was a hematologist and chief of medicine at the Cleveland Clinic, the Crile Clinic in Cleveland. And he said to Russell Hayden, who had been professor of medicine at Hopkins before he went on to Cleveland, he said, "Russell, my son thinks he wants to be a doctor. What school should he go to?" Russell Hayden, having come from Hopkins, said, "Well, you know, Hopkins has just been gutted by this new school, Duke University, which has gone up there and hired away most of the young, good faculty to set up a new school in connection with the newly reorganized Duke University, which, previously, had been Trinity College and was renamed because it was the recipient of tobacco money of the Dukes. And he said, "I think if I were a youngster, I would go to Duke, because during his professional career, that will be one of the solid scientific schools, as opposed to just applied medical care." He said, "Your son's interested in science, so let him go to a school where there's good science." So that's how I happened to go to Duke. Now, at Duke, there was a standard curriculum--that is, I guess there still is, at most places. It wasn't just freelancing like it has been here at Harvard in the 1970's. One had to go over certain specific hurdles and almost all of them--very little elective time--but again, they operated on a four-quarter period of the year, rather than two semesters, and one could take the four quarters by going to school year round. Each quarter was eleven weeks, and one could go--I'm sorry, twelve weeks, and one could go year-round or one could go three quarters or two quarters, whatever he wished. I think this was done because in the Depression days, there were many students that couldn't afford to go to school year-round, couldn't afford the tuition--they had to work part of the time. And in those days, there was no federal money or any other money for scholarships. The beauty of that was, for me, that I was able to go to the four semesters, for the first couple of years. Then I had some--I mean, quarters--time saved up and was able to work on this project which I was just burning to get into, where I could study permeability effects of exchange of water and salt and whether or not one could swell cells, shrink cells, and so on, if they had been damaged, which is what the X-ray of the Paramecium was.

Tullis: No, no, no. I just wanted, I wanted to study permeability. Well, now, where could one study permeability? Well, with single cells. Where does one get single cells biologically, you know---like a Paramecium for $2 a shipment?

Tullis: Oh, they had beautiful scientific buildings. It was really a superb school. Because it was so new, it had--things were so inexpensive in those days--very excellent equipment, and nice laboratories, and so on. Things were not so crowded then as what you've probably been used to, you see. When I went to the professor of pathology, Dr. Forbus, I said, "I have a project I want to work on." I described it to him; he said, "Well, I'll give you a laboratory." It was as simple as that! Today, you'd have to strangle somebody else to get room to get into the laboratory, you know.

Tullis: That was 1936 to 1940, in that period.

Tullis: 1932 was the first class, I think. I believe the first graduating class was 1932.

Tullis: It was strongly influenced by the Hopkins.

Tullis: And because most of the professors--a few were brought from Harvard, but most of them, however, came from Johns Hopkins, because the dean of the school, who was brought down to establish the school several years in advance, was himself a professor of pediatrics at the Hopkins. A very bright young man, and he brought with him a strong influence of the early days at Hopkins, which had only been, you see, thirty or forty years before that, that it had been formed. So he had these ideas strongly in his mind.

Tullis: No, at the medical school, they had their own departments. It was in the same large building that was adjacent to, or connected with, the hospital itself. But there were separate clinical laboratories in the hospital, so that the laboratories were run just like any basic laboratories were.

Tullis: Oh, yes; oh, very much. Very much. Yes.

Tullis: I don't think so, because most of the influence came a little bit later in my life.

Tullis: Except for Wiley Forbus, the professor of pathology, who was, I think, the epitome of the seventeenth-century man, which I feel was the height of the combination of the humanities and science. He was skilled and scholarly in everything he did, and was a very broad person, and could talk opera as easily as he could talk pathology. He was writing a textbook on pathology, so he spent much of his time in his office just with his books, and so on, but he always made himself available to me. And I had quite a lot of inspiration from him.

Tullis: That's right. I left Duke in June of 1940, and went for my internship and medical residency at the Roosevelt Hospital. The war started while I was there, there in training. We had what was called an affiliated unit at the hospital. These were units that were taken in as a whole hospital into the Armed Forces when the Armed Forces needed them, and then we were assigned the enlisted men. But we brought our own professional team, including nurses, doctors, and soon, because of the abrupt urgency of threatened invasion of England, we were marched out onto the boats in the summer of 1942 and shipped abroad directly to England as an affiliated unit, the 9th Evacuation Hospital.

Tullis: That's the Roosevelt unit.

Tullis: Roosevelt Hospital in New York.

Tullis: Well, at the time, I hated it, but, in retrospect, it was a very helpful period for me, because in my internship and residency I had gotten a glimpse of the clinical practice in medicine, was being pulled strongly in that direction. And this gave me a three-year hiatus where I was still doing medicine, because we had the same teachers, the same doctors as teachers, and so on, but free of the pressures of an immediate career decision. It gave me an opportunity to think over how much I would like to get into a more academic background than I was receiving at the Roosevelt Hospital.

Tullis: Well, medically, the most important experiences were the diversity of disease to which I was exposed. We were only in England briefly; we were sent there because they thought Hitler was going to invade England, and they didn't have enough hospitals, they didn't have any supplies. They had nothing. This was early in 1942, and there was just every indication that soon it would all be over.

But, after we got to England, apparently the concept of invading Africa as a diversionary thing was conceived, and our unit was then attached to the English army, because, again, they had no mobile hospitals, and we went into the Oran invasion in North Africa as back-up for the English forces. That war only lasted in Africa four or five days, and we were then detached from the English troops and assigned to the Free French forces, which had been left in North Africa, which were not part of the Vichy regime. It was mostly their colonial troops: the Senegalese, the New Caledonians, the Goums, the Moors, and so on. And we remained a French hospital there all the way through Africa through the Tunisian Invasion and took care of vast amounts of tropical kinds of illness that I had never seen before in my life! Worms such as I've never seen, I hope I never see again, quite a bit of, well, such things as leprosy. I'd never seen leprosy before, and I have never seen it since. All types of strange diseases of underdeveloped countries that we would never see in the United States. A great deal of hepatitis in North Africa, a lot of malaria when we went on into Sicily.

Then, once we got on over to Italy, we were detached from the French and assigned back to the U.S. Army, and our 9th Evacuation Hospital--our Roosevelt unit--then remained with the American forces for the southern invasion of southern France, and all up into Germany, and so on.

But the main influence of war on me as an individual was not that medical exposure but a pure chance exposure. In the fall of 1942, we were over in Sicily, and the Sicilian campaign had been won, and the Italian invasion was just starting, and we were left in Sicily as back-up troops for going into Italy, not knowing whether we'd be sent to Sorrento, where the early invasion had started, or to Naples. While they were trying to make up their minds where to send this extra hospital unit, we had nothing to do. So three other physicians and I decided to go to the Holy Land. We'd never been there, we thought the war was in the other direction, and I had heard about it ever since I was a boy in Sunday School, so I wanted to see that whole area around Palestine, and so on. This was before the State of Israel had been founded. So we decided we would go. We went to the commanding officer. He said, "Well, I can't give you leave to go, but I won't look if you do go." So we went AWOL, and hitchhiked on a British supply plane over to Algiers one afternoon, and then decided we'd sit at the Algiers airport; each of us would try to hitch a ride to Cairo, and we'd meet there and take the train to Jerusalem. This was at Christmastime. And the others were tired, and said they were going to go to bed; there was a tent area for loose officers there, so they went to bed. And I decided I was going to sit there until I got a ride.

So around about ten o'clock at night that first night that we were there, a plane landed, which was just a little old DC-3 plane, the kind that's called a C47--well, whatever it is. One of those with its rear end dragging along that ground, just two motored. And I watched it come up to the porch I was sitting on there, where the refueling was, and only six people got out. The plane holds many more than that. The first person to get out was manacled to his briefcase, had handcuffs on with his briefcase. The next one got out, and he, too, had a briefcase with handcuffs attached to him, so he couldn't leave it someplace. And the pilot got out, and the pilot was a general! And I thought, great heavenly days, what's going on? Well, these people came up to use the facilities and get a cup of coffee while the plane was being refueled, and I went up to the general, who was flying the plane, I said, "Have you got a ride? Have you got room for a stowaway?" And he said, "Oh, no, no. This is a very secret, urgent flight." And I said, "Thank you, anyway." So I just sat there. It took them a long time in those days to refuel, because they didn't have those big trucks they have nowadays. Maybe an hour, an hour and a half later, he came back to watch the refueling, to be sure it was going right, and he said to me, "Lieutenant, you get on that plane." No, first he said, "Where are you going?" I said, "Well, I'm just AWOL; I'm hitching a ride out. I want to go out to the Near East, and I'd like a ride to Cairo or someplace like that." He said, "Well, you get on, and walk up. Sit in the very front seat and nobody will see you. I have no passengers, practically, because this is a mission going someplace." So, I said, "All right. Thank you very much," and got on the plane, and sat way up at the front. Now, this was North Africa, Algiers--people think of that as being hot, but believe me, at Christmastime, it is really cold and I had a heavy sort of half-overcoat on.

Do you want me to go on with this?

Tullis: --a half-overcoat on that had my caduceus on the outside. But I quietly sat there so these important people, when they got on the plane, would not see me. The plane took off, and after it got up--it was still dark, it was now about three or four in the morning--but after it got up over the Atlas Mountains and over the desert, the temperature changed, and then it began to warm up at that point, because of the heat of the sun. So I got up to take off my overcoat, and, as I took it off, I saw this man lean out, way down the aisle, and spot my caduceus. Pretty soon he came running up and he said, "You're a doctor!" I said, "Yes." He said, "Well, I'm Baird Hastings." And I didn't know the name, which I'm embarrassed to say, but Baird and I joked about this subsequently. He talked to me a while: where was I in medical school? what was I doing? and so on, and I told him about my experiences thus far. I was just a plain lieutenant in an Army field hospital and evacuation hospital, and we chatted maybe ten or fifteen minutes while he was squatting on the floor next to me, and then he went back to his seat, and said nothing more.

About four hours later, we were over a place called Marble Arch, which is an interesting spot. It's just nothing but desert, but a gigantic marble arch which Mussolini built to commemorate the division between Libya and Egypt, which was settled during the time of Mark Antony, which I had not known about, but apparently, in those days, the way they settled the border between Egypt and Libya--this is two thousand years or more ago--was to start a runner, one from Tripoli and one from Cairo, and wherever they met would be the border. So the fastest runner got the most land. Apparently, the Egyptian was a pretty poor runner, because it's further from Tripoli--Libya--than it is Cairo. Anyway, Mussolini wanted to celebrate this event, because in those days Libya was part of Italy, and he built this huge arch, and there's nothing there! It's just total sand, and there's this arch sticking up!

Shortly after we flew over that, we were near the area where Rommel's forces were, and, to make a long story short, we were forced down. The plane landed. It was a little bit damaged in landing. We were right out in the desert, so we knew we were stuck there for a while. They had some pup tents on board, to bunk in, and the general, who was the head pilot of the plane, said he had made radio contact and he knew we would be rescued and everything, but we would have to bunk up. They only had three tents, and we had to choose up sides, and so on, as to who would sleep with whom for the two or three days we'd be there. And we had provisions, so nobody was worried about running out of water, and stuff. Then Dr. Hastings was kind enough to ask me if I would bunk with him, in this little pup tent, two people!

Well, for the first couple of days, we just talked about standard things. But each day he asked me more about, "what is it that your research is pointed towards?" So I got an opportunity to discuss with him my concepts of cell permeability and action exchange in relation to water, and tonicity, and so on. And he said, "Young man, I want you to work in my laboratory on this when the war's over." Well, I thought nothing about it. I thought it was like one of those shipboard friendships that I'd never hear anything more about. Then, that last night, when we knew we were going to be able to get out the next morning because somebody was coming for us, he pulled a watch out of his pocket just before we put the lantern out in the pup tent, and it was an old fashioned pocket watch like my father used to carry. You may never have seen one. It has a front that's glass, and you wind it at the top, and it has a back, a gold back that opened up, that sometimes would say, you know, "From Grandfather," or something, "to Grandson." So he showed me the watch. He said, "What do you think of this watch?" I said, "Well, it's full of mold." He said, "Yes, young man, and that's going to change your career in the practice of medicine." I said, "What do you mean?" He said, "This is the original culture of Fleming's penicillin and Roosevelt wants to teach the Russians how to make penicillin, and I am on a mission going to Russia to teach them how to do deep-vat cultures of penicillin, because most of the casualties from Stalingrad are deaths from infection." Tens of thousands of people were dying of sepsis, and they had nothing with which to treat it. Well, it turned out that this man Hastings, who was professor of biochemistry at Harvard and with whom I was tented, was head of the National Research Council Division of Biochemistry. And when the English, about two years earlier in the war, before America actually had gone to war, became afraid that England was going to be invaded, they wanted to get knowledge of penicillin someplace else, so that it could be developed there, rather than in Germany, and they had come over to the Division of Science in Washington and asked for help in learning how to make penicillin more avidly, because they were growing it just as a culture on top of vats, and you didn't harvest much penicillin that way. This man Hastings had conceived the concept of deep-vat culture, where you culture all the way down, you see, and magnified by a logarithm of three, three logs, the amount you could produce in twenty-four hours. So Hastings was selected to take this knowledge to Stalin for Roosevelt. It was a very secret mission, and one of the people with them was somebody who was from the NIH who spoke both Russian and English, and then there was Baird, and two other back-up people. That's why they were manacled to their briefcases, because of the knowledge that they were taking with them, all the formulae, and everything, for what to do and how to do it, and they didn't want to leave this in some washroom along the roadside, because you tend to forget briefcases. But anyway, that was just one of those episodes, you know.

Later, three years later, two years later, when I was discharged, I was surprised at the time of discharge to have a message there from Dr. Hastings saying, "Please call me in Boston and come to see me." And I came to see him, and I never have left.

Tullis: Oh, it worked!

Tullis: Oh, sure, sure, sure. Yes. After he got to Russia--and he told me this years later; he's now out in La Jolla and retired; he's in his high eighties, almost ninety--he spent three weeks there. He didn't travel by air but by rail, entirely. And they sent him to different areas that still were not invaded and had some industry, and he talked with biochemists and biologists md so on in these different places about how to do it, so they could make their own, and they did. And they started with that vial that he had.

Tullis: All inside a watch.

Tullis: No, no. There's a recent book that's just come out on that. I'll give it to you later this morning; I have it here someplace. The Lactams. It describes it all.

Tullis: I came straight here; still had my uniform on. I got out of the Army, I came straight here!

Tullis: December of 1945; right after the bomb in Japan. They knew they wouldn't need us in Japan, and our hospitals disbanded in southern Germany. I came straight here, and went to work using blood cells to apply the same studies that I had evolved in the Paramecium, you see. So I began to study the permeability of the white blood cell, because that was a single cell that you could work with, like an organism, something very simple. It's the only reason I was interested in blood, was because I wanted the tools, and the tools, the end product, were blood cells. So I studied this in Dr. Hastings' laboratory for three years.

Tullis: He was professor of biochemistry at Harvard.

Tullis: Well--

Tullis: Yes, they were standard for the time. I didn't use anything novel.

Tullis: Well, there are publications on it.

Tullis: Well, we showed that one of the effects of circulating cells in the blood was related to the tonicity of the extra-cellular fluids. If you produce a hypertonicity from any mechanism--I did it with dogs, I did it with humans, and so on. And it can be, in a dog, deprivation of water, for instance. In a human, it can be diabetic ketoacidosis--anything that gives total colligative properties that are increased, results in an outpouring of polymorphonuclear cells. Anything that produces a hypotonic state, such as an excessive sodium diuresis and so on, things of this nature, we found would produce a depression of neutrophiles and an increase in lymphocytes, and this was based on the observations we made, just in vitro.

Tullis: Oh, yes, yes.

Tullis: Yes. Now, the next step, then, was that in the next building at Harvard Medical School, where Dr. Cohn was located. Edwin Cohn's work had been in plasma fractionation, the separation of blood into its component parts, or the separation of plasma into its protein parts. That work was based on Naval support. The U.S. Navy was desirous of getting an oncotic fraction that it could use to treat shock. Its submarines and so on would sometimes be out from base for weeks at a time, so they couldn't keep plasma, or anything of that nature, very well. So they wanted something that would be small, compact, easily transported, light, and not require refrigeration. The concept was that perhaps albumin would do this. So they came to him with a contract to produce albumin, which he originally did from bovine plasma, and then he later did it from human plasma. Being a superb individual, and a brilliant person, he said, "All right. I'll do this work for you on one guarantee." And they said, "What's that?" He said, "I will have total control over all the other parts that I get out of the plasma." He was smart enough to know that the gamma globulin and the fibrinogen and so on would be very much more valuable than the original albumin, which is really only something for use in disasters, and things of that sort. So he indeed did, and developed this huge program, and was made what's called a University Professor, which is different from being a professor in the department of a school, because a University Professor reports not to a dean but only to the president of the university. His budget is totally free, in the sense that he can go out and raise any funds doing what he wants to.

He, then, got together a multi-disciplinary group to work, and he decided in the late 1940s, primarily because General Marshall had then become head of the Red Cross after he retired, and he began to realize there was a little more to blood than just plasma, and he wanted to broaden it into a total blood program of support, and storage, and all of this business, and he went to Baird Hastings in the next building, and said, "Do you know anybody interested in blood cells?" And Baird was kind enough to say, "Yes, I have somebody working here with me, and that's why I was asked to head up a division for cytology in the Department of Physical Chemistry.

Tullis: Yes. And then in 1948 I went with Cohn.

Tullis: That's right, and now, the reason for that, again, relates to what I was doing. We needed blood to find blood cells for these studies I was doing. Well, leukemics have more white blood cells than normal people, and I said to Baird Hastings, "Where can I get a stable of leukemic patients?" "Well," he said, "Shields Warren, who's Chief of Pathology at the Deaconess Hospital, has just come up with something called radioactive phosphorus," because he had helped design the linear accelerator over at the M.I.T., and they were developing many isotopes to work with, so he had P-32 as an isotope to work with in acute leukemia. So he had quite a collection of leukemic patients there. And I came to Shields, and Shields said, "Yes, indeed, I'd like to have you work in the department here." So I split my time between the two departments. I got the raw materials here at the Deaconess and did the work at the Medical School.

Tullis: Yes, yes. They both had a profound influence on me as did Dr. Cohn, too.

Baird Hastings was sort of like a father figure to me in the sense that he was from the Middle West; he had gone to the same high school my brother had gone to, and that sort of thing. He just sort of took me under his wing and helped me get established. And without his help I wouldn't have achieved it.

Shields Warren, with whom I was partially assigned, had just been made the head of the Division of Medicine of the Atomic Energy Commission, because when the bomb was shot off in Hiroshima, Shields headed up the team to go in immediately after the capitulation by the Japanese to assay the biochemical, the pathologic, and the medical changes in survivors. This was because of Shields' early work, if you look in the literature in the 1920s and 1930s, he had studied radiation biologic effects with animals, and so on. He had been interested in what effects radiation had, because the Deaconess Hospital, at that time, had the only supply of radium--from the Curies--the first supply that came over to this country, from Madame Curie, and was being used for treating carcinoma of the cervix, and so on. So there was so much radiation going on as therapy in this hospital, he felt, as Chief of Pathology here, it was his duty to become skilled in the knowledge of how radiation affects tissues biologically. So a lot of his reports have been in that field. Hence, after the atom bomb affair, they picked Shields to head up the medical team to decide, actually, what took place. So he was really essentially never here. The three years that I worked with him my only real contacts with him of a scientific nature, where I would ask for approval for what I was doing and whether he thought the research made sense, would be as I'd drive him to the airport to fly back to Hiroshima or someplace like that. He was really very rarely here. But, he was a very charming, modest man, whom, in later life, I had as a patient and got to know very well, and admired greatly.

Tullis: At the Brigham. No, no, I was not practicing. But, you see, I had originally been trained in medicine, and I wanted to complete my training, get my boards and so on, which I did. So, I worked one or two mornings and two afternoons a week, over at the Brigham, right across the street from the Department of Physical Chemistry where Cohn was and Baird Hastings. That kept me involved in medicine enough so that I was able to get my certification and my boards as a specialist, and that sort of thing. But I was not practicing at that time, no. I didn't.

Tullis: Edwin Cohn trained as a physical chemist in the early 1920's and he was greatly influenced by the Swedish school of chemistry, which was studying protein separation based on charge effects, and, similarly, the ultra-centrifugal approach to separation of proteins on weight characteristics and electrophoretic identification and so on. In the 1930s, he had been asked by George Minot to purify the liver fraction that Minot had found would bring people with pernicious anemia back from the edge of the grave to full life. These people had to eat pounds and pounds of liver every day in order to maintain their blood counts, and he went to Cohn and asked him to use his knowledge of protein chemistry to try to concentrate the fraction, which he did and which was brought out and used by physicians in the 1930s as a liver concentrate, and later on was found, of course, to be the B-12 fraction. But Cohn was working on those separations of a physical system, trying to separate the different proteins until he found one that had the concentrated material.

At the time, as I mentioned a few minutes ago, when the Navy decided it wanted to take plasma, and separate it, and try to get albumin, because, again, albumin, could be packaged in such a way that it would draw on the water of the recipient to attract water from the extra-vascular bed into the blood so you wouldn't have the weight of the water to carry around in the submarine, or tank, or airplane, or wherever. It did prove to be a very stable product, and so on, and so stable that it could be heat-treated and hence was free from hepatitis, and so on.

So they came to Cohn, and Cohn was a very interesting man. He was brilliant, and, at the same time, a very, I won't say, irascible person, but very difficult, as some brilliant people are, to relate to. And I'll never forget--I had no problems relating to him, but I think it's because I was in a different discipline from his. I'll never forget the afternoon that I was asked to be interviewed by Cohn--

[End of side one of tape one; beginning of side two of tape one.]

Baird Hastings apparently had recommended me to Cohn, and Cohn was never one to be bothered with details, and so, he just assigned it to some secretary to set up an appointment. They didn't know how to reach me, so they called the man who was chief of Hematology at the Children's Hospital, Louis K. Diamond, because Lou obviously knew me, since I was doing hematologic research. Lou called me on the phone and said, "You know Edwin Cohn, in the next building?" I said, "I know who he is." He said, "Well, he wants to see you about a personal matter, but before you go to his office today, come by and see me." So I went by, and Lou said, "Jim, I don't know whether he's going to offer you a position, but I want to warn you, the highway to success is littered with the wrecks of people that have hit head-on against Ed Cohn." Because he was such a powerful figure. So I said, "Well, thanks for the tip." Well, I went over to Dr. Cohn's office, and he described this very attractive idea that he wanted to broaden his department from just a plasma fractionation thing to a blood fractionation thing, to design equipment that would separate blood cells, to learn how to stabilize blood cells, to preserve them, totally to characterize them chemically, and so on, and offered me the opportunity to start this. I said, when we got through, "There's just one thing I have to say, Dr. Cohn, and that is I'm trained as a physician. I'm not trained as a scientist or as a Ph.D. physical chemist. And I am going to continue, no matter what I do, to maintain contacts of some type with clinical medicine, because someday that may be what I want to do." And he said, "What does that mean?" And I said, "Well, I go to the Brigham a couple of days a week and see patients in the outpatient clinic, and go on the rounds, and do a little teaching." He said, "Young man, you have to learn, if you're working for somebody, you're working for somebody. You're not working for somebody else. Thank you just the same." I said, "Well, thank you, Dr. Cohn," and left. So I thought that was the end of that. When I got back to Newton, about fifteen minutes later, the phone was ringing. It was Dr. Cohn's secretary. She said, "He wants to see you again." So I turned around, went back, and he said, "All right." He said, "You'll learn one thing, and if nothing else, you'll learn that the man that's paying you the salary is where your loyalty will be. I expect you to be available to me any time of the day or night that I want you." And I said, "Yes, Sir." And I made myself available. Whether traveling abroad with him, or whether working in the laboratory, or what, I was careful to keep any clinical medicine out of my time commitments in such a way I could be available to him. Now, I did do increasing amounts of involvement with clinical medicine, but I'd get to the Brigham or over here at the Deaconess, where I was also doing some clinical practice then by seven in the morning, so I could be in the laboratory by nine in the morning. That way it worked out all right.

Now, Edwin Cohn would have been successful in business, as well as in science. He was a great organizer. He ran a department that was like a corporation would run today. There was a sort of "corporate luncheon" we had every Thursday, a brown-bag luncheon, around a large desk in one of his conference rooms. It would sometimes last an hour, sometimes it would last till six o'clock that night! And everybody would sit there: Dr. Scatchard, from M.I.T.--all of the very famous people in science--Dr. Edsall, from the Department of Biochemistry over at the undergraduate school, Dr. John Enders and people of that type. Dr. Gibson, from Red Cell Studies at the medical school. People whose names would have meaning to you. We would sit there and just interact in an interdisciplinary fashion, and it really was excellent! I'd never seen anything like it before or since. Again, we had Cohn, because of what he had done in regard to plasma fractionation, he had unlimited research funds available to him; the Rockefeller Fund said they would support whatever he wanted to do. You know, when he wanted to hire somebody like me, it was just a question of hiring, you know. No clearance, no committees, nothing. Just boom! And he would make these empiric decisions free of administrative control. It worked very well, and it led to a dissemination of people who had been partly touched by him in a good sense, scientifically, who then ended up some in industry, some in universities, some in governmental positions, all over the world. It was just a procession of people through that department: visitors, students, Fellows, et cetera.

Tullis: Yes, yes. Again, you'd have to put yourself in the era that this took place, because the same kinds of things can't take place today because of regulatory controls of one kind or another. As an example--well, let me give you an example. A little bit peripheral to that, the Red Cross, under General Marshall, who had become head of Red Cross, hadn't made up his mind whether it wanted to stay in the field of blood collection, which it had done just for the war--

Tullis: Late 1940s. They hadn't decided whether they wanted to continue in that field, although there was quite an attraction to do so, because it was a public image for the Red Cross. But just collecting the blood and sticking it in a refrigerator didn't have much meaning. Marshall and Cohn developed a very close friendship in Washington because of a very exclusive club, intellectual group, that they both belonged to in Washington. And Marshall would come up here and talk, and he decided that the Red Cross should put a little bit of its public money into support of research. One of the first things I began to work on there in the department was platelets, because this is one of the cells that was most easily damaged in trying to separate blood. Nobody had even been able to isolate or concentrate platelets, and so on. I got a call one afternoon from Washington. Someone said, "Are you really going to do some work on platelets?" And I said, "Yes." He said, "Well, we'll give you some money," and about a week later I got a check for $50,000--just said, "American Red Cross; $50,000"--nothing! No responsibility, no one to report to, nobody knew who I was. I felt like a thief! And I called up and said, "I don't even want to deposit this in the bank, because I feel responsible for it." They said, "No, it's for you to use in platelet research." And I did. I used it in platelet research, and we published several papers in this area. But there was not tight regulatory control. There were so few people working in science, and, in the Washington arena--because this was just before Korea, you see--they realized that blood and the products of blood were essential for the proper management of any kind of casualties, and that people should know more about these things. So, they wanted to stimulate the research, but they had nowhere to give the money. The NIH in those days was a small institution, very small. So I did this, but, you know, they might have given it to somebody else and nobody would have known the difference. But that's the era I'm speaking of. I don't mean it was an evil era at all. It was a very dedicated era, because there were very few people working in basic science, and those that were had unlimited opportunity because they could just decide what they wanted to do, and there was plenty of support. One didn't have to fight and struggle and compete for support. So that this got started that way.

Now, to go back to your question again. I'm sorry; I got a little bit diverted from how--

Tullis: Yes, that's right. Government agencies.

Tullis: Well, this was difficult to do, but this is again one of the things that Cohn sensed the need for, and so he set up not only these weekly conferences in our department, but he also set up an annual meeting, a scientific meeting, which he had here, and he then incorporated something called the Protein Foundation, and the Protein Foundation sponsored these annual meetings. They specifically were directed both to government and to industry and to academia as a common forum where the three could get together without bringing their prior prejudices.

Tullis: I believe it was 1950. The reason for the Protein Foundation is again interesting to those of you today who live in the era of doctors patenting their inventions. Cohn had gone to Harvard University when he first was working in the plasma field. He said, "Do you want me to patent these things?" They said, no, it was contrary to University policy; we don't profit from patents. But he and the Board of Governors, or the Overseers, as they're called at Harvard, finally decided the smart thing to do would be to patent these products for purposes of quality control. Only for purposes of quality control. So everything was patented, and everybody in Cohn's department then had to agree to do the same thing. For instance, I had four patents that I took out on different equipment for separating blood into different parts, and so on. Some of this is used today by a number of manufacturers. But all of those patents I turned over to the University for one dollar. Then they turned them over to the Protein Foundation, which was just a holding body in Dr. Cohn's department to elevate standards and insist on quality control. Then any manufacturer--and there were at that time seven manufacturers of albumin, and so on, pharmaceutical firms: Amour, Smith Kline, French, all of them, you know, Merck, et cetera. They all had plasma fractionation plants, headed up by people who had trained here with Cohn, scientifically headed up. Then the Protein Foundation, holding the patent, would license these companies, and, before anything could be distributed in interstate control, we had to certify that it was okay. Well, this led to much higher quality products than ever would have been achieved in that era. Because in that era, the F.D.A. had no power whatsoever. I mean, it was essentially powerless--all it checked on were horse vaccines and a few things like that. In fact, the F.D.A. was not even involved. It was something called Bureau of Biologic Standards which was part of the NIH. The Bureau of Biologics, when they wrote the existing regulations for the production, use, and all of this, and sales of albumin, gamma globulin, all of these products, they came up and let us write the standards because we had the patent, and were licensing these people. They just took them verbatim, and used those, and published them as the standards. We even had higher standards than that, because they could not, at that time, insist on human proof of safety. For example, with albumin, every lot of albumin that was sold in the 1950s until the patents ran out sometime in the 1960s, every lot of albumin we would test out here, and I would bring it over, and find somebody that needed albumin, where we could check their temperature, and their pulse, and their blood pressure and be sure there were no allergic reactions, and so on, no febrile reactions, no urticaria1 reactions, anything of that sort. Because the only standards the manufacturers were required to use was a rabbit test, and rabbits are a little different from humans. But the NIH had no such standards. They do now. But they didn't, you see, at that time. So, I think these patents were used very wisely. But that's what the Protein Foundation was, just a holding body for those patents. It had no money. Everybody misinterpreted it and thought it was a wealthy thing to support research, which it wasn't at all. It was just the use of patents for quality control.

But we had--and getting back to your original question of the interaction between government, university, and so on: Cohn was really quite dedicated to the importance of bringing these diverse bodies together in such a way that they could function, and talk the same language. He felt they could never do it if they did it in Washington, because the federal people would be inhibited for fear they'd say something that would be misinterpreted by a Congressman. They could never do it in the university under ordinary circumstances because the university was so, sort of, snide, it wouldn't accept people who were in industry. And industry wouldn't do it because of patent problems. So all of these things were kept separate. So our annual meetings were held at the Hasty Pudding Club over in Cambridge, which is where the shows are held by the undergraduate students every year. At the Hasty Pudding Club, every November, we would have a scientific meeting, and one-third of the audience would be government, one-third of the audience would be university, and one-third commercial, and we really had a good total exchange of knowledge without barriers.

Tullis: Yes.

Tullis: Largely because of the need for him to relate to the Navy, for example, as the source of his money for his research, and all the other bodies around, to justify it.

Tullis: He was the driving force. Absolutely! No question about it. He was, as I said, he would have been a good president of Merck, or something of that sort, because he was an organizer. He knew how to delegate authority. He gave people responsibility and as long as they did a good job, he left them alone. But if they did a bad job, boy, their head came off right at the shoulders! He was a very strong personality, totally without a balance wheel. He was the Type A personality in its most epitomized form, just--he didn't know what the clock was.

One time I was in Europe with him. At about two o'clock in the morning the telephone rang. He said, "I've got the greatest idea." He didn't start with hello, or anything of that sort: "I've got the greatest idea." "Yes, Dr. Cohn." So, I said, "I'll get my pants on and be right over." And he started telling me what he was thinking about at that moment. He was this kind of a person. Then, he might not come to work the next day till four in the afternoon, because he slept when he was exhausted and then he worked when his mind was working. He was a very, very strong person in that respect.

Tullis: I've been interested in this for many years, and I don't know the answer to your question. But one of the things that I have thought about on many occasions is why, if you look back through history, there have been these bursts of original knowledge in strange places with no apparent reason. They'll flower in a period of fifty years, and then die out. One of those, I think the best example, is Padua. Now, Padua was a little university in Italy--it's maybe forty miles or so south of Venice--that in a short period of time, it had, I believe it was, Fabricius there in anatomy. It had strong people in the then developing concepts of body fluids. It had, as a summer student only, the man Harvey who later discovered the circulation. It had another man, Vesalius, who was a great anatomist and, if you will, the first physiologist. Just a vast amount of knowledge evolved from that little insignificant university in this one period of time, and then it just disappeared. I've gone over there in recent years, and sat in the amphitheater there, just sat, and thought, "Well, now, what was there here to get all this knowledge together?" I think, probably the most important thing was, first, it was multi-disciplinary, and, secondly, there was good, relaxed, free communications between people. For example, now, if you look at Harvey's publication, De Motu Cordis, and his claim for the discovery of this knowledge of circulation, he states that one of the things that made him think about it was the valves in the forearm and he shows a forearm with a tourniquet on it, making the valves stand out. If you go back and look at a publication from Fabricius, one of the other people in this group, you'll find that Harvey's woodcut is of the opposite arm from the one that was published about ten or fifteen years earlier, which, obviously, he got his knowledge from, you see, and took it back to England. And it was just that the woodcut produced it from the other side when they printed it. It just means, you see, that Harvey was thinking about something else, so that when this man showed the veins, it meant something to him, because of a different disciplinary background than it meant to the man who was looking at it purely anatomically.

I think that this is--and again, this is where I think Cohn's department flourished, was the same way, that biochemists were talking with mathematicians who were talking with practicing internists who were talking with cell biologists. You know, everybody was looking at it with a different perspective, whatever the problem of the day was.

Tullis: --that had medical implications--

Tullis: Yes, yes, I do. I think that has a lot to do with it, but I think you have to have a multi-disciplinary approach in order to plant the seed, you see, that will really go beyond the barriers of just what one person thinks, and you have to have freedom of communication.

Tullis: Well, it's interesting, you know, all of those are available. Every one of those lunches was taped and transcribed for a period of perhaps eight years or more. I have most of the volumes either here or at home, and I have never looked at them--but I could some day--but it would go--from one day it would be a discussion of the sedimentation of blood. Because, you see, right at this time we had fibrinogen available, and we found that fibrinogen accelerated the sedimentation of cells, and there was a graduate student from--what's the town in Sweden right north of the capital--

Tullis: Uppsala. There was a graduate student from Uppsala, who was partially supported by the company that later brought dextran out, who was there working, because he wanted to understand fractionation principles. He said, "Oh, but dextran will do this, too." So we got into a whole thing, and I published a chapter in a book on the relationship of molecular size, shape and charge to the precipitation of, the lining-up and rouleau of red cells. So something would come up that way and different people with different backgrounds would make great contributions on it. The next time we might talk about surfaces, and why platelets were destroyed by rough surfaces like anodized aluminum, but not by stainless steel; why plastics were non-wettable; why non-wettable surfaces didn't degrade lipoproteins, whereas wettable ones would. The next time we might talk on equipment or how one could theoretically separate blood atraumatically, because this was what one of our hang-ups was, unless you get blood in its true state in nature, there's no way properly to study the proteins or cells, because they're damaged, and if you collect it in a media with a chelate, you've already damaged it, you see! So we were interested in native blood in its native state in order to do studies that would have meaning. That was the driving force. But blood is, after all, a pretty diverse liquid, so we got into all aspects of it, from gas exchange to everything else.

Tullis: Not with hematology, no. I'm sure it did in other disciplines, but not with hematology.

Tullis: The Cosmos Club. I know Cohn would go down about once a month to meetings with other scientists.

Tullis: Many others. I don't remember who they were.

Tullis: I can't give you the details of that except that I know that's how they became so friendly.

Tullis: Yes. [William B.] Castle and [George R.] Minot.

Tullis: Murphy. Yes.

Tullis: Murphy? No. Minot and Castle and Murphy had their theater of operations, shall we say, at the Thorndike Laboratories at the Boston City Hospital. They were heavily involved in red cell work because of their original studies on pernicious anemia. They were so heavily involved in everything related to the red cell, and the development of the standards there, that they didn't participate in any of Dr. Cohn's work. They had their own separate interests.

Tullis: Yes, yes.

Tullis: Even though Cohn had done the liver fractionation for him, there was no interaction later on, because Dr. Minot was getting elderly at that time and he himself was not involved, and Dr. Castle, who was running the laboratory, a man who was many years younger, was Professor of Medicine running a whole department of medicine there, and was deeply involved in that, and kept that as a separate activity. Moreover, the group at the Thorndike laboratories was more interested in the diseases of the blood; Cohn was more interested in the nature of blood as a biologic fluid. It was really quite an intellectual separation. Not that they didn't like each other or respect each other, or anything of that sort, it was just they were in different fields. Dr. [T.H.] Ham was, of course, down with Dr. Castle.

Now Murphy was purely a clinical practitioner of medicine. He never was a researcher nor was he interested in research, really. I think Dr. Minot, out of kindness, insisted that he be on the Nobel Laureate award, because he used one of Murphy's patients, and Murphy had given the injection to that patient. It was one of the first patients that they treated, and Murphy was here at the Brigham, and not down at the City Hospital, but he contributed some of the patients to Minot's original studies.

Tullis: Thinking back on it, it was strange, I guess, but I was so interested in what I was doing that it little by little began to get reoriented toward diseases. As I got more and more into the physiology of separating platelets--I began to study the platelet diseases, and got into studies of remostasis as I separated the clotting proteins, with Dr. Cohn's help, and we made the first concentrated prothrombin and then different things of that sort: an accelerator globulin, and Factor VIII, for hemophilia, the first fibrinogen, and so on. This got me more and more into the disease phase, so I didn't lose my interest at all in clinical medicine. As I told you earlier, I insisted from the beginning I would maintain that, and then in 1964, I was asked to come over here to the Deaconess Hospital and head up a new department in medicine and it worked out very well.

Tullis: Characterize it in terms of what it was, or what?

Tullis: Yes, that's right.

Tullis: I don't think I can make much of a contribution in that regard. One can see this, I think, more in Japan than in the United States, because the early Japanese scientists and physicians had all been trained in German schools. German schools were where morphology reached its height. They went back to Japan, and all they were interested in was microscopic appearance of blood cells and things of that sort. They were really hung up on this, and then, after World War II, with the American influence coming in, more of the physiologic approach to the analysis and pathologic approach to pathophysiology of cells, and that sort of thing. Then they totally changed and now they're leaders in molecular biology and things of this sort. But they had to undergo this, I think, more dramatically than you saw in this country. I think the reason that I published on cell size, shape morphology and things of this sort was in part the appointment that Cohn first gave to me. He said, "I want you to be a Special Associate in Cytology to the Department of Physical Chemistry." Well, you know, here I was, I was a physician. I was none of those things, but I had felt an obligation to give real attention to cytology. So I did. I studied the blood cells, and the shapes, and all this sort of business under different pathologic conditions. But, little by little, as I'm sure you saw, I got more and more into the clinical aspects of diseases of blood, rather than just the chemical approach to it.

Tullis: Yes. As a specialist in cytology in the physical chemistry lab, I first studied surfaces to determine which surfaces would best support normal morphologic appearance of cells, and then, later, biochemical integrity of the cells. Next, I got into studies on the kinds of media that would support viable cells, ex vivo, in various storage states. Next from this, I got into the long-term storage of red blood cells, because the equipment, which by then we--Dr. Cohn and I--had designed, and which I had then named, although he was deceased, I named it the Cohn Fractionator in honor of him--that work had to do with equipment that made it possible to put--well, let me give you the story--put glycerol in. Let me give you an interesting little aside on that.

Tullis: In 1951, Dr. Cohn and I had designed a prototype of a separating machine which a lot of people degradingly referred to as a "washing machine," where we could collect blood over an ion exchange column to decalcify it, so we wouldn't be putting a chelate in, and directly into equipment that, as the blood flowed out of the body, would separate the plasma. One of the projects that Dr. Cohn suggested theoretically in one of the luncheon meetings we should design was a way of collecting blood so that it would not be damaged in the collection. Up until this period of time, one collected blood through a rubber tube into a citrate solution in a warm bottle and essentially everything that was labile was already denatured by the time one got it separated to study it in the laboratory. So we started with simple concepts of pH control, temperature control, et cetera, and he said, "Now, we'll have to design some way to do this." So the first thing we did was have blood flow over a resin column that decalcified it, so that one did not have to add an anticoagulant solution. Then it flowed into a bowl where we would siliconize the inside of the glass bowl to make it non-wettable to protect the lipoproteins and platelets which, by then, I had found out what nature to make it--glass--and with control over the temperature, and so on, and separate the cells from the plasma as it flowed through, eventually ending up with a concentrate of white cells and a concentrate of platelets and a concentrate of red cells and then cell-free plasma. All this could be done with the red cells flowing back into the body. It sounds easy, but, believe me, there were many years of hard biomechanical engineering that went into this.

I want to pause to give a word of grateful thanks to a Mr. Robert Tinch, a superb young black scientist who came to work with me in 1947 as a summer graduate student from M.I.T. and who just died in October of 1984. He worked with me his entire scientific career, and he was a superb contributor to this early mechanical equipment development.

Anyway, we had gotten this to the state of making the first prototype in our own laboratory shop over there at the Department of Physical Chemistry across the street in the Medical School, and Dr. Cohn said, "Well, we've got to show this someplace." He was a great showman. He believed in demonstrations, and so on. So he said, "There's a meeting"--and it was either the first or second meeting of the International Society of Blood Transfusions--"and it's going to be in Lisbon. Let's go show the equipment." Later, I may tell you of the errors that occurred in the show that I had to put on. But, anyway, at the program, the day that we were to put our demonstration on for all of the congresses, the paper right before us was by Audrey Smith. Now, Audrey Smith was a young woman biologist at Mill Hill, in England, which was their state supported medical research laboratory just south of London.

Right after World War II, the cattle industry was essentially wiped out, in England, because they'd had to eat all their cows, and so on, during the war because they didn't have enough provisions to feed them. So they wanted to re-stock their cattle industry with good, genetically strong bulls, and the cost of shipping a bull from Australia to England was rather prohibitive. So they began experimenting with sending testicular biopsy specimens of semen of Australian bulls to England. And Audrey Smith had suggested, on the basis of thinking about why her radiator didn't freeze in her Ford car in the winter in London, that maybe ethylene glycol or propylene glycol or even glycerol would keep the sperm from freezing. So she had had them collect some needle biopsy specimens of the bulls in Australia, put them in glycerol, freeze them, and send them to England. She had found that when she warmed the specimen up, the sperm wiggled away and seemed to be perfectly normal. She also made the observation that some of the red cells of the bull that had contaminated the biopsy specimen weren't lysed when it was frozen. Well, we all knew if you froze blood, the red cells busted wide open from the presumed hypertonic effects that took place when the ice was melting, you see. Yet here were some red cells. So she had suggested that they just take a tube of blood and put glycerol in it, and freeze it, and thaw it, and they looked at it morphologically, and the cells weren't broken.

So she came and put on a demonstration of this right after our demonstration of how to separate blood cells. Well, that night, Dr. Cohn suggested he and I have dinner together. He had--again, showing crossing disciplinary lines--the vision to say, "Jim, that will not work with blood, because when you put the red blood cells back into an isotonic media like blood, there'll be a rush of water into the cell to equalize the glycerol pressure, because the red cell is more permeable to water than it is to glycerol. Water will come in faster than glycerol will go out. So, he said, "It's a shame this will never be applicable to human blood. I said, "Well, let's talk about this." So we sat there, talking about could we not devise a system whereby one could put a nonpermeable ion--and this goes back to my original work, you see--put a nonpermeable ion, like lactate or something of this sort, in the media, that would hold the water outside while washing the glycerol out.

Do you understand the science of this?

So here we were. We had just demonstrated this machine that day. So he said, "I think we could redesign this bowl, so you can wash the red cells at the same time in the same equipment." And he actually drew it on the tablecloth, and he said, "Now, go home and do it!" In those days, I was very much the subservient, way at the bottom of the totem pole, the youngest member of his department. I had to do what he said. So I had to stop all of my other work for a period of about four years and work on the extraction of glycerol from red blood cells, and this made it possible for us to develop a system for working with large volumes of blood.

Now, you could do this, even before we did it, in a test tube, by a slow process of dialysis, but you couldn't do it with a pint of blood for transfusion purposes. So, one of the other things I happened to be doing at the time was I served on the Defense Department's Medical Advisory Council. Now, the reason for that was that the chief of surgery in the Roosevelt Unit in World War II, was made the Assistant Secretary of Defense for Health and Medicine after the war, Dr. Frank Berry, a thoracic surgeon in New York City, at the Roosevelt, also at Bellevue and a couple other hospitals. Frank asked me to be on his advisory committee--why, I don't know; just because he wanted to, I guess. So one day on one of our trips, I mentioned to him what I was doing with frozen blood, and I said, "Frank, this has real implications for the navy and army," and so on. He said, "You're right." He said, "Let's go talk about it." So he took me by the arm and we went over-and talked with the Secretary of the Navy, who sent us to the man in charge of their research, and they said, all right, they would support research to see if this could be made clinically useful.

Tullis: That was 1956.

Tullis: They would support the research to see if it could be made clinically useful if I would promise to be the consultant to see that it worked and it didn't just bog down as an expensive exercise in futility. So they got organized about two years later, and then along about 1957 or 1958 they sent Mary Sprowl up here to spend the summer working with me. And then we went over to the Chelsea Naval Hospital here in Boston, and established the first laboratory for the long-term preservation of red cells. That's where it all began, with the Navy.

So that was an example of where cytology sort of was a diversionary thing. But it brought together lots of other things I had been involved in in the past.

That equipment, then, was later used for many other biologic applications, such as plateletphoresis, and leukocytophoresis, and so on.

Tullis: Well, the work I was interested in was not that. The work I was interested in was coagulation and platelets. I was interested in platelets because of their relationship to hemostasis and in clotting, because I was privileged to have had access to the first clotting protein concentrates to study. I've devoted my entire life since then to these, once I was over here at the Deaconess and independent, doing my own things. Because Dr. Cohn's laboratory was no longer officially funded when he died, that was the problem: what to do with the team he had brought together. The University considered it, and then declined to sponsor it as an institute--Harvard never had sponsored institutes, unlike Madison, Wisconsin, with its Alumni Research Foundation. Harvard didn't want independent--and they still don't want--independent institutes with outside financing operating directly under the umbrella of the university. So what they said was, "It's nice to have that group together. You take the Protein Foundation, because it's already created, it already exists, and use that as a holding mechanism for going out and getting grants and contracts. And you can have space in the University, but your appointments will all have to go through departments of the University." No longer will it be independent, you see, and this was smart, because it maintained the quality of the appointments. My appointment, for example, reverted to the Department of Medicine, and my promotions and everything had to go through the Harvard Department of Medicine, which is where it belonged. Biochemists had to go back through biochemistry, and so on. So once Dr. Cohn died, which was tragic, because he could have lived many years longer if he had been properly diagnosed, once he died, the group stayed together for a transition period of a few years. Then little by little we got back into our own original departments.

Tullis: Yes, 1953 or 1954, I think it was '53. It was at lunch; he had a C.V.A. right at lunch. He just suddenly slumped down, dropped his spoon, and he was dead in an hour of a cerebral hemorrhage.

Tullis: Yes, because what was called the Protein Foundation continued to operate, you see, and it supported my research, both there and then later when I was over here in my own department. We changed the name of it, because everybody thought as Protein Foundation, that we had money to give away instead of to get! So we changed the name of it; it's now the Center for Blood Research. For a very short period, it was called the Blood Research Institute, and then, eventually, the Center for Blood Research. It's been there ever since then, and it's a superb, very efficient, very effective, high quality institute, and one of my patients--well, this is how, again, things cross-fertilize.

A woman came along, was hospitalized by a physician at this hospital, the Deaconess, with thrombocythemia, which is a malignant disease of the platelets, that resembles polycythemia in the red cells, or leukemia in the white cells, but it's a disease that's compatible with many years of life. The problem is they have too many platelets, rather than too few, but instead of clotting, they bleed--almost always, occasionally one of them will clot. The reason they bleed is that most of the people with this disorder have non-functioning platelets, even though they have lots of them. So they present with bleeding episodes. Well, there was a very wealthy woman with the name of [omitted]. She was a widow, had no heirs, nothing else, and she kept bleeding, and being hospitalized all over the United States. They were trying to find out what was the matter--and finally, they made the diagnosis. And she would need platelets to support her. Well, I had been working on the separation of platelets in such a way that they can be used for transfusion purposes, and the storage of platelets. So I made these platelets available to her. This woman was so grateful that she used to call up regularly. I remember one time, changing planes in Chicago and getting a message that she was on the phone. She said, "I'm filling out my tax return. Now, I must give you some money for your research," which was just very helpful, to say the least, because this was now getting into the era where money was in short supply to support laboratories, and she would buy equipment and do all that sort of thing. Then, before she died, she asked me to come out to her home one last time, just to talk, which I did, and she said that she was going to leave instructions in her will, which the trustees would not have to follow but they probably would follow, and she divided her estate so that about a quarter of it came to the Deaconess Hospital and a quarter of it would go to my original research laboratories, which was the Center for Blood Research. The Center for Blood Research needed that money. They bought a building right up the street here on Francis Street, across from the Brigham, and established new laboratories there, and they have had a very successful laboratory ever since. Now it's all NIH-supported, because it's good, high-quality research, but the buildings and all of that, and all the overhead and everything, was originally supported at a critical time by this money.

Tullis: That's right. Because they were available, you see, for the first time, for people to study. How did they function? How did they enter into clotting? How did they enter into work on sealing off blood vessels? And things of this sort. Because, you know, platelets were just one of these tiny little things you looked at morphologically, but you never had your hands on them, never had enough of them to work with them.

Tullis: I think so. As an example of that, one of the diseases I was interested in, published on, is idiopathic thrombocytopenic purpura. We devised a test to make the diagnosis, and so on. Well, nobody could get enough platelets from a person with idiopathic throbmocytopenic purpura--because they have so few platelets--to do any chemical studies on them. And I wanted to analyze them. So we took this equipment of Cohn's, which permitted continuous flow, and brought from the Deaconess here across the street to my laboratory right up on the next floor over this office, brought patients over here that had ITP, and would let them be on this machine for several hours at a time, perfusing their entire blood volume through there. And even though they had a tiny platelet count, we would end up with enough platelets at the end of several hours, to do chemical studies on them. Then we found out that the sertonin was absent, the histamine was low, catecolamines were normal, and so on. Well, these were studies that one couldn't have done without having that other equipment simultaneously available.

Tullis: Well, I'm not a hawk. On the other hand, I feel there's nothing bad that doesn't have a little bit of good in it. There's no question but what medicine, in particular, has benefited from some of the tragedies of war, because under wartime conditions, you'll find people will work together who ordinarily are not very companionable.

One of the questions you asked me earlier had to do with the interaction between government, for instance, and the university, and so on. There's a book that's just recently come out--I think it's called Lactams or something. I have a copy of it sitting here can give it to you later on. It deals with the manner in which, under wartime conditions, penicillin was able to be developed by cooperation between the federal government, which had a need for it and the industrial concerns, which ordinarily would be so concerned about patent rights that they wouldn't disclose what they were working on. They were willing to throw all of this into a pool, which they decided they would settle after the war as to who got how much, and what percent, and all of this, and put all of their best scientists together to work on the same project at the same time. That's a type of cooperation you don't get in peacetime conditions, because people's parochial interests override their national interests.

The role during peacetime that I played in the Department of Defense, obviously, was that of the policy of Berry, the man who was the Assistant Secretary of Defense and the one who had asked me to be a member of his committee. His principal concern had been the misuse of physicians during wartime conditions, wherein they would be placed into administrative positions where they were not using the talents that they had been trained to use. They would be assigned to collecting statistics on something that had no relevant value, just to get them out of the way, and that kind of thing. So our committee, for example, one of the things we came up with was a plan, which we were able to put through Congress--that was later called the Berry Plan, wherein during peacetime, physicians who were drafted into the armed forces would have a prior opportunity through lottery to determine whether they would go in immediately after medical school, before their internship, or after their internship and before their residency, or after their residency, when they're Board qualified. They could pick the first, second, third, fourth or fifth year to serve their two years of obligated service, because there was a peacetime draft of physicians, which you may remember. That, then, was a concern of ours, after we got this Berry Plan adopted: to be sure it was applied properly. So that our meetings--we met every other month, six times a year--always were held in an armed forces installation somewhere where we could check on what was actually going on. And it was a small committee; there were about half a dozen of us on the committee, plus a couple of people to assist us. We would meet in Panama, Alaska, Nevada, wherever there was either an Army, Navy or Air Force base to check on, we would go out and actually talk with the soldiers, and we'd talk with the
physicians: were they practicing medicine, or were they counting beads, or buttons. I think it had a salutary effect. We had very little to do with the actual policy decisions about the way medicine was practiced, because there are Surgeons General in the Army, Navy and Air Force who are responsible for that. Our policy was more global and more in terms of total manpower use, and that type thing, but we could, from time to time, bring new concepts in, like the frozen blood one that I mentioned to you.

Tullis: No question of it. And immunizations! Never has there been an easier way to study the effects of vaccines than if you have a control body of a million soldiers, you know, or ten million, as it was in World War II. These, you give this amount of vaccine, these, you give that, and we'll see who gets sick and who doesn't get sick, and that sort of thing. So it's a superb study in public health. I'm not in public health so I don't have a basic knowledge of it, but it's good from that standpoint.

Tullis: That's right. That's when I was first beginning to practice, you see.

Tullis: No, not a bit. And I was able to keep it, if you will, subservient to my basic science background, which I was determined to carry on.

Tullis: That's right, which was a small group of independent physicians.

Tullis: That's right. It was the physicians who were not part of either the Lahey Clinic, which was also using the Deaconess, or the Joslin Clinic, which was also using the Deaconess. But then, in 1963, I think it was, they--the trustees of the hospital--wanted to change the character of the hospital, and make it a university-affiliated hospital. So they got the staff to vote to have new by-laws, and to organize a set of traditional departments. I was still working full-time, salary-wise and everything else, at the Center for Blood Research. It was then the Protein Foundation, but later the Center for Blood Research.

Tullis: No, it really didn't, because what I did was bring back the part of the work at the Center for Blood Research that was under my personal supervision, bring it over to the Deaconess, and set it up in departmental laboratories. The financial support continued to come through CBR: my grant support, contracts, all of that business. I operated it as a separate division of the Department of Medicine here. Now, I continued that way until I retired in 1982, and the present chief has it all as part of his Department of Medicine. It's just administratively easier, that's all.

Tullis: Primarily outside, not physicians. The Fellows were all physicians. The Hematology Fellows were all physicians who were, in part, getting their training, and they would divide their time between clinical hematology and research hematology, a year of each. But the persons who worked full time with me, like Francis Chao, who is a Ph.D., M.D.; Dr. Kenny is a Ph.D., she's still with me, these people are basic scientists.

Tullis: I think so. I didn't do it with intent. But in talking with people and meeting people now, at meetings, who have trained with me, I see that they tend, some of them do, to stay in basic work.

Tullis: That's right. I think there's no question of that. Plus the fact that blood is such a diverse fluid. Well, you remember that--I don't know whether you're an opera buff, but Goethe's Faust, you remember Dr. Faustus, says, "Blut ist ein ganz besondere zast." It's a very strange liquid; it's got everything in it! It, therefore, has to interact with so many disciplines of science, you see.

Tullis: Yes, I think so. Let's take some of the clotting work, for example. I was interested in having a prothrombin complex that would be stable after it was isolated from the blood. Prothrombin complex
consists of four closely allied proteins: Factor 11, which is prothrombin, Factor VII, which is SPCA, Factor IX, which is Christmas factor, and Factor X, which is the so-called Stuart Prower factor. These four factors influence both the intrinsic and extrinsic clotting system. If they're deficient, as is the case if one takes coumerin, the so-called "sweet clover disease" of cattle, called warfarin. There are certain disease states where there is one or more of these four proteins consumed; more would result in bleeding diathasis. So I was interested in having some of prothrombin-complex to study, and I asked Marshall Melin, who was a Ph.D. who was working with me in the Center for Blood Research, if he would attempt to do this chromatographically. Chromatography was a new concept at that time, a way of gently isolating proteins without damaging them. He devised a system, a flowing system, of removing the prothrombin from plasma, because we had still the resin way of collecting blood, which didn't have chelate in it. You couldn't do chromatographic techniques in the presence of citrate, you see, or oxylate, things of that sort--

Tullis: About 1960. There was another stumbling block. At this point, hepatitis had begun to rise on the horizon, and blood transfusions that previously had been present in World War II had been whole plasma, as opposed to albumin, but people began to be concerned about it. So I knew that any prothrombin fraction made from pooled plasma would tend to have hepatitis in it, because you were making it from a large pool. So I went to the NIH and told them the problem, told them what I wanted to do, and they supported the concept of plasmaphoresis. Now, that was a brand-new term, which we developed in our laboratory, because we had this equipment where we could hook a person up, run his blood through, and give back everything except what we kept. If you're only keeping the plasma, you can take large amounts out without harming the individual, you see, whereas if you take the whole blood out, you can only do it maybe four times a year, something of that sort. So I said I would be willing to identify some hepatitis-free donors that we could certify were free of hepatitis, that it would be costly, because we'd have to go through a pedigree one-year testing period, and find these people. They said, "All right, do it." Then I had to find some stable donors that were not gay blades and I went to the police department, which was then very much in the doghouse in the City of Boston because the Superintendent of Police had been found with his hand in the cookie jar and they were trying to improve their image, and I said, "Would you like to select some of your best stable officers from the community, and let them be blood donors for a plasmaphoresis program." Well, they'd never heard of that, nobody else had, so I explained what it amounted to, and we took a hundred volunteer policemen, said we wouldn't pay them for anything except for the time that they were actually out of work--just for their time on their days off, when they'd have to come to the laboratory. From that, we honed it down to forty people--eliminated some on the basis of blood tests, and other things, that made them look like they'd been sick--took forty of them, then, and took a unit of their blood, and gave it to voluntary recipients, and followed the recipients for a year to see whether they developed hepatitis, and they didn't. So we knew that their blood as of that time was free of hepatitis. Because one didn't have tests, then, like the antibody tests and the radioactive tests now available that show you who was exposed, and so on. Then, those forty people who passed this screening, I asked them to promise they would never donate blood, or receive blood or anything outside of our program unless it was an emergency situation. These were stable, middle-aged men with families and everything---we knew they weren't, you know, gays, if you will--and they entered into this plasmaphoresis program, and I still have access to three of them today. Now this was 1960, so that's twenty-five years ago. So, we took their plasma, we would plasmaphoresis these policemen every week. Each had a day off, and so we'd do it on his day off. And we took their plasma, and then Melin fractionated with chromatographic techniques and produced a concentrate of this prothrombin material. Then, I was able to use that here for the treatment of people with Christmas disease--including the boy Christmas, the first one that ever had it; he came down from Toronto for his injection--and also to treat people with liver disease, or people who were going to surgery when they were on the coumarin and had to be reverted to normal clotting for an emergency period, that sort of thing.

So this was a, if you will, cross-fertilization, where some of these basic ideas you were asking about came into direct application to clinical medicine. And it's been in the clotting field and hemostasis that my interests have been, primarily, ever since.

Tullis: Late 1950s through the 1960s, we were primarily working on the fractionation of the globulins that were present in people with immune thrombocytopenic purpura, primarily the autoimmune ones, and trying to identify what the proteins were, and also in the immune neutropenia, what the globulins were: were they gamma, or were they alpha, and so on. It was later on that I got into platelet work that's of much greater interest to me. That I can come to later on, if you're interested.

Tullis: The hospital was re-organized.

Tullis: Oh, very much.

Tullis: Well, at that time, for the first time, we had federal funding to support Fellows. This was a tremendous asset, because, if a young man went through his basic internal medicine in the program here at the Department of Medicine, and at the end of three years qualified as an internist, if he got the spark of hematology--and a lot of them did because it was one of the interests; we obviously taught a lot of hematology--it was easy. Anybody that wanted to do it, I knew we could fund his salary as a Fellow, you see, without going to hospital funds or hard money. And it was very easy to get a federal grant specific for the Fellows. We even had grants that we could use from the American Cancer Society and other places as faculty development grants. So if I identified somebody who I felt had a real future, I could get him a grant that would cover up to five years after his basic training was completed, while he was further developing as a young person in the department and in the field, and he could do research, because his time would be supported. He would also have to do some practice in order to remain au courant in medicine, but it wouldn't be his source of support, so he would be able to devote lots of time to research. So, I think, primarily, financial support was the thing I would say--as I look back on it--made the biggest impact on our ability to train large numbers of people. So the persons who had interest in and knowledge of hematology grew along with me. Just, from essentially nobody to--as Barry Coller told you--in ten or twenty years scores of hematologists! It was interesting that many of the chairmen of the departments of medicine in the medical schools and hospitals throughout America were hematologists. Lots of them were, and I think this had an influence, you see, in the training of the next generations. Dr. Doan at Ohio State, he was Chairman of Medicine there, Dr. Moore in St. Louis at Barnes Hospital; Dr. Sprague in Charity Hospital, down in New Orleans, and so on. All around the country.

Tullis: Well, I think it comes back to one of the questions you asked earlier about the interaction between hematology and other sciences, that the hematologists had a tendency to have a strong scientific orientation and interest, which was attractive to committees that were appointing professors of medicine. It's as simple as that. They had lots to work on and no inhibitions, and they didn't, I don't think, as a rule, go out and deliberately write papers as a career thing to try to make themselves look better, but there was so much to write about there was plenty of opportunity to collect a large bibliography.

Tullis: Well, it was before the era of infectious disease as a sub-specialty interest. Pulmonary disease was on the down swing because people were starting to stop smoking, and tuberculosis had partly been wiped out. Infectious disease didn't have a great deal of appeal at that time---I think rheumatology had a lot of interest, because of its interaction with immunology. Rheumatology and immunology were very closely allied from the work on cortisone and so on. Endocrinology produced a number of professors of medicine, but hematology was unquestionably way out front.

[Tape interruption.]

Tullis: I think one would begin a discussion of the journal Blood by referring first to Henry Stratton, whom you probably already have information on. He was a young Viennese who came to this country in, I think, the middle 1930s, or late 1930s, and decided to publish scientific journals and medical journals. I think, secretly, he had always wanted to be a physician, but for reasons that were personal, he never achieved this, except as an honorary degree late in life. But he was a very knowledgeable, very suave, very sophisticated individual who could get along with people, and he started a couple of journals, and formed his own publishing firm of Gruen & Stratton. One of the journals he wanted to start was Hematology, which later was called Blood.

Tullis: I don't know.

Tullis: I don't know. I never met Gruen; I knew Henry well. Never met Gruen, can't tell you anything about him.

Tullis: Yes. So in the late 1940s, Henry began to come to a club that we had organized in Atlantic City called The Blood Club. The Blood Club was a totally structure less, unformed meeting of the kind I just loved, and my training with Edwin Cohn had made this such a natural thing that I was one of the sponsors of this--which was just to sit down and talk! People working in the same discipline. And we decided to have it always at the time of the Young Turks' Meeting, which was the Society for Clinical Investigation, and the young people working in full-time departments of medicine throughout America. It was always held at the Chalfone-Haddon Hall Hotel--I guess those are gambling places now--in Atlantic City.

I have to pause to say that my grandfather was a very austere Quaker who not only didn't believe in gambling, he didn't even believe in music. He had a friend, Mr. Leeds, who had formed Haddon Hall, and so my grandfather spent the summers always at Chalfonte Hotel in Atlantic City. I used to go as a little boy to visit him and they wouldn't even allow string music in the dining room because it was a thing of the Devil! And when I think of the gambling palaces that are there now, I'm sure my grandfather's bones are turning over in his grave.

Anyway, the Young Turks used to meet there, in March, or April, I don't remember which--April--every year. So we began having, on one of the Sunday evenings of that meeting, an informal meeting where we'd just sit around and drink beer and talk medicine, and somebody'd get up and talk about what he was currently working on, and so on. Then we began to formalize it a little bit, and have dinner with it, and it moved up to the top floor of the Haddon Hall, where a room seated about a hundred people. And we would discuss single themes. We would take one theme; one year, it was platelets. So I discussed what I was doing with platelets, and so on. Somebody else would discuss what he wanted to do with platelets, and so on. Henry would very much be a part of sitting in to sort of assay what was going on and determine whether it was of value, and he started the journal Blood in part because of this. And he closely related to that, and he began, then--I don't want to anticipate your questions, but you'll be coming to ASH, I'm sure; the American Society of Hematology--and he began saying at our meetings of The Blood Club, "This is so good, it's got to be published. It's got to be formalized. You've got to have a real Society of Hematology." And one person that immediately supported this concept was William Dameshek. Now, William Dameshek, who was in a different medical school here in Boston, was down at Tufts, and he very much got interested in this. Then, in 1954, at our meeting of the International Society of Hematology in Paris, Bill was elected President of the International society, and there were about five or six of us at that meeting from Boston. That was the fourth international meeting of hematologists. There were five or six of us from Boston, and he got us together right after the Paris election, and he said, "Now, you people have to, to really help this." When we got back here to Boston, he asked me to come over to his house one evening, he said, please, would I do the administrative part, because he said he was so busy, he couldn't? And I was young enough, so I didn't have any pressing obligations. So Bill's interests in hematology were so world-wide that he very quickly picked up the concepts of wanting also to have a formal American Society of Hematology.

Tullis: Yes. William Dameshek was a very sound man; not brilliant, but excellent in his fundamental ability to transfer knowledge to young people. He was the son of Russian émigrés who had come to America when he was, I think, three, or four, he told me. He didn't even remember it, he was so young, but his mother was the figure that had raised him and gotten him through medical school, and really had just done an excellent job of making him a fine man. He was head of hematology down at Tufts and did not represent the, if you will, vested interests of the old-line group, if you know what I mean, and yet he was able to stand up to them on every level, you know, and prove himself over the years. So they accepted them, which I think is great, and he just did a fine job of this. And he developed Tufts; really, he was one of the main movers of Tufts. He began to get referral patients coming here because of his skills and knowledge. It wasn't that he did any unusual research, or that he was brilliant in science, or anything, it was just that he was a good teacher, every inch a good teacher, and he had vision that when somebody told him something, he could see the potential of it. Of course, his editorship of Blood, which Stratton conned him into taking, again, was a great thing in advancing his career, because everybody then knew William Dameshek.

Tullis: It was all private, always during the Stratton era. It didn't come under control of the Society until years and years and years later.

Tullis: Well, you didn't feel much influence, except from, I would say, the two people who were pushing the concept of trying to establish hematology as a recognized specialty, and those two people were Dameshek and Stratton, because they were in a position to do it. You see, one of them controlled a journal, and the other one had a heavy influence academically on teaching hematology. There were other persons around the country that felt this shouldn't go too fast. Believe me, there was a strong negative feeling about this. For example, Doan, who was a superb hematologist--

Tullis: That's right--

Tullis: Yes, I know. But he didn't much believe in pushing hematology too fast. Dr. Moore was absolutely paranoid against any formal organization in hematology. He fought against formation of an ASH until he saw how successful it was, then he realized he had made a mistake.

Tullis: Well, I don't know. Everybody was busy in his own shop. There was just limitless work to do. They were all well-funded and they didn't want to get too involved in national or international things. They felt they were doing their own thing--do you follow this? It was almost like there was a political movement at the same time in the United States, away from world involvement, you remember, and this was part of the same thing. It was the parochial re-establishment of schools as independent entities, anti-nationalistic, if you will.

Tullis: I don't know.

Tullis: Ham, yes.

Tullis: Roy Kracke.

Tullis: Max Wintrobe, yes.

Tullis: No, they weren't all in resistance, but there was a strong feeling I'm just trying to get across to you--

Tullis: --of, "Well, is this the right way to go?"

Tullis: Oh, yes. That's right.

Tullis: No, they were specifically selected because of different interests in hematology, and they were all participants in our Blood Club, and doing research, quality research, that had been published in some areas of hematology.

Tullis: No, no, I don't think it influenced the discipline of hematology. I think it--well, that's a good question. No, I think hematology, in those days, was growing and determined to grow, no matter what happened, because there were so many people now beginning to work in the field and to publish, and so on. It's a way that brought it together, so that it was cohesive, but that's all. I don't think the journal influenced it in the sense of making it more, or anything else; it just made it easier to read what somebody else was doing.

Tullis: There were some European journals. There were some published in English that were very good that were in the blood field. But there were--well, look at my own reprints. In addition to publishing in Blood, I published in the New England Journal of Medicine; I published in the American Journal of Physiology. I published in all kinds of journals, depending on what the particular report was. If it was a report that was in biochemistry, I'd do it in a biochemical journal, that sort of thing. But there was no place that you centralized things for hematology, but you didn't have to. It just depended on what it was you were publishing. You could publish in medicine; you could publish in lots of sub-specialties.

Tullis: Oh, much more organized than we were in America. Their organization of blood began as a medical subspecialty. They even had professors of hematology in the 1940s and 1930s in different countries in Europe. We not only didn't have a professor of hematology, we didn't even recognize it! And I remember one of the arguments I used against the establishment of the American Society of Hematology--because I was one of the doubters in the early conceptual phase--I said, "Tell me, what is a hematologist, and I'll tell you, whether we should have a society." Nobody could, because you had people now getting into nucleonics, that were into isotope work, and so on, who also considered themselves hematologists. You had basic biochemists who were doing hematology work. You had clinical people doing hematology work. You had physical chemistry; you had all these different people. It was such a heterogeneous group that I felt it would be disastrous if we overly structured or defined what hematology was. It would keep us from growing.

Tullis: That's right; that's right. I liked the informality of the Blood Club, but I was the first one, finally, to admit it: "Yes, you know, we're never going to get anywhere--we need something more formal than this."

Tullis: Yes, that was Bill Dameshek.

Tullis: Yes, because he had, I think, more Latin American Fellows than anybody else.

Tullis: At Tufts; yes.

Tullis: Latin American Fellows were very uncommon in most of the places. They aren't now, but they were at that time, except Dameshek had a lot of them.

Tullis: Well, I can tell you some of the ones from Latin America that I think stood out. First, beyond any question, is A. Pavlovsky, and Pavlovsky, who was of Russian heritage--well, three generations earlier; he's an Argentinean--was a superb individual. Some of the South American cities, like Buenos Aires, and San Paolo, and Santiago, in Chile, and Lima, to a lesser extent--some of these superb cities and countries have excellent schools and highly cultural academic scientists. You don't hear about them because their countries are not rich enough to support basic research.

Tullis: Yes. Pavlovsky was interested in clotting, and in leukemia, two apparently separated parts of hematology, but he was skilled in both. Because of the hemophilics that he had to take care of, he went to some of the wealthy people of Buenos Aires in the 1930s and got funding to re-establish on a good scientific basis the national academy of medicine of Argentina and it funded his laboratory for hemophilia. In this he was different from most other contemporary scientists. And because of the knowledge of the hemophilics in South America that this was a good place, he certainly had all the ones in Argentina, and many other places, too.

I remember one time--I guess the first time was about 1960--that I was asked to go down and work there. They took me and my whole family, brought us down to Buenos Aires, and here was a building devoted to nothing but hemophilia! There wasn't anything like it in the United States! On his staff, he had biochemists working on new ways of fractionating plasma to get the Factor VIII out. He had priests advising the hemophilic women, the carriers, what their odds were for having affected children, and whether it was appropriate to have children, even before one talked about such things as birth control in a Catholic country, if you can imagine such a thing! He had clinicians who were taking care of these hemophilics; he had physiotherapists showing them how to get the joint free. He had everything right there! The research, and treatment, all together. I remember he had four hundred active hemophilics under care the two months I was first there. And that's a lot of hemophilics in one institute.

When freezers first became available, which would be, I guess, about the time of World War II--of course, they weren't involved in World War 11, so their work was able to go on--he had some of the first freezers installed there, and had one of his young women, Dr. Simonetti, an Italian coagulationist, mix the plasma from all these hemophilic patients. This is in the first journal of Blood--first copy, first journal--Pavlovsky was smart enough to postulate that if hemophilia is a deficiency disease where one of the proteins needed for clotting is missing, one should not be able to correct the defect of hemophilia with another hemophiliac's plasma. So he started taking out of the freezer these scores of plasmas, frozen, and mixing them, and by golly, along about, I don't remember, ten, twenty, thirty mixings, there was one plasma that corrected another, and he found, when he had done his whole study, that about ten percent of hemophilics would correct the hemophilia deficiency of other hemophilics. So, obviously, there was more than one kind of hemophilia. This was published right at the time that the Christmas boy first got sick in Oxford, and the Christmas boy was the son of a woman who was a singer on the stage. She had her boy in England, and he bled, and he had been diagnosed as hemophilic, and Rosemary Biggs, working in Oxford, found that when she did the standard test that she had just devised for hemophilia, that he was different from all the other hemophilics, and it was a serum, rather than a plasma factor which was missing. So all of this came out right at that time when Blood was first published, and Pavlovsky really was the first one to prove that there was more than one kind, and then Rosemary Biggs substantiated what it was. Later on, there were three kinds of so-called hemophilia.

Anyway, Pavlovsky was a good scientist and had a good coagulation laboratory with a high level of quality research, and so on, and similarly in the lymphoma era. Now, currently, two of his sons, two twins, have carried on. One is a coagulationist, and the other is a leukemia specialist. The leukemia person is currently in Bethesda, and is head of Latin American studies supported by the NIH oncology. The other one is running the coagulation laboratories in Argentina.

Tullis: Oh, yes. Not with his lab, but with Dameshek.

Tullis: Yes.

Tullis: Yes, I think Honorato in Chile was very good, Rene Honorato. He had trained with Armand Quick, and then he came as a National Science Foundation Fellow and worked with me for three years here around the late 1950s. Then, I think, Dr. Jamra in Brazil would certainly qualify as a leader of Latin American hematology. He was more clinically oriented: he was a professor of medicine at one of the medical schools in San Paolo. And what a city, San Paolo! It's a city of three and a half million people. We don't realize that here in North America. We're so smug about ourselves. Then, Venezuela because of the early oil money, early being in the 1950s and early 1960s, was able to set up more basic research than any of the other South American countries, because they're on federal funding for it through their oil revenues. They established a National Institutes of Health, copied verbatim on our National Institutes of Health out in Bethesda. They have an institute of mathematics, and one of physics, and one of chemistry, and so on, and in all the medical sciences. And they produced some very good hematologists. I'm not very good on names but one of them was Tulio Ahrends, and one of them, whose name I can't think of at the moment, was working on red cells and did beautiful work. Then, in Mexico, there was Gonzalez Gutzmann, and who else? I can't remember the name of the other man that was doing most of the Mexican work.

Tullis: They related closer to Europe than they did to America, there's just no question about it, I think, probably, because of language differences. They simply cannot handle English very well, you know. Pavlovsky could, he was a very polished person who could handle about five different languages, as can Jamra, and some of the others, but most South Americans speak Spanish, and most Spanish-speaking people have trouble with the English language, the enunciation of English. Whereas with a Romance language, like French, or something else, they can get along; with Italian, they can get along very well. So that they tended to relate to where they could read the journals, and they related more to Europe than they did to America.

Tullis: Somewhat different. More clinically oriented, less science, less basic science, with the exception of places like Pavlovsky's.

August 8, 1985

Tullis: The needs of the Latin American hematologists are really quite different from those of the American hematologists. And when we use the word "American" incorrectly, I obviously refer to the English-speaking countries of Canada and the United States. In South America, the development of the basic science of hematology is considerably behind the development of clinical hematology as a practice specialty, except for the few areas that I've mentioned where excellent work is going on, such as Pavlovsky's work, and Jamra's work, and so on. Four or five of the South American countries have major basic work, but with that exception, the vast bulk of the hematology is clinical practice of hematology. Persons in the clinical practice with weak backgrounds, as many of the South American hematologists had as far as the science of hematology, were totally unable to get their knowledge transcribed into American journals like the new journal, Blood, because the new journal, Blood, set very high standards of either basic research or standards of clinical types of study that require prospective double blinded studies which they could not get the people in South America to cooperate with. The great bulk of the articles from South America would be universally turned down for publication in Blood. This created a feeling of hostility and inferiority amongst people who really were good clinical practitioners in hematology, as I'll discuss later on when we get to the International Society and the role I tried to play there in South America. They became very paranoid about the United States, and, indeed, feel that way somewhat to this day, feeling that this manner in which we've handled them scientifically somewhat resembles the way we've politically handled things in Central America, which is sometimes heavy-handed and not with a true understanding of the local needs.

Tullis: Not immediately, no. I think it will wait until twenty years, or maybe two generations, forty years of education and raising of the standards throughout all of South America, so that their universities are doing scientific types of evaluations and studies before the hematologists there will be on a par as far as their ability to get their knowledge printed and disseminated.

Tullis: I think it was very definitely seen by Dr. Dameshek. Yes, he understood the needs of South America, he had lectured there extensively because he had had a number of Fellows who had trained here in Boston at Tufts University with him in his department, and he had tried to help them out, but it was difficult for him to do. He was careful in the first copy of the first journal of Blood to include an article by Pavlovsky to represent South America, but from then on it was downhill as far as the numbers of Latin American publications that were actually turned out.

Tullis: Yes, they publish more in European journals than they do here. Again, this is partly language, because they converse and write and read other Romance languages better than they do the Anglo-Saxon based English language, and it's easier for them to express themselves. So that they have published in Swiss journals; they have published in German journals, in French journals, in Italian journals. Mostly French, Spanish, and Italian, I would say.

Tullis: Yes.

Tullis: It was started to be a journal which was of such high standards that it, itself, would elevate the standards of hematology. In other words, it wasn't being started merely to reflect the current modus operandi but rather as the carrot on the stick to which people would aspire, and it filled that role very well. I think Dr.
Dameshek as the original editor, and Stratton as the man who was financing it should be given great credit for that, because it had that role, and it made hematology, from the very beginning of its crystallization as a specialty, it made it strive to be of the very highest quality.

Tullis: No. The journal, Blood, was primarily concerned with the basic research, rather than the clinical studies, because, again, the clinical studies have meaning to a broader base of persons practicing medicine, and therefore should be published in the journals that are read by internists, rather than read by hematologists. Whereas the hematologic publications in Blood were those that the specialists working in the field, and often not practitioners at all, would need to read in order for them to stay informed of this specialty.

Tullis: I don't think so.

Tullis: I mentioned earlier in our discussion that in Europe hematology as a specialty and as an academic entity was established long before it was in this country. This in part probably relates all the way back to the original morphologists who were the pathologists that defined blood cells, and so on, and less to the physiology and the biochemistry of blood. But it was an accepted subspecialty throughout Europe. So that there were societies of hematology of many years duration in France, and Holland, and Denmark, Switzerland, Italy, Spain. Throughout most of Europe as we know it today, there were societies that were well established. After World War II ended, the persons who had been thrown together from America who were interested in hematology as a specialty had been influenced by the Europeans because of their presence for several years in Europe during wartime conditions. As a result of this, and the catalytic effect of a meeting on Blood Groups in Dallas and Mexico City in 1946, an organizing committee was convened in Buffalo, New York, in 1948, to consider founding an International Society of Hematology, which would represent North and South America, as well as it would represent Europe. In 1948, I was just a youngster who could barely make enough money to support his own eating habits, and I happened to be on vacation in Buffalo. Obviously, I was not invited to that meeting. But I was visiting a classmate of mine there and picked up the morning paper and read that this convocation was going to take place at the Statler Hotel. Being interested in blood, although I had no stature in blood--I was so new, and young--I went to the meetings. I was privileged to be present at that organizational meeting. I don't want to give numbers, but just by visual recollection I would say there were a hundred to a hundred and fifty people who had come. France was well represented, England was well represented, and Mexico was well represented, because of their interest in blood-groups and blood transfusions, which were just getting started in those days. As a result of this, the organizational meeting was held there, and it was a good meeting. And from that, which was the first meeting of the ISH, a biennial convocation was established which would meet in rotation, first in Europe, then in America, then in Europe, then in America, and on each fifth time someplace in the Pacific-Orient area. Then, it would go back to the cycle of Europe, America, Europe, America, then the Pacific.

Originally, the Society was set up with two divisions: the European division, and the American division, and there was no Pacific or Asian division because it was not felt there were enough hematologists, as such, to support the administration. Of course, that was just part of the ignorance of Americans, who always think nobody else knows anything. The American Division assumed responsibility for hematology in the Pacific area. The second meeting of the Society after that Buffalo meeting was in Cambridge, England.

Tullis: Yes, of course, although names are not my forte--I constantly forget names. I would say at the original meeting--well, from this country, obviously, Dr. Dameshek was prominent, and Dr. Saul Haberman from Texas, and Dr. Joseph Hill from Texas; and Dr. Gonzalez Gutzman was there from Mexico, and Sir Lionel Whitby from England. The French hematologists were represented by Dr. J. Bernard-- a wonderful hematologist in Paris whose father was a physiologist at the turn of the century, and invented the concept of an "interior mileau." Marcel Bessis, who was an associate of Bernard at that time, later set up his own separate laboratories; and from South America, Pavlovsky; and that was essentially it at that time. Those are the leading names that come to my mind.

Now then they decided to have a meeting every other year, and--well, first of all, they set up offices for the two divisions. The American office, representing North and South America, was set up at the University of Baylor, under Saul Haberman, as the Executive Secretary, or Secretary-General, as they called him. The European division was set up in France under Bessis, Marcel Bessis, who was the Secretary-General, there. They were the two young men that had the time to do it and the organizational ability and so on to do it.

The third meeting, then, was held at Cambridge University with a very good British hematologist, Sir Lionel Whitby serving as President. From then on, the president was always the prominent person in the city where the meeting took place. After the meeting in Cambridge, on the rotation of America, Europe, America, it came back to America and went down to Argentina. That was a meeting that, I think, the world political situation kept on tenterhooks until the last minute, because two months before the meeting was to take place Peron took over the government of Argentine by seizure. No one knew whether any of us would be allowed to go, or whether a meeting would be allowed to take place, and so on. But Dr. Pavlovsky successfully manipulated and maneuvered and had a good meeting, down at Mar d'la Platte, about 150 miles south of Buenos Aires.

The fifth meeting then after the Argentinean meeting, two years later, in 1954, was held in Paris, under the presidency of Jean Bernard--no, I beg your pardon, it was not under his presidency. There was a more senior individual, Dr. Chevalier, a man in his eighties. Jean Bernard was the vice-president, in charge of the organization of the congress. That meeting at the Sorbonne went off very well and was attended by over a thousand people, which was unheard of in those early days for a scientific gathering of any type, in any specialty. Dr. Dameshek, at that meeting, on the last day of the meeting, was elected the president for the next time, which would be two years later, when it was to come back again to America, and it came to Boston. That was in 1956. Dr. Dameshek asked me at that time if I would be willing to become the vice-president for that congress, to set up the congress and organize it, because he was so busy he couldn't give it the time that it needed. He had to be traveling a lot. We did, and we had the sixth meeting here.

It was on that occasion, as I'll come back later, that a group of us, about ten of us, got together, one of the noons of the one week of the International Society meeting and said, "Well, this is wrong; America doesn't have a Society of Hematology, and maybe they should have a Society of Hematology." I spoke again at that luncheon meeting, which was just an informal discussion, iterating apprehension that since we had such a difficulty defining what hematology was that it might be inhibitory to start an American society because I wanted to be sure we didn't think of it as a practice-oriented society, which is what I was afraid it would become, and that it would discourage the anatomists and the chemists and the physiologists, and so on, who were just as much knowledgeable about blood, and the physical chemists, perhaps more knowledgeable about blood than the practitioners who were treating blood diseases as a specialty. But my fears were sufficiently overcome that when they asked me if I would be willing to be the repository for organizing a preliminary meeting of an American Society of Hematology two years later, I said I would be willing to do it.

We'll come back to that when we discuss the American Society later on. Now, then--yes?

Tullis: In part it was that, and in part it was giving a forum to the basic sciences that impinged on blood and had to know about all aspects of blood in order properly to do their work. For example, at that meeting in Paris, which was the first one I attended truly as a scientist--the others I was too young, I just went as an observer--but when it was time for that meeting, and the submission of papers from Dr. Cohn's laboratory in the summer of 1953, he asked us to get things together, and there were some eight or ten good scientific papers on totally different aspects of blood proteins, and so on, that had applicability and poignancy for people, whatever they were doing with blood. So he asked me not only to give my own paper on the work I had been doing on platelet antibodies, but to take all the other papers and read them for the person because transportation by boat in those days was a laborious, time consuming expense, and so on. One didn't just go off to Paris for the afternoon, like one does now! So that, I think, reflected that the new international society was fulfilling a role quite beyond defining the limits of hematology. It was exchanging basic knowledge which, up to then, had been inadequately exchanged.

Tullis: I think very much so. Let me just give you an example: one of the papers that I gave at that international meeting in 1954 was a description of a technique that we had tried to evolve for the diagnosis of autoimmune thrombocytopenic purpura, which was a disease that had been known for several decades, but no one had any way of diagnosing it or separating it from other platelet deficiency states. We had worked out a chemical way of absorbing the clotting proteins, and removing calcium, and doing it as an exchange type of column chromatography, ending up with a serum that only had the albumin and the gamma globulin in it, so it was non-reactive to platelets in the coagulation sense, but would react, if there were antiglobulins, specifically directed against absorbed globulins on the surface of the platelet. I had that paper, and there was a paper, also, from the laboratory in Holland under Dr. von Loghem. He was the principal hematologist in Holland. One of his students had a paper where he was trying to do the same thing, and lo and behold! there was another paper from somebody in another country trying to do the same thing. As a result of hearing each other's papers, we called a special convocation the last afternoon of the last day of the congress, and said, "Anybody interested in this field, please come, and we'll discuss result."

Tullis: 54! There must have been twenty people that came, including several from the United States that had already begun work in their laboratory but weren't far enough along to have anything formally to say in a meeting. But, then, under the informal atmosphere of just the exchange of scientists sitting around the room, we had about a two- or three-hour session that was of just great value to all of us, because we saw problems we had not ourselves unearthed, and they saw answers that they might not have thought of. We exchanged knowledge, and then got home and exchanged sera to do the same tests--you know, each man to do his own on the same serum, that sort of thing. So there was a quantum leap in that particular subspecialty. Well, the same sort of thing was going on in many different aspects of hematology. I just cite that as a single example. So that, already, there was this catch-up going on from the years when there had been poor communications because of the war, and so on, and when there had been poor exchange of knowledge. That, to me, was the greatest value.

Tullis: Well, hematology is high quality in Europe, and it has been traditionally right across the years. It's difficult to cite one country being better than another, because they were all doing good work, each in his own way or her own way. I don't want to try to favor one country over another, but in traveling around and meeting with these people and visiting in their laboratories, I was constantly impressed that, in their independent way, they had plowed ahead--

[End of side two of tape two; beginning of side one of tape three.]

I keep saying this, but I'll say it again: we have a very parochial attitude in this country that we've got all the answers and that the rest of the world is behind us. Truly, it isn't, in some aspects. It may be economically or it may be politically, or something--I don't want to get into that!--but in this, just the hands-on, bench-top, basic knowledge, they are good.

Tullis: Well, let's see. After the meeting in Boston, we went back to Europe for the Seventh Congress because that was before this rotation to the Orient had been put in--

Tullis: No, in 1956, it was Boston.

Tullis: Then we went back to Europe, to Italy in 1958. Let's see, what was the name of that man, there's a disease named after him, a malignant disease--sort of a strange one, DiGuglielmo. Dr. DiGuglielmo was the president at that time. And the Japanese came to that meeting and, indeed, they had come to the Boston meeting. The reason they had come to the Boston meeting was that Dr. Katsunuma, who was a very excellent hematologist at the University of Osaka, and a professor of medicine at the University of Osaka, had taken his training in Boston at the Thorndike Laboratory in the early 1920s, and not long after Minot and Castle were first doing their work, and, right at the time that they were uncovering the principal which cured pernicious anemia.

As an aside, an interesting little humorous aside, years later, Dr. Katsenuma told me that all he really saw in the two years he trained at the Thorndike was pernicious anemia, because the Irish, at that time, occupied that whole area around Boston City Hospital, and all of the outpatient department was visits by people of Irish ancestry and north European ancestry, where pernicious anemia is very common. Well, there isn't such a thing as pernicious anemia in the Japanese race, or in the black race. When he got back to Japan, he said he had never seen another case of pernicious anemia since he had been in practice. So that his years of training were not very practical, as far as his specialty, but, of course, it had broadened his concept, and everything.

In any event, he had come to the Boston meeting, and at the Boston meeting the decision had been made, that I mentioned a few minutes ago, of rotating after Europe, America, Europe, America, then the Pacific, and then back to Europe, America, Europe, America. So the Pacific was selected, then, for 1960. Dr. Katsunuma was elected president in 1958, at the end of the Italian meeting. The new president goes in two years before his congress is held, you see. So at the meeting in Italy, we--well, I remember the evening. We went out to the Japanese Embassy with Katsunuma and some other Japanese he had with him, and the arrangements were laid out for the meeting then.

It was then that I became administratively involved in the society, because Dr. Dameshek, after the Boston meeting was successful, asked if I'd be willing to become the new Secretary- General of the society, itself. So having just assumed that post in Italy, I had to help set up the meeting for Japan, which, again, was somewhat of an eye-opener when I got there in 1960, and I went several weeks in advance because the State Department asked me to go lecture in different Japanese medical schools and find out what the state of knowledge was, vis-à-vis basic knowledge in Japanese teaching at that time, because they had no updates since before World War II.

Tullis: Yes. As I look back on it, it was an interesting foray for me, very broadening. First of all, we almost didn't go. The State Department had asked, in response to a Japanese request from the Japan Science Council, that I come over and teach. They asked me if I'd be willing to go as a consultant, and that they would pay my way, et cetera, before the meeting that I was going to be there for, anyway. I had responded hesitantly, yes, because, again, you have to put everything in the context of the era when this was taking place. 1960 was the time that President Eisenhower had made his, I think, first Pacific trip. He had gone out to a conference at the SEATO nations in India, or Thailand, or some place. Thailand, I think--or Australia, perhaps. On his way home, he had wanted to land as a peace mission in Japan, and there was such an anti-American feeling that the people, the protesters, lay down on the runway and refused to let the presidential plane land. You probably don't even remember this; it's buried in history, because, you see, this was just ten or twelve years after the end of--well, fifteen years after the end of World War II. There were those that felt that America had been excessive in its use of force in Japan, and that Eisenhower, as a general, represented the military, rather than representing the more peace-loving other aspects of America.

So my wife and my children, who were going to accompany me on this several months foray said they weren't going to go. Any country that didn't like their President they weren't going to go to! And I made a little trip down to Washington to the State Department to express my apprehension about this trip. Was it really safe? The Japanese didn't even want to let an American President in. What would they do with ordinary Americans? The man that was responsible for setting up my trip laughed and said. "Come into my office." He said, "You know, we have contacts in all the countries of the world, and I want to show you what was going on the night of the so-called demonstrations to keep Mr. Eisenhower's plane from landing." He said, "It was only about a hundred or two hundred people involved," and he said, "Here were some scenes taken the same night." And they had secret photographs of baseball games that were going on: Tokyo is very nuts on baseball, and here were people waving American flags, and cheering American baseball players, and he said, "There's really no anti-American feeling at all. This was just a political demonstration to accomplish something in the Diet"--I don't know how to describe the courtesy, the kindness, the friendliness, the total lack of any attitude of aggression towards this country or resentment, and so on that I found.

The trip took me to some eight or ten medical schools on, essentially, all of the islands except the north island of Hokkaido. I would spend from a week to ten days at each of these medical schools, lecturing, making ward rounds, working in the laboratories, commenting on techniques. The knowledge that I had been given of what to expect, even by our State Department, was totally wrong; it was outdated. It was information that had been gleaned before World War II. And this is one of the reasons they asked me to go, of course. They wanted new information. And to my pleasant surprise, I found that there was good science going on there, even at small universities--well, small to us--like the University of Fukuoka, and places of this sort, down in some of the southern cities. They had, apparently, through their contact with Italy and Germany kept their scientific standards quite high. They had good equipment. They had made some of their own equipment. They had good knowledge of the new techniques in science.

Tullis: --that they had managed to do that. We didn't know that, you see. We thought they were very backward, but, quite to the contrary, they weren't backward at all. They were really quite progressive. And, although I had assigned to me an interpreter for the whole trip, often what I would do is, I would say two or three sentences and then pause for her to translate it into Japanese from English, but often if it was a humorous remark, they'd laugh before she began to translate. I mean, they obviously were able to understand the English, because the textbooks they were then using were mostly English textbooks.

Tullis: Yes. Yes, there was. Blood banking was further behind than the fractionation, and so on. The blood banking was behind for a couple of reasons. Part of it was just the physiognomy of the Japanese. They're so small, or were at that time before McDonald's hamburgers, they were tiny people as a race, and one could not remove more than a couple hundred ml. of blood without causing a semi-shocklike state, whereas you take more than double that out of the American donors, or donors in most other countries. So that, even up until recently, the standard blood unit was a half pint or less for Japanese blood donors. Secondly, the establishment of these blood donor centers was somewhat contrary to the Japanese interrelationship with their health-care system. For example, although the medicine was good, the hospital management was, by our standards, very primitive. I can give you an example of that: one day, I gave a lecture at the University of Tokyo, and the dean of the school, after my lecture, took me on an official tour. We got to the first ward that I visited, and there by each bed were members of family of the individual who was sick. And the family members gave the nursing care, not the hospital. The family prepared the meals, did all of that, because the Japanese felt, you see, the members of the family knew what Daddy wanted to eat better than the hospital would know. So the family would do all of the housekeeping, the cleaning, the washing of him, the bathing of him, feeding, et cetera.

The only relationship to the health care system would be the specific medicines that the patient needed. So that they weren't in intimate contact, the medical staff, with the patient, as far as such things as, let's say, the donation of blood, because that would be done in a non-health care context. So that there were reasons that blood transfusion was behind.

On the other hand, blood fractionation, which is, again, a protein-chemical thing, was really quite advanced, because the Japanese had studied in Sweden, and they had studied in a number of countries. There were students of Dr. Cohn from here who had already set up satellite units, and so the Japanese were really quite knowledgeable.

Tullis: During World War II.

Tullis: Yes.

Tullis: Yes. Throughout the world.

Tullis: You mean how had they done it? Well, they had--yes, I can comment on that. First of all, most of them were sponsored by the governments of the countries that they came from, which is a difference, again, from American, because the system of medicine, science and everything is under university, and public and private aegis in this country, the health care system. Whereas the health care system in the European countries and the Scandinavian countries, and almost everyplace in the world, was supported financially by the government. So if they decided a fractionation laboratory--take Australia, for example--they just picked out some chemists that they thought would be good people, who were young and could then make careers out of it, and they would send them over here for two years, three years, whatever was necessary, to Cohn's laboratory to train. They'd even buy the equipment in the United States with which to do it, the Sharples centrifuges, and all of this business, and the cold tanks for the precipitation of fibrinogen, et cetera. And they would take the knowledge back to their home country and set up the laboratories, usually university related, but governmentally sponsored.

Tullis: It took place in the period immediately after World War II, from about 1945 on, because, when it was during the war, it was very much an American operation, because of wartime, not secrecy, but nobody was talking about it, anyway. It wasn't until right after the war that all these other countries sent people over.

Tullis: No, not a bit. No. All of the publications from our physical chemistry laboratory were in physical chemical journals.

Tullis: That's right. In fractionation, and so on.

But now, then, returning to this Japanese situation. Many of these small medical schools really turned out to have quite advanced work going on. And, from a personal standpoint, I formed friendships and contacts from which I'm still having research fellows sent here to work with me. The most recent one was the son of dean of Hiroshima, whom I worked with for a while on that trip in 1960, and his son just finished three years here; he's now back at the University of Tokyo. So we've had strong contacts over the subsequent years.

Tullis: Oh, yes. I've been back several times again to lecture and teach, and so on, and they, here. Again, this brings out another point that you haven't asked about, and that's the language. At the first meeting of the International Society of Hematology, translation was not only helpful, it was essential. One could not converse with these people from other countries, unless one could use the tongue. I can speak enough French so I can be understood. I can speak some German because I had studied it in school as a youngster, and had studied it because one couldn't learn medicine without knowing something about it. But they could not use the English language. Only the people from England, Canada, and the United States spoke English. But after World War II, there had been such a resurgence of publications in America, and to a lesser extent in the United Kingdom, that people throughout the world began to read journals of all kinds, written in English. Now, it is no longer necessary to have simultaneous translations, as all the educated physicians and scientists read, write and understand English. The last congress with simultaneous translation was the one in 1958, in Italy, where there was translation into Spanish, French, German, English. Whoever was speaking, you had to dial the little instrument on your headset. Dr. Katsunuma, who had trained here in Boston but was a Japanese, said to me in Rome in 1948, "I am going to make the Tokyo meeting the first where people have to speak the English language in order to communicate." He was very pro-American. The Japanese papers that were submitted from Japanese hematologists would not be considered for acceptance on the 1960 program unless the Japanese would promise to learn English well enough to stand up and deliver the paper in understandable English. Now, this was not well received, particularly by the French, and to a lesser extent by the Spanish speaking people, because their attitude was--and the Russians who were there, too--their attitude was, "Why English? Why not Esperanto, or Dutch, or something else, or Belgigue, or, you name it?" But Katsunuma said, "No. The Japanese will have to speak English. If you want to have French for some of the translations, for some of the plenary sessions, I'll do that." And he did, for just a very few papers of prominent people who did not want to speak in English. This was during the period of De Gaulle, and De Gaulle was a strong person for raising French back to its glory days, and wanted French spoken by French hematologists. In fact, they were told to speak it. But that meeting then was almost entirely in English.

The Japanese, because this was that same summer that I had a translator, were able to understand most of the speaking I did. They, now, years later, when I go over there, they speak English as well as you or I speak or communicate in English. They write in English. And their Japanese journals--like the Japanese Journal of Hematology, the articles are written Japanese, then there's an English summary at the end of each, because sometimes it's easier for them to understand scientific English than it is to express themselves appropriately in Japanese. The English language adapts itself better to science than it does to their own native tongue, because of the way one has to have characters rather than phonetics. So that now the idea of a translator is unheard of.

And there have been no meetings of the International Society, subsequently, where there's been any translation. I think it's hard for us when we try to maintain competency in a foreign language, but it makes it awfully easy for Americans to go abroad to scientific meetings.

Tullis: I don't think so. In fact, I think one of the tragedies of our improved communications is that we may end up with only one or two international languages, which would mean the world will lose something, just like it did when cuneiform script was lost, and so on, and Sanskrit, and other languages that have disappeared. For example, on another occasion, I went to China, to lecture on hematology at the request of our State Department. The Chinese language is even less adaptable than the Japanese to modern speed of communications. I remember when making rounds at the University of Taipei hospital, and, again, the professor of medicine would hand the chart to me and then the student, or house officer, would present the case, and I would then discuss it, and they would make notes. When I looked at the charts, they were all written in English, yet no one, at that point, could understand me well in this Nationalist Chinese medical school. I asked why were they able to write in English. He said, "Well, they have to in order for us to get the records done in time." And I said, "Well, what does that mean?" He said, "Well, have you ever seen a Chinese typewriter?" Do you know this? Well, I won't bore you with it--

Tullis: "Well," I said, "why, no; as a matter of fact, I haven't." And he said, "Well, we'll go down to the basement, and I'll show you one." A Chinese typewriter: each tray of type has 2000 figures in it, and here was a girl seated, with five trays of type above her knees, and a single key, like a Ouija board, that she would move around over the type until she was centered over the figure--the hieroglyphic of the Chinese character that was to be printed--and then she would touch the thing, and the key would pick up the character, print it, and drop it back down again. And if the word, the symbol she wanted to use was not in that tray, she'd have to pull the tray out and put another tray in. Perhaps, to type a page, it would take her three-quarters of an hour, because there were no phonetics whatsoever, entirely the characters. Now, the Japanese, when they assimilated the Chinese language hundreds and hundreds of years ago, put some phonetics in with it. And if you look at a page of Japanese science, in a scientific journal, you'll see dots, dashes, squiggles, dots, a couple of points, you know, and then, a character. Well, maybe there would only be one or two characters on a whole line of type, because the rest is phonetic, just like shorthand for the secretary who takes dictation, so that they could adapt with IBM typewriters, that only had about twenty key rows on it, as opposed to this laborious Chinese system. But my point is that the Chinese characters, they're beautiful artwork--I don't know whether you've ever studied them, beautiful artwork. If you ever try to make a Chinese character, you can only put your brush down in one spot to start to make it, you know, and end up at the right spot, so it doesn't smear. It's an art form that's going to be lost, I'm afraid, because it's not compatible with a newspaper every hour, that sort of thing.

But in any event, pardon that. It's part of the background.

Tullis: I think the way they handled the new science that they were learning from America, as opposed to the morphologic science that they had learned from Germany, was the way they handle microchips and automobiles, in the present environment: they learned how to do something, then they did it meticulously, and they did it efficiently, and then next they did it inexpensively. That's the way they approach problems. They engineer the problem to something that can be handled well.

For example, they got into the fractionation game along about 1950, and by 1960 the Green Cross in Osaka was one of the major fractionation facilities for making various plasma fractions, and so on. Now, they bought out Abbot's Division, out on the West Coast here, and created a company they call Alpha Therapeutics, an excellent company, but it's an extension of Green Cross from Japan. That's their way of doing business. There isn't so much original thought as more efficient use of tools they have learned from somebody else.

Tullis: Yes, but again, we were very naive in our attitude that they didn't have many students. For example, at that 1960 Congress, the first one in Japan, under Katsunuma's presidency, I had no idea there would be many hematologists of Japanese origin. Well, it turned out that the well established, already well established; Japanese Society of Hematology had seven hundred members! And this is a country we didn't think had any hematology in it! That was many more, you see, than dreamed of for the United States. I haven't even gotten to the American Society yet. The American Society, at that point, was only two years old, and nowhere near that big.

Tullis: No, not research, certainly--except clinical research. There was a lot of work on the nutritional anemia in India, where poor nutrition is so endemic. There was good work on the parasitology of blood, in terms of the malarial infestation of red cells in places like Thailand. Then in Australia, of course, there was good, classic, university-type work, but that was so small numerically as far as their total population that, again, the number of persons working in science was pretty small. But it was good work, what was going on.

Tullis: Yes, I would say so. Within most of southern Asia, yes?

Tullis: Yes, they're doing their own operations, now. India, for example, has a comparable institute of health, like we have at the NIH, with good basic science in it. They're playing catch-up ball, but they're catching up.

Tullis: No. I think the biggest--well, I shouldn't say no, because there was not any place where I had enough observations to say that. But I should go back to say that we determined--"we" now being the International Society of Hematology--several things: first, that when we saw what was going on in Japan in 1960, that we should split them off with their own division, and give them autonomy, thinking they would increase faster--which has proved to be the case. So, the new constitution, which I helped write along about 1964 or so, set up a third division, we no longer call them hemispheres, but a third division of the International Society for the Asian-Pacific area. Everything from Australia through India, even including all the way to Israel, and including all of China, if it wants to come in, and Japan, India, Thailand, et cetera. Then, we began to--"we" again being now the Western Hemisphere division, or we now call it the American Division, the North and South American division of the International Society of Hematology--again, to concentrate on North and South America.

So I set out to, in my role as Secretary-General for this part of the Society, make regular visits, frequently, to South America, to meet with hematologists and to listen to their problems, to understand their problems--not as an American, but as a representative of an international organization. I regretted I had to speak English; I didn't speak Spanish. I wish I could have, because I think I would have been able to be more effective, but I did this, and had to raise the funds independently, because the International Society had no money. But I was able to raise money through various sources, pharmaceutical firms, and things of that sort, to pay for these peregrinations. I would go down and meet with the individual societies, and try to elevate their standards, and so on.

Tullis: I think not. They're particularly good in coagulation, I will say that. The next President of the World Hemophilia Association is Japanese, Dr. Abe. Those fields of hematology that they have gotten into they've done very, very well in.

Tullis: Some, but very limited. Again, that was not part of my area of responsibility, so I can't speak definitively about it. I have met a few hematologists from some of the countries that had good clinical practice in medicine, in the armed forces, and so on, of France and England, and in Belgium, parts of Africa that had previously been underdeveloped or controlled. In some of those, there were some very good, young black hematologists whom I met and was impressed by. But as far as the quantity and quality, and so on, at the local level, I can't answer.

Tullis: I would answer, "No." I think it still pretty much fulfills a role of trying to keep basic science as the forum, but presented in a manner that gives an opportunity for people at the practical level to apply it in their practice. For example, at one of our more recent meetings in Hungary, Budapest, the summer before last, there were people there from Eastern Bloc countries who obviously had not themselves been privileged to have worked in basic science, who still were very interested in knowing what was being presented in such a way that they could translate new advances into their practice of hematology.

There again, as an aside, even in Budapest, the only official language of the congress was English, for all the Russians, and everybody else.

Tullis: Oh, yes. Bound to be, but relatively minimal.

Tullis: Yes. Right now, there is--I won't mention the personalities involved--but there is a real discontent in the South American countries over the probable person who will be selected as the next president of the International Society when it comes to America. Not that he isn't perfectly good, because he's superb, but there is somebody else whom they felt better able to relate to, that they were pushing strongly to have become president. But these things have been kept in bounds, under control, and so on.

Tullis: No. I think it's been a powerful force and a good force. And it's been able to be done, which took some doing, but all of this has been accomplished with no budget, essentially, no fixed big overhead of administration, like you would have for the UNESCO, or Red Cross, or something like that. The two Secretaries-General operate on a shoestring budget. The dues is--I can't remember, I think it's five dollars a year we pay, and that's not even enough to hire a secretary for the man who's running the office. But usually, it's a man who can draw on other secretarial support he has from his grants, or whatever else, practice, or something else. Then the cost of the individual meeting is assumed totally by the place where the meeting's going to be. For instance, a meeting, to put it on today, an international meeting costs the local congress committee a minimum of $500,000! A minimum! Because there are some people you have to give free transportation to. You have the cost of the meeting rooms; you have the cost of the exhibit halls, and the publications and reprints, and getting the talks lined up, and writing the people, and so on. It costs a minimum of $500,000 for each meeting. There's no way to pay for that except by going to the local committee and then they figure out what the local costs will be--this has nothing to do with room and board, just the cost of the scientific sessions--and then they charge an admission fee equal to what it will be, less whatever they're going to take in revenue from display people, commercial display people, and so on. So it's a lot of responsibility, but we've done it, and without ever having any large overlay of administration.

Tullis: No. This has been repeatedly discussed as to whether we should ever have an international journal, and again, we have felt not, because the international society is an amalgamation. It's more a confederacy, you see, a confederacy of different states, each having its own society, each having its own journal, and we don't want to play favorites.

Tullis: Oh, yes. So that each person moved ahead with his own journal.

Tullis: In the beginning--when I say, "In the beginning," I mean back, 1945 to 1950, there was nothing but the informal Blood Club, in this country, that served as a forum for people working in the field. Many of us felt that was adequate because we were hesitant to let hematology become overly rigid and crystallized, and we also did not want it to become a society of practitioners, of the practice of hematology. So we used the journals, and used the forums of our subspecialty societies--again, physiology, biochemistry, physical chemistry, et cetera, and the ones that were clinically oriented in hematology used existing journals, like the New England Journal of Medicine, and the Journal of Clinical Investigation, and so on. But we began to realize we were wrong, and at the time of the 1956 meeting, largely catalyzed by Dr. Dameshek and his vision, and to a lesser extent, Henry Stratton, who always liked to see societies form, because he had a ready circulation list for his journals, and so on. And I say that humorously because I used to say it to him: "Here's 1800 new subscriptions, Henry, because such-and-such a society has been formed."

Tullis: I don't remember, but he started subspecialty journals in heart, and so on. Many different ones. Rheumatology, et cetera.  

But at the international meeting in 1956, at the Somerset Hotel here, just a few blocks from where we're talking, we had an informal lunch during the ISH meeting. There were ten or twelve of us there, who said, "We need to do this." The logical place to do it was here, since the city was Boston, and I already had organized an administrative office for putting that Congress on. So they said, "Please, would you be willing to sort of pull this together, and see if there is a need?" So I said, "All right. If I can be shown there's a need, I'll be willing to be the organizer of it."

I put an announcement in Blood, that said, "If anyone is interested, we tentatively plan to have an organizational meeting at the Harvard Club in 1958 to precede one day before the meeting of the American College of Physicians," which was meeting here at that time. I knew that would at least bring the clinical hematologists to the city-The American Society of Hematology, of course, didn't exist, but the letters I got back--and I just used my postal address--were warm enough for the concept that we went ahead and rented the Aesculapian Room of the Harvard Club down on Commonwealth Avenue, for two reasons: both because Aesculapius was one of the original Greek physicians, and more importantly, this was a small room that was set up for a society I belonged to called the Aesculapian Club, which meets there, and has about fifty members. It's a small room, but it could comfortably seat fifty members, which I thought would be about right.

This meeting was scheduled for an April Sunday morning, and I took the secretary from our research laboratory and went down there and set a card table up. Before eleven o'clock that morning, we had overflowed the room, and I had gone downstairs and moved everything-- gotten the management to let us move into the Massachusetts Room, which holds about 150 people, and is adjacent to the Aesculapian Room, And there were at least 150 people who showed up that day for a very small scientific program which I had scheduled and for an organizational meeting.

We decided to start that day with a preliminary constitutional committee and officers of the, if you will, society to be formed, because it was still very informal. They asked me to be the interim president of the organizing committee of an American Society of Hematology, At that point, there were several things that had to be done: first of all, the constitution, which I asked Dr. Israel Davidson, now deceased, who was from Chicago, to organize that; and we had to incorporate so that we could go after grants. That meant that we had to be tax-exempt, so we had to become a charitable organization in Massachusetts.

[End of side one of tape three; beginning of side two of tape three.]

--a humorous aside of that is, I went to my next door neighbor in Newton, who's a lawyer, Richard Lovell. I said, "Dick, would you do this free, because we have no money, we don't even have a society." He said, "Yes, but it has to be three people." So it was Dick Lovell, myself and my secretary who were the original incorporators of the American Society of Hematology. We then had to petition the state for a charitable review. And about six months later at my research laboratory which was then the Harvard University Laboratory of Blood Preservation and Characterization, and was located in Jamaica Plain--one day I was sitting there in the laboratory at a bench, working, and this big, burly policeman came walking in, and he said he was looking for the Society of Hematology. I said, "What?" And he said he was looking for the American Society of Hematology--I can't repeat his accent--and so I said, "I'm the American Society of Hematology, and my secretary, here, is the other incorporator." So, he said, "Well, where are your offices?" So, I said, "Well, we don't have any." So, he said, "Well, where is the bar?" And, I said, "Where is the bar?" He said, "Yes. You mean you're not going to have a liquor license as part of your tax-exempt status?" Apparently, the Chowder and Marching Societies of New England have all incorporated over three hundred years in a tax-exempt, charity format, and then they can have a liquor license without paying a fee, and all of this. He couldn't believe that this was an organization that was really going to do some serious work, even though it was charitable! It was very amusing. But, anyway, that was the American Society of Hematology for its first couple of years.

Then we had the actual first meeting down in Atlantic City, at the Chalfonte Hotel in 1958, and there were 350 people that came to that. And it was my privilege to be elected at that time as the regular president of the Society, and we set up--although that was another spring meeting of April--we set up the rotational schedule for December meetings because, when I looked at the calendar of scientific events, the first week in December was the only week that there wasn't some conflicting meeting of national importance. So we scheduled it for the week right after Thanksgiving, and it's been on that schedule.

Tullis: Well, I saw very clearly that I was wrong, and that there really was a need. People wanted a Society, that was the first thing. Secondly, we were able in discussing in that first informal meeting with all of the people there the importance of keeping this as an inclusive, rather than exclusive, society. We got this incorporated into the bylaws--BANG! right in the very beginning, so that people wouldn't do what people often tend to do the second they form a group: they want to keep everybody else out. That would have been a disaster for hematology. We got them all to accept the fact that, first, it should be totally inclusive. Anybody that worked with blood would be, as long as he was reputable and had published some papers, would be eligible for admission to the Society. It would not be an exclusive group. Secondly, it would be a forum where they could get up and speak their piece. The result of this was rapid growth. So that by the meeting in St. Louis in 1959, which was the second meeting, we had grown to about 600 or 700. I think I had over 150 papers submitted from which to select the program. Then the next one was a thousand attendees, in Montreal. Columbus was maybe 1500, and it just grew like that. So now we have 3000 people.

Tullis: Well, we still have a problem with this, because, by definition, it's going to remain a problem, because constantly, the professional hematologists--and when I use the word "professional," I'm speaking of the practitioners of hematology--exert influence. Because, for example, with third-party payment, if, let's say, I'm a practitioner in Cincinnati, Ohio, if I put in to Blue Shield or the Social Security Administration, or anybody, for reimbursement for seeing a patient with a hematologic problem, I can't be paid as a specialist unless I have fulfilled certain requirements, you see. We call it a "specialist," which means either I've passed the American Board of Hematology, which is now a subspecialty board, with its own regulators and its own exams and everything else, sponsored by the American Society of Hematology. Or, I have to be grandfathered in because of my history of having done it, or something of that nature, which means there's constant need, because of the economy of the practice of medicine in the United States, the way it's administrated, one has to have standards for certification. The moment you do that, you begin to say, "This man's a hematologist, that man's not a hematologist," when, from the standpoint of the basic science, the one that's not may know much more than the one that is.

Tullis: It did, and I was one of the last hold outs against certification of hematologists. Dr. Carl Moore, who was Professor of Medicine at Washington University in St. Louis, Professor of Medicine at Barnes Hospital--he and I were the two main voices in the wilderness saying, "Beware, beware, beware, because if the American Society begins to set standards and write exams for the specialty, then it will become more and more beholden to the practice of medicine than to the other parts of hematology." But we eventually lost, just simply because of the economics of the practice of medicine in America.

Tullis: No, but it led to feelings of hostility, and bruised pride, and so on. It was necessary to be sure that the hubris of the practitioner didn't begin to shine in front of the man who was working in an anatomy laboratory, which to me is just as important.

Tullis: I don't think is has. No, it has neither damaged nor assisted the exchange of information at the national meetings. It has not influenced the kinds of publications that are in Blood, the manuscripts that are in Blood. No, I think it's been just our fear about the future more than anything that's actually taken place. We just want to be certain that hematology continues to sponsor breadth and to be inclusive rather than exclusive.

Tullis: No, but they have been able to change the programs a little bit. For example, the pressure of the practicing hematologists, when they attend the American Society of Hematology, has been strong enough that there now is a section that's devoted to the practice of hematology. It's held on a different day, and draws a good audience, and instead of discussing the newest research, let's say, in the field of Protein C, one of the newly identified clotting proteins, or inhibitors of clotting--Protein C was discussed in Miami last fall at the practice meeting, so that those who were in practice and had a person who was clotting too much would know about this protein, you see, the clinical aspect of it. So there's been a more formal subdivision of the Society to answer the needs of the practicing hematologist, but not as yet to a level where it interferes with good basic science.

Tullis: Well, it began very early, just as we'd predicted it would, and we stamped out the fire every other year, Dr. Moore and I, up to the 1960s. Finally, by the middle 1960s, it was evident that if we did not do it, if we, as a society, didn't assume the responsibility for overseeing subspecialty boards, that somebody else was going to do it--probably the pathologists, because the pathologists already had their boards for certification in atomic pathology, in clinical pathology, which included a division of hematology, which was just diagnostic hematology in hospital laboratories.

Tullis: I can't answer that. I don't know.

Tullis: I don't think so.

Tullis: Yes, it is, but I think this, again, goes back to one of the questions you asked me early yesterday, and that had to do with why were so many persons who were professors of medicine and chairmen of departments, hematologists.

Tullis: You must have looked it up!

Tullis: Let's see, I had Wayne Rundles speak, and Ivan Brown speak--yes, we did have a session on bone marrow transplantation. I'd forgotten that--

Tullis: Paroxysmal nocturnal hemoglobinuria.

Tullis: That's right. Because Crosby was working on that here in Boston, and so he was logical to do it.

Tullis: No, that's the organizational meeting you're speaking about--

Tullis: --and I just got on the phone and called some of my friends, like Wayne Rundles at Duke, and so on, and I said, "You know, we're going to have this organizational meeting. Will you come?" He said, "Sure." I said, "Well, would you give a paper on so and so?" The same way, Crosby was right here working with Dameshek, and so that made it easy, you see, and natural. Now, when the next meeting, which was the first actual meeting of the American Society of Hematology, took place in Atlantic City--again, I put a notice in Blood that it was going to take place in one year, to send abstracts in for review, manuscripts to look at. Then we picked a program from that, and that was the first meeting. Then, again, I was still president for the second meeting, before Dr. Moore took over, and for that meeting I'm sure I must have had three or four hundred abstracts submitted.

Tullis: Yes, that's right.

Tullis: Yes. Because from then on, you see, there was a format for it, and papers would be submitted, and the president would pick out referees in different specialties to judge the quality of the papers and decide what would be a good program. There's always been more to have than there's room to have, so there's no question about having good quality.

Tullis: I had forgotten that. Well.

Tullis: No, no. Just to sense what was going on that was of value, and something new would have that. Then we'd begin, not long after that, to have papers that were memorializing individuals. You know, "The Dameshek Paper," "The Dameshek Prize," and "The Stratton Prize," and so on.

Tullis: Not really. They haven't played a role in developing it. They've played a role in disseminating the knowledge of it. Yes. And they're usually very good.

Tullis: At the organizational meeting, we got the sense that the people there understood what we were saying and recommending and wanted that, which was a loosely structured society, minimal overhead, minimal administration, maximal inclusion of people from different branches of science, and to do it in a way that would lead to the development of the field. That was not too hard to get into a constitution. We only had, as I recall, about three or four constitutional meetings under Dr. Davidson and myself, Scott Swisher--and you may have the list there of who were the original members. I had a man from Montreal whose name slips me, a very good hematologist, now deceased, who was on the committee to represent Canadian interests. Who else? Hale Ham, I think, was on it when they--yes.

Tullis: Yes. I know he was. Hale Ham was on it. Because, again, he was here in Boston; it made it easy for us to meet.

Tullis: We were very conscious of wanting to fulfill these principles, and try to--well, even though we didn't put it in the constitution, we carefully advised the officers that the society, once it was formally formed, should not meet in tandem with the American College of Physicians, for example, which is where we'd had the first two meetings, because we felt that would influence the nature of the program to a clinical program, which we didn't want. So we would meet independently, and that's why I had to find a date in the year that there wasn't a competing meeting. And that turned out to be the first week in December. We set the constitutional guidelines up for that, an annual meeting, and all that. [Interview interruption]

Tullis: The relationship was very informal in the beginning, but after two or three years--this is about the Society--the Advisory Board, which consisted of the retired presidents plus some elected ones, requested that the editor of Blood meet annually with the Advisory Board to be certain that there was a commonality of desires and interests in the field. There was no attempt of one to influence the other. But this relationship began to grow and strengthen. There was some resistance in the Society to letting Blood become an official journal of the American Society of Hematology. This was due, I think, primarily to personal feelings on the part of some hematologists from strictly non-practice type of backgrounds--and I'd rather not get into the names of the individuals--who, for reasons of their own, were not supporters of Dr. Stratton. They felt that he was not scientifically trained, and that his medical degree was an honorary degree, which it was, and that he didn't have the qualifications to be a member of the Society, and therefore his journal and his influence should not be in official control of the American Society of Hematology for fear the financial aspects of Blood would influence the Society. So they resisted this for a long (period of time, but, little by little, it became apparent that, for continuity of quality after Dameshek left, and to be sure that the editor would be an appropriate person, and be sure that there was something other than a single individual, like a publisher, making a decision that could influence hematology, it became more and more evident to the officers--

Tullis: I can't specifically say the years. Just to give you a rough frame of reference, I'd have to go back and look at my notes, but it was about ten years or twelve years ago, the obvious move, officially, was going to take place. But it began to build within two or three years after the Society started. I think it's been to the best advantage of Blood, and vice versa.

There was also some worry within the Society, the American Society, that it could be economically a very difficult thing to do, because the publication of a journal is a very expensive business, in this day and age. But with the increase in dues, and with the increase in the circulation of Blood, so that it became apparent that it was as journal that was being read internationally and not just nationally, I think that the wise thing to do was what took place, which is to make it the official journal.

Tullis: Not appreciably. I don't think so. It had changed somewhat with the new editors, but--when Dr. Marks, Paul Marks, became editor--not a lot.

Tullis: Yes. Because, you see, again, an editor-in-chief in a scientific journal cannot have competence in all of the fields--the subspecialty fields of hematology now are many different fields in themselves--so that he has to call on an Advisory Committee to do this. When one has an Advisory Committee, it's going to be used, so that the editor would use associate editors and Advisory Committees that would smooth out any bumps in the road that might relate to him as an individual.

Tullis: I think the influence of individuals can be felt in the early stages of societies much more than in the later stages, because institutions, whatever they are, become so strong in themselves that single individuals can't have very much impact, and I don't see any significant impact in the last decade. Now, that may be just that I'm not as much personally involved and don't see some of the decisions. I think that there have been some strategic errors within the Society, but they're not due to any one individual. To me, one of the errors was to lose oncology as it grew from hematology. Oncologists, originally, were one hundred percent just hematologists, because one of the major side effects of any chemotherapeutic drug is bone marrow depression, whether these are deficient platelets or deficient white cells, or red cells, and all of the consequences thereof. So that, in the beginning, those of us that were in hematology and treated leukemias and everything were the ones that then took over the treatment of solid tissue tumors [?]. But right away, this put a huge number of new concepts, ideas, new chemical knowledge and so on, new pharmaceutical knowledge of particular nucleic acids' synthesis and management, that was important to hematology, but somehow or other, we lost it. And the new societies that came out of oncology were formed independent of hematology. Now, there are those who say that was good, because if oncology were still part of the American Society of Hematology, it would dominate the meeting. Admittedly, we still have some oncology at the American Society of Hematology meetings, and some oncology published in Blood, but I think that there will reach a day, in the not-distant future, when oncology will have reached its apogee and will begin to come back closer to hematology, because it won't have enough new things to support it as a subspecialty. It would be too bad if it couldn't be brought back under the umbrella of the American Society of Hematology.

Tullis: I think it was partly that the oncologists were a brand new specialty, they wanted to run with it themselves--as the new child on the block with the new bicycle wants to drive it himself--and they wanted to be their own boss and have their own institution, and made demands of independence and so on that were not consonant with what the American Society felt was appropriate. I think it's as simple as that. I don't think there was any one person that did this, but I think with a little bit more input to a cosmopolitan, ecumenical approach back ten or twelve years ago in the American Society, we might have been able to accommodate a temporary big growth of oncology and then have it come back into hematology as the new observations in oncology ran their course. There are going to be just so many drugs one can use to treat so many tumors, and then you've done it all, and that day, within ten years, I think will occur.

Tullis: There was no single event, or no single date. It just gradually evolved as oncology blossomed, and oncology blossomed, I would say, around 1970.

Tullis: Yes, but I think it was mostly just the vast numbers of persons that suddenly were involved in oncology. It became a very attractive subspecialty, and it's really a driving force in most medical schools not academically, but, economically, for support of hematology. So hematology, really, if you were to go out and say you trained as a hematologist today, at the university of wherever, and set up the practice of hematology, you would have a hard time supporting yourself, because hematology is primarily the basic science--this is what I've been saying over and over now, for several hours--and the clinical aspects of it are nominal. So you have a patient with pernicious anemia. You prescribe B-12, and he's cured for the rest of his life, you see. If you had a patient with a coagulation disease, you identify what it is, you either put him on anticoagulants, if it's too much coagulation, or you put him on support with fractions[?] if there's something missing, and he pretty well manages by himself, with the exception of things like hemophilia--even there, home treatment is now the treatment. So the practitioner in the specialty of hematology doesn't have enough to support himself as an individual. It's the oncology division of departments of hematology and oncology in hospitals, it's the oncology that, because of the huge number of patients who receive chemotherapeutic management for advanced malignant states, support this large group of people that do it. Hematology alone would have a hard time supporting--without grant support for basic science, you see, in hematology--it would have a hard time supporting itself in the university.

Tullis: It might be, yes. Except, nowadays, you see, good science still can get American money from things like the National Institute of Health and some of the private foundations. The good science is still going to be supported; that's the basic science in hematology. It has nothing to do with the man who's, as we say, a practitioner of hematology. On the other hand, in oncology, the practitioner of oncology is in control of vast amounts of money, quite independent of basic research money going into mechanisms of carcinogenesis and mechanisms for the treatment of cancer.

Tullis: In oncology, you mean.

Tullis: I don't know.

Tullis: I don't know, but it's been a problem, and many institutions have expressed worries about its long term significance.

Tullis: No, I think not. I've enjoyed it. I have no role in it whatsoever now. There's nothing that in a young country like America is more evident than how quickly people pass over the horizon. One of the humorous stories of my life, as I've told many students, having founded the Society, having been the interim president and then the first regular president for a period of a year an a half, I then went to the next meeting after the St. Louis one where Dr. Moore took over. The next meeting, a year later, was in Montreal, and I got there to register, and they said, "What was the name?" And I said, "Tullis." And they said, "Are you a regular member of the Society?" And they couldn't find my name listed on the rolls. My secretary had left it off. You know, like old soldiers, people fade and die very fast in young countries. So, other than having served my standard time that we put into the constitution of five years on the Advisory Committee, and having served now--I shouldn't say that--but all I did afterwards, when they rewrote the constitution the first time, not the second time, I was on the Constitution Committee, and a few things of that sort--but I've had very little official interaction with the American Society.

Tullis: I've gone to all the meetings, but that's all.

Tullis: Ask the question once more.

Tullis: The funding of research.

Tullis: At the present time, the research money--now, this is not official; this is my view of it. As I view the research money that's passed out by the federal agencies, like the National Institute of Health, and to a lesser extent the Environmental Bureau in the Defense Department, and so on, it has two purposes: first, it identifies quality research, because of its peer review mechanism, which is the best in the world. But then, equally importantly, they try to evaluate the individual who is the P.I., the principal investigator: is he full-time, or is he part-time? If he's full-time, is he young enough that this is part of his career development? And this is the way it should be. I mean, they don't want to give any money to me--why should they? Because my career doesn't need anything. I'm at the end of the career, rather than at the beginning of the career, so that I should have to get my money elsewhere, which I do, for my research, through private foundations and things of this sort, grateful patients, and things of that nature. But the increasing difficulty of getting federal funds is in part robbing the future to support the present. This is a real apprehension to me. It's an apprehension of mine, because I see youngsters, who, as I've watched them come through medical school--for years, I've been a professor here at Harvard, and had to teach these youngsters, in medical school--then have them again as house officers in my program at the hospital, and watch them make their career decisions; ones that twenty-five years ago would go into basic science for a period of ten years, or maybe for life, see the uncertainty of funding that good career investigators constantly face every time their grant comes up for renewal. Even ones doing superb research, every five or ten years are right at the edge of not knowing whether their whole career is going to stop for lack of funding. And this creates a fear that has driven or frightened some of the bright young people out. Now, we haven't felt this yet, because there are enough people still willing to take that risk that America's staying au courant with international knowledge, but I'm worried for fear that ten years, twenty years from now, we will see less volume of good basic knowledge constantly advancing the field of hematology--I shouldn't use the word, hematology--just the field of medical science, because it is not satisfactorily funded as a career for the youngster.

Tullis: Yes, in a way, because certain diseases become popular, you see. When it's popular, whatever it is---whether it's cardiac research, or transplantation biology, or what--it's easier to get a grant for a period of time. but that's not major influence, because you'll always find some people that have their own idea of their own subspecialty, their own field, who will plow ahead whether they're adequately funded or not. But I think it inhibits the volume, rather than, so far, the quality.

[tape interruption]

Tullis: My own current work in this field is right at the border between neoplasia and hemostasis. I'll get into that in a few minutes, because I've got some concepts of the manner in which platelets interact with tumor cells and lead to local hypercoagulability as part of the metastatic process. That's what I'm currently working on. But let's look at a background, first, of hemostasis and of bleeding in its broadest sense, which includes both coagulation and hemostasis, in order to understand some of the things I'll be referring to in the next few minutes.

Historically, the first person to, in modern times--by modern times, I mean something since the Greeks--to study the kinetics of blood clotting was a man in England, at the same period of time when Benjamin Franklin was over there to the Court of St. James, representing the colonies which were organizing into a confederacy before America was formed as a country. This young man, Mr. Hewson, was a surgeon--they called them, "Mr." in England--at St. Bartholomew's Hospital, and Mr. Hewson, in the afternoons, would pass the marketplace, which still exists, right outside St. Bartholomew's Hospital, in route back to his boarding house, because he was courting the daughter of the woman who owned the boarding house that Mr. Franklin was living in. Hewson saw them, one afternoon, slaughtering a sheep, and apparently when one slaughters a sheep, one cuts the throat, and the sheep immediately bleeds to death and goes into shock as the carotid artery pumps out. He noticed that the blood didn't seem to clot at fast as he thought blood usually clotted when he was dealing with it surgically in the operating theaters at St. Mark's Hospital. So, one day, he took five or six glass vials, and put them on the ground just at the moment when they severed the neck of one of these sheep, and he directed the out flowing blood into each of the five or six vials, and made the observation that the blood which was put in the last vial clotted before the blood which was put in the first vial, which meant that as the sheep was going into the agony of pre-terminal biochemical changes, its blood became more coagulable, hypercoagulable, rather than acoagulable, and he timed all this, and philosophized on what it might mean.

I mentioned the role of Mr. Franklin just as an aside, because shortly after Hewson made this observation--he was only twenty-three or twenty-four years of age, he infected himself accidentally while doing an autopsy and died of sepsis, and his young wife had apparently became enamored of Mr. Franklin, followed Mr. Franklin afterwards--Mr. Franklin went back to Philadelphia, where the American Constitution was written, and started the Hewson family, which is a famous medical family in America, with the child of the man who had died. But Franklin was very much her supporter, and confidant. 

Hewson's original observation prompted people to think that there was a dynamic element to clotting, which they later referred to as enzymatic ways of changing blood from a liquid to a solid when anything took place that deranged the circulatory integrity. But it stayed pretty much at that level, until about the 1900s when, unfortunately--I say, unfortunately, from the standpoint of research, but fortunately from the standpoint of medical treatment--Lewisohn, at Mt. Sinai Hospital in New York, conceived of collecting blood into an anticoagulant solution, like citrate or oxylate, to block the action of calcium, which was shown to keep the blood from clotting. The moment they did that, they could collect blood for transfusion purposes without using direct transfusions, but they simultaneously were able to traumatize the blood so badly that there was nothing hemostatically left in it. The platelets were damaged, the coagulation proteins were activated and damaged, but one didn't see it because the blood didn't clot.

I mention this because, if you look carefully at the literature of the late nineteenth century, you'll see the first reports suggesting that platelets, these strange little plate-like objects which were deficient in the blood of people that tended to bleed, could be replaced by transfusion. But, of course, those were direct transfusions of freshly collected blood, not anticoagulated, and the only way they could do the direct transfusion was to use what was called a Kimpton tube. Empirically, they had observed that if they took a glass tube and coated it with wax that the blood could be collected, and particularly if they shielded it from losing the sealed tube, the blood could be collected and would remain liquid for a half-hour or more, rather than clotting like Hewson's sheep. And they reported that blood so collected would replace the missing platelets in people with platelet deficiency diseases, and stop the bleeding. Then, if you look at the literature twenty years later, you'll see very astute clinicians saying that these old observations of the people in the late nineteenth century were poor observations because blood transfusion would not replace the platelets. Well, now, the reason it wouldn't replace the platelets is there were no viable platelets left in the blood. The platelets in turn were essential to give something to the endothelium which is essential for the endothelium to remain impermeable to colloid solutions like plasma. In the platelet, that's one of the functions it fulfills. This substance was called "Substance P" in Switzerland after permeability, and then much work was done in an attempt to isolate what it was, but it was a part of the platelets. We then found another one of the functions of platelets, because of the increasing knowledge of adhesion and aggregation of platelets was to form a plug, which, if one damaged the vessel wall by either touching it with an electrode, or cutting it, or anything of that sort, the blood would begin to leak out of the capillary bed where it was damaged, but a platelet plug would form and, if you will, cement the area. Then a third function of the platelet, totally independent of that, we found was the supply of what had been called PF 3, platelet factor three, which was the precursor of thromboplastin, that was being generated in the plasma. So all of this was worked out and evolved in the last ten or twenty years as part of hemostasis. If you have qualitative abnormalities in your platelets where some of these functions are lost, or if you have quantitative deficiencies in your platelets, where there aren't enough of them, these three mechanisms are deranged--and I'm speaking of just the grossest aspects of it; there are some aspects that are too technical to go into.

Tullis: I wouldn't use the term platelet as a sponge; I'd use the term, platelet as a truck. It's a system for delivering things which never was thought of before, and the platelets, tiny as they are, deliver and carry a lot of important monoamines, and things of this sort, to local areas in the body--serotonin is one example, catecholamine is another example, histamine is another example--and this is quite independent of their role in protecting the integrity of the vascular bed. But probably their primary role is protection of the vascular impermeability. If you look at hemostatis phylogenetically, if you go down the scale, you get back to the Limulus, which, as you know, has no clotting system whatsoever. All it has is giant platelets that plug up the holes when you damage the circulatory system. There are all gradations in between the Limulus and the human, where nature has supplied proteins like fibrinogen, to strengthen the hemostatic plug and maintain it.

Now, I mentioned that my personal work had to do with sort of an interface between cancer and clotting.

Tullis: Well, it dates back to about 1970. I've only had preliminary publications in the field. I publish now only when I am absolutely certain. I've always thought I was certain, but the older you get, the more cautious you get. I'm just ready to publish now some manuscripts in this field. But the field dates back to the observations of a young surgeon by the name of Cliffton working at the Memorial Hospital in New York City. He observed that if he heparinized an animal before injecting tumor cells into the portal circulation, he cut down on the 'take' of the tumor--the number of positive 'takes' that he had. He knew from the work of Dr. Warren here at the Deaconess, who had been my chief at one time and for whom I have great respect, how many tumor cells it took to establish a metastasis with a transplantable animal tumor. Shields Warren had studied this because of his interest in tumor biology. The young surgeon found that if he heparinized an animal, as I say, and then repeated Warren's experiments, the animals did not get the tumor. So the anticoagulant appeared to be doing something to prevent the growth of local metastases.

Immediately, everybody said, "Well, heparin has lots of other chemical effects, and these are probably what kept the tumor from growing. It's not the anticoagulant effect, but rather that heparin blocks a translation of what we call messenger RNA, for example, and that would interfere with protein synthesis in a broad basic way. But the Russians, then, did some work where they found out if they defibrinated animals by using snake venom, that the defibrinated animal, which doesn't clot, also resists transferable animal tumors the same way. This was followed, a few years later, maybe in the middle 1960s, by an epidemiologist in England by the name of Allen, who found that people who had been put on coumadin anticoagulation for heart attacks, when matched with controls of people with similar heart attacks and similar age, sex, and background, who had not been given anticoagulants for their heart attacks, that the incidence of death from cancer was sixfold less in those that were on coumadin than it was in those who had not received anticoagulants. So this made it look like something of an undescribed nature was influencing cancer metastases by cutting down on either the rate of growth of the tumor or its ability to set up housekeeping in other parts of the body of an anticoagulated individual. I should say that the work thus far--this other work, to which I'm referring in the literature--has not led to a lot of concrete data vis-à-vis therapeutic effectiveness of such an approach, and I'm not discussing it from that standpoint, but merely from the historical aspects of the development of the science and then finally my own personal involvement in it. But there was a lot of work instituted in different countries simultaneously because of this. I think the best thing that can be said is that it's now been proven quite definitely that, certain animal tumors, particularly in mice, rabbits and rats, are favorably suppressed by anticoagulant therapy by diverse means: either removing fibrinogen, or giving heparin, or suppressing prothrombin, or even suppressing platelet function by giving aspirin. But the work at the human level, from the therapeutic standpoint, really hasn't progressed very much, although a good  multi-institutional study that's sponsored at Dartmouth University has recently published some data to suggest that with certain advanced malignancies, particularly carcinoma of the lung, if one anticoagulates the patient at the same time as starting the standard chemotherapy protocol, and that those patients who receive both the standard chemotherapy protocol, plus anticoagulants, live longer than the ones who get the same chemotherapy, without anticoagulants. But the beneficial effects are still relatively minor, and that's not the reason I wanted to mention this.

My own interest in this field began because of platelet work. Platelets as part of hemostasis, and, secondarily, as part of clotting, seem to play a role, and the role that we more or less stumbled on was the following. Because of this work that I've mentioned from the other countries, I thought that the logical way to approach it would be to take tumor cells, fresh from the operating room--fresh specimens--and bring them here into the laboratory, analyze the cells, and see what coagulant or anticoagulant substances I could recover physiologically from the cells. What we did was take growths like carcinoma of the colon, where one can take normal cells identified right adjacent to the tumor from the same specimen, so that one had normal and abnormal cells from a single individual, and we would bring these here, and wash the cells, make single-cell suspensions, then homogenize, and so on, and try to identify the clotting proteins. Well, to our surprise, what we didn't find is easier to discuss than what we did find. There was no prothrombin, there was no hemophilic factor, there was no fibrinogen nor accelerator globulin. There was none of the usual clotting proteins, with the one exception of thromboplastin, which was also being worked on by Dr. Gordon, a superb investigator at the University of Colorado, who was identifying the chemical nature of tumor-derived thromboplastin from tissue cultures of melanoma cells. But, in our studies here, we didn't do that.

However, there's a lot of empiricism in research, as you know, and there was an assay that we had developed in our laboratory, called the Platelet Anti-Thrombin Assay, which is still an experimental tool, because it hasn't yet been applied enough at the clinical level to know what its parameters are. But when Dr. Kioaki Watanabi was with me as a graduate student for three years, in the late 1970s and early 1980s, we asked him to set up the Platelet Antithrombin Assay, based on an observation of one of my younger Tullis associates, Dr. Francis Chao, who had identified platelet anti-thrombin and which we'd published data about. So, we had this Assay in the laboratory, and I said one day to the technician after we had found that cancer cells had no significant amount of coagulant protein, I said, "Well, for heaven's sakes, let's dump some of the tumor cells into a Platelet Antithrombin Assay and substitute the tumor cells for the platelets to see if they have any anticoagulant properties," and to our amazement we found that tumors from the colon--and we later found tumors from the pancreas, and certain other organisms--bind thrombin, and bind it very avidly. They have both high-affinity and low-affinity binding sites for thrombin, apparently on the tumor cell surfaces. Thrombin is the principal coagulant substance that's generated when blood clots, and the question, obviously, was, well, why do they bind thrombin, because if there's a receptor there, there has to be a reason for it, because obviously the internal aspects of the cell are affected by activation from the ligand.

Thrombin is a peculiar enzyme. In addition to its role in conversion of fibrinogen to fibrin, which is its principal role in the blood, it also is a very potent mitogenic substance. This has been shown in tissue cultures. It stimulates rates of growth, the cell division. It may even be mutagenic, although that has not been as well established as its mitogenicity. So, we philosophized that maybe certain cells of the body had binding sites to begin with and if you activated these often enough and already had a hypercoagulable state, such as, if you will, cigarette smoking, or estrogen use, or stress, or many of the other things that turn on clotting, like the sheep outside at St. Bartholomew's hospital, that this type of mechanism would make the temporary presence of thrombin cause the tumor cells to break down and liberate more thromboplastin, this would create for a microsecond longer the presence of additional, molecularly active, thrombin to bind to the receptor sites on the cells, and set up an increased rate of tumor cell division. Not that it started the tumor, simply that if a tumor was already there because of something else--genetics, radiation, you name it--that this would be a propagating force for a self-supporting, autocatalyzing process to increase rates of growth, and division, and dissemination. Now, having found that these tumor cells appeared to have thrombin binding sites, the next question was, well, where did the substances come from that did this, and what were the substances? So we looked at the platelets from the same individuals in the next series of studies and found out that the thrombin binding sites on the platelets, which is what we had set up the Platelet Antithrombin Assay to measure over the years, are decreased in these same patients where the tumor cells have more binding sites for thrombin. So, the question was, first of all, what was the substance, and, secondly, had a transfer taken place from one cell strain to another? With respect to what is the substance, our study is attempting to identify by gelelectrophoresis, and so on, the protein bands that are in the membrane of the platelets. The data thus far suggests that there is a deficiency of glycoprotein l-b from the surface of the platelets, and it's particularly the glycocalicine part of this Protein l-b that is lost from the platelet of these people with advanced cancer and is present on their tumor cells.

Now, the answer to the second question, how does it get from one cell to the other, I don't know. I have two theses, but we're just now starting some experiments on this. One of the theses is that it's a direct cellular interaction. Two researchers in England, Vale and Warren--that's a different Warren than Shields Warren--published some electron photomicrographs a few years ago that show quite clearly that platelets interact with the surface of tumor cells as part of the lodgment of a metastasis in the vascular bed. So one of the possibilities I'm entertaining is that the platelets actually transfer by direct physical adherence temporarily to the tumor cell, part of the membrane of the platelet to the tumor cell, instead of to the endothelium, and that this, then, is the site which will bind the thrombin. Another possibility is that it's indirect and mediated by activation of proteases within the platelet leaking out from the platelets having been activated through coagulation mechanisms, or particularly fibrinolytic mechanisms, having these proteases leak out from the platelets and from the tumor cells--because tumor cells are full of proteases--and that these, in turn, have split off sialyic acid, like Protein 1-b, splits of glycocalicine, and that this then is free in the plasma and later picked up on the tumor cell.

Now, I don't know which of these it is. We're just starting some in vitro experiments, and trying to do this thing. Come back in five years; I might have an answer for that. 

Tullis: Well, the systems of hemostasis and coagulation appear to be far more important than just an intrinsic mechanism for keeping blood in the vascular bed, which is what nature apparently designed it for in the first place. Many of the biochemical and physiologic changes of your other organs and systems of the body draw on the enzymes that are activated at the moment clotting is activated, or when platelets are functionally altered so that they release some of their internal substances. There are many other tissues of the body, and my area right now is to see if one of these is neoplasia. We know, for instance, that clotting is necessary for repair. Otherwise, every time you severed your skin, you would never heal with normal skin again. You have to have, first, a clot, then you have to have fibrin formation, as a matrix, and then you have to have fibroblasts and other new cells laid down on top of the matrix. So all of the enzymatic systems of coagulation are activated for even minor things such as that. Similarly, any mechanism that causes an end product, like a clot, has to have a system of building inhibitors to keep the whole system from turning solid the first time you activate your clotting. So you have to have an anticoagulant system that's even stronger than your coagulant system. And these have to be kinetically balanced, so that you constantly are both making clot, when it's needed, and lysing clot, when it's no longer needed. Otherwise, you would not be able to restore vascular integrity after you have had a thrombosis someplace. So that these systems apparently play a very fundamental role in resistance to infection, because of the mediators, and so on. So I think coagulation and hemostasis create a fairly fundamental, basic--going back to Claude Bernard--milieu interieure, necessary for normal cell function.

Tullis: No, this is work that's been since the 1950s. Yes. Very definitely. I'm not building at the present on historical scientific knowledge that antedated this century, no. This is current.

Tullis: Well, pick one other than clot retraction, because I'm not sure clot retraction has any role whatsoever physiologically in the human. I think it may have a very fundamental role in very primitive animal forms, but there's no data that clot retraction per se exerts, if you will, a plastic effect on blood vessels to keep blood from leaking out. That remains to be shown. I think it's sort of a phlyogenetic holdover from earlier stages of biologic life.

Tullis: Pick out some other area other than clot retraction!

Tullis: Well, yes, now, the interrelationship between fibrin and platelet plug formation is, of course, very fundamental, but the subsequent retraction, which is a function, if you will, of platelets and their need for ADP and energy hasn't shown that the retraction itself has a role, either in strengthening the clot or in doing anything else to restore the potency of the vessel.

Tullis: Very--you mean with regard to platelet aggregation.

Tullis: That's right. I think we have tended to become too pure with respect to working with single cells from the body. For example, everybody attributes to the platelet all of these functions when I think there is some evidence to suggest that platelets and red cells have to interact under the normal circulatory dynamics to have proper balance exist. For example, if you look at the platelet itself, you have an energy need which is apparently supplied, in part, from the red cell, for the right amount of ATP degrading to ADP to AMP and then reverse. Because, if you look at platelet aggregation in the absence of red cells, you'd get totally different findings, from which you get in the presence of the red cells, which was first found out in Scandinavia many, many years ago. Contrary wise, people look at red blood cells and say, "Well, this is what we call a schistocyte, a red cell that's been damaged. Therefore, that means that there is activation of clotting, and the red cells are being pushed through a clot someplace, and they're being physically damaged by this pushing through a clot." Well, that's totally fallacious reasoning, because you can take a red cell and hit it with a hammer, and it just deforms, but comes right back to its normal shape because of its elasticity. You don't damage a red cell unless there has been activation of platelets in the area of the red cell, because it may be one of the prostoglandin byproducts that then changes the red cell from a deformable cell to a rigid cell, so that then, if you push it through a clot in circulation, you have damage to the envelope of the red cell. But it takes the interaction of these processes.

I don't know whether you've ever looked at a living preparation--maybe you have--of the circulation through a microscope, or through an everted hamster cheek-pouch. If you have a big enough vessel, you see something that is really quite distinct. There's the central core of red cells, which are quite dark, and then the light yellowish plasma around the periphery, with a Newtonian kind of flow. Meantime, the platelets are bumping along the endothelial layer, and the white cells, too. So that they're coaxial, they're separated during flow, but then, the moment you damage the vessel and have turbulence there, I think the turbulence creates the interaction between the platelet and the red cell which is necessary to set off the whole process of hemostasis.

Tullis: Well, there were many meetings in support of the field that unquestionably had a good effect on increasing the flow of information and speeding up the dissemination information from individual laboratories, so that everyone could work simultaneously on it. There were so many it's almost redundant to go through the whole list, but I'll mention just a few: the Macy Foundations, the Josiah Macy Foundation conferences were important. Walter Seegers had a conference every year in Detroit that was very well attended and quite high quality. The Henry Ford Foundation sponsored a series of the same type. We had the meetings of Protein Foundation and later the Center for Blood Research here.

Then, at about this time, the committee on thrombosis and hemostasis, the international committee on thrombosis and hemostasis changed from a committee to a society. This has had a very good effect on the whole field as a subspecialty within hematology. I just returned from meetings last week out in San Diego of the International Society of Thrombosis and Hemostasis, and these are very good meetings, attended by, perhaps, a thousand people, all in the subdivision of what we're talking about. The Committee on Thrombosis and Hemostasis had another good thing to its credit. When it started, it was started purely from a need to standardize the nomenclature after one of the Princeton meetings on coagulation. This was in the late 1950s, I believe. At that time, everybody who had identified a missing coagulation protein, usually named it after a family, or a person, or a drug, or he named it after his patient, or himself, or his town or university, or something else. There was no system. The International Committee got together with the principal investigators, and they all agreed that henceforth they would use a nomenclature system of numbers, Roman numerals, starting with the first protein identified, which was fibrinogen, as number I, prothrombin as number II, which converts, of course, to thrombin; number III was left blank because it, in essence, was the thrombin activated one. Then there was IV, which was assigned to calcium, because that was historically the next thing that was known in the coagulation field. Then the accelerators, beginning with proacclerin which became Factor V, and so on. There was only one that they made a mistake on. That was VI. There is no VI because the one originally assigned to number VI proved to be an artifact, and not real. But VII, VIII, IX, X, XI, XII and XIII were then accepted as bona fide. And each man agreed, and the editors of the principal journals agreed, they no longer would accept for publication any article dealing with these coagulation proteins without using the Roman numeral first, then they could call it anything they wanted afterwards, in brackets. Within a matter of just a very few years, standard nomenclature came in, which clarified the field, so at least students could understand what one was talking about. Unfortunately they have not done anything about new proteins like Protein C and Protein S that have been described and well characterized, I'm sure that they should get numbers, too, but that'll be on down the road, somewhere.

Tullis: Platelet Factor III, probably, but Platelet Factor III then ended up being called PF-3, rather than Roman numeral three, so it's an artifact too, in that sense.

Tullis: Well, I shouldn't say, "artifact," but the way they used the Roman numeral was incorrect.

Tullis: No.

Tullis: Oh, I think it was. I think it probably was, yes.

Tullis: Precisely, because in those days when he published his original paper, we didn't have the rapid means of dissemination of knowledge that we have now.

Tullis: Yes, sure. That's the only way they would get it, because there was no hematology journal, there was no coagulation journal, there was no hemostasis journal, all of which there are now. So they would have to comb all of the biochemical journals.

Tullis: Not uncommon at all. It's just like the "World News Tonight" you hear on the television--everything that's happened in the whole world, today! And believe me, in 1934, you didn't know what was going on in the world or in blood cells!

Tullis: Well, they're not forerunners, but there are many people working in the field who are certainly very credible people--more, I think, in Europe than in this country.

Tullis: I don't think so.

Tullis: Well, let's see.

Tullis: Yes, if you'll just give me the name, I'll tell you what it was for.

Tullis: Hoekten Silver Medal. That is a prize that's awarded by the A.M.A every year, I believe, for research in a new field that has direct implications in the practice of medicine. The biomechanical equipment which I had helped design, and which I named after Dr. Cohn, had reached the stage where we put on demonstrations of how one could collect blood, and separate it into its component parts as part of the collection process. We demonstrated this at one of the meetings of the A.M.A and were surprised later to find out that we were awarded the Hoekten Prize because of this.

Tullis: I'm sorry; I'd have to look it up. I believe it was 1954, 1955, along in there? Maybe a little later than that. Yes, I'd say about 1956.

Tullis: The Mary Lasker Group Award was given by the American Public Health Association; that Winged Victory that you see behind your chair represents that. It was given each year in honor, not to a single individual, but a whole laboratory that was working as a broad, multi-disciplinary group, an approach to a new set of problems in medicine that had public health implications. It was given to Dr. Cohn's group. I was the youngest member of the group, so I didn't have access to that Winged Victory until all the others had left, I guess I'm the last one alive or not retired, and so it's now in my office here.

Tullis: Oh, yes: Dr. Edsall, Dr. Cohn, Dr. Oncley, Dr. Surgener --can I stop there, because I don't remember who the official members were. Those names come to my mind first.

Tullis: That had to do with the work I was doing on platelet antibodies and their role in ITP. That was awarded in the early 1960s--it seems to me it was about 1962, at the Pasteur Institute in Paris.

Tullis: When Dr. Katsunuma was President of the International Society; he wanted to start an award which would be given at the annual meeting every other year, each time the International Society met. On that first occasion, Dr. Bessis was privileged to get it from Europe and I was given the award for the United States for the fractionation of the proteins which dealt with autoimmune processes, such as immune nutropenia, and idiopathic thrombocytopenia purpura, which we were doing just by an electrophoretic analysis, and so on. Unfortunately, Dr. Katsenuma died shortly thereafter, and he had not done the necessary legal things to make this a permanent prize, so there were only the two awards that were ever given.

Tullis: That had to do with the work I was doing for the Defense Department in establishing frozen red cell as a technology which could be practically applicable through the use of our biomedical equipment, for the freezing of blood, and apparently they have a prize which they award.

Tullis: That was given to me because of the role I had helped play with Dr. Berry in establishment of the Berry Plan as a law of the land for how to use physicians who were being drafted during peacetime as civilians and to be sure they were used in the proper medical specialty, rather than in work unrelated to their training.

Tullis: The Alpha Therapeutic Award was set up by a Japanese physician by the name of Dr. Naito. He was head of Green Cross Pharmaceutical Co. in Japan. He purchased the biologic division of Abbott Laboratories in California about 1970, and started a plasma products firm, called Alpha pharmaceutical using the Abbott division. They gave me the prize for what I had done with albumin in about 1976 or 1977. The National Institute of Health asked me to do a study, and then organize a national meeting at that time, on the use and abuse of albumin. A series of papers derived from the meeting followed by published guidelines on the appropriate clinical use of albumin. It was for this that the Alpha Therapeutic award was given.

Tullis: I think not. I've enjoyed thinking this through myself. I never looked backwards before!

[End of interview.]

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