ASH Oral History: Louis K. Diamond (6/7)
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Q: An interesting point is raised here. We've seen in a number of instances where important conceptual foundations for a new discipline of hematology was laid by work done by practitioners in other fields. You had physical chemistry and techniques, introduced by someone like Edwin Cohn. You have the work done in genetics, Mendelian genetics, around Rh factor, around thalassemia, around sickle cell anemia. You have the work of Landsteiner and his group in immunology. Are there other such cases where this is borrowing, or transfer, of important techniques and theories from other fields?
Diamond: Oh, there must be several different instances of this kind. I'm not familiar enough to be able to translate it immediately. But now the genetics, the method of probing for genes -- the location of genes, the inheritance of genes, how genetic engineering can be stimulated -- are all examples of the same development. The ability to manufacture anti-hemophilic globulin for example, the ability to manufacture the human growth hormones, and outstandingly the ability to manufacture insulin are good examples of how this has carried over. This is really the future of medicine. We will have methods of treating any number of diseases.
Q: If I might follow up on this question. It's clear that there's this transfer of concepts, and transfer of techniques or technologies, if you will. The other aspect that would be interesting to delve in to a bit is the institutional context. I don't think that transfer would be possible unless there were institutions set up that could allow for this interdisciplinary approach. This might, perhaps, have laid the foundation for hematology as a self-conscious discipline. I was wondering if you could speak about your own experience at Children's Hospital in Boston, going back to the 1930s and 1940s, where you were in a position to come into contact with the latest in the scientific developments, and how you saw your role during that period?
Diamond: Various foundations have been set up over the past dozen or more years, increasingly now, to support research by giving money for research laboratories -- even for putting up buildings in which research laboratories can be established. In Boston, for example, we have what is now called the Enders Building, named after John Enders -- who recently died. He was the man who developed polio vaccine, to prevent infantile paralysis, which used to be a great scourge in medicine and crippled thousands of people, children particularly. He also developed a vaccine for measles, and German measles. That was the sort of thing that developed. Various agencies, and various organizations were set up to sponsor such laboratories.
Then, to mention just one other -- one of many, this is the largest one -- the Howard Hughes Foundation has billions of dollars. They also established Hughes Fellowships, given for five years to gifted research men. Now not just the Hughes Foundation, but several other similar foundations are giving money not just for research work, but for bricks and mortar that are necessary, and continued support for research. So this, really, was an outgrowth, if you want to think of it so, of the blood bank, RF, blood grouping, and IgM, IgG, and other immunology research that came along with this. You might say it wasn't just that, but the blood bankers and the hematology research people like to think that this was the stimulus that got things started in that pattern.
Q: This corporate interest in development of medical sciences, through philanthropic foundations, through the allocation of funds, etcetera. Has that gone through different cycles? Certain times more money comes from corporate sector as opposed to other times? Has that affected the types of research in any way?
Diamond: Only to a very limited extent. That possibly -- I don't know that this is so--maybe Eli Lilly is more likely to support research in the field of insulin, or something of that sort. The Ortho Laboratories did sponsor some research in blood groups, but very little comparatively. These pharmaceutical companies are working more closely with research organizations, because eventually it'll be to their interest. Now a good example of that might be the fact that the Lederle Company was the original sponsor of research with anti-cancer drugs, particularly methotrexate. That came about in an interesting way, too. Dr. Farber, the pathologist at the Children's Hospital in Boston had always been interested in cancer in children. Our interest in leukemia was close to his heart, too. A research finding that he made was that if you gave large amounts of folic acid to an individual with a certain type of cancer of the lung, the cancer cells grew more rapidly. In so doing, they outgrew their blood supply and the cancer started degenerating.
Q: With the folic acid.
Diamond: With the large doses of folic acid. He wanted to pursue that. Folic acid was being manufactured in part by the Lederle Company. They had a research man named Dr. Subbarow--S-U-B-B-A-R-O-W--at Lederle Laboratories. They offered Dr. Farber the opportunity to get Dr. Subbarow off to Boston to work on folic acid. Dr. Subbarow and Dr. Farber, said, "Why don't we try something that will prevent folic acid from stimulating this -- an anti-folate." Dr. Subbarow came up with an anti-folate, which indeed in animals prevented the cancer from growing because cancer cells needed folic acid to grow. So this anti-folate, a very toxic material unfortunately, could then be tried on some human cases and, although its toxicity was such that it couldn't be used routinely in a large enough dose to help everybody, it did slow down the growth of tumors--particularly leukemic cells. Dr. Subbarow proceeded to develop a half-a-dozen different anti-folates, and eventually came up with one that was much less toxic. This eventually was the material now known as methotrexate.
Q: Was this work done-
Diamond: In Boston.
Q: In Boston. Not in the Lederle Labs.
Diamond: That's right.
Q: But Subbarow is still associated with the Lederle Labs.
Diamond: Right, and they sponsored Dr. Subbarow's work. He was their employee, in a sense, even though he worked in Boston at the Children's Hospital pathology lab under Dr. Farber. At that time, I was setting up the National Red Cross blood banks. This would have been the early 1950s. Although I was involved -- I came back and forth to Boston, and I still had charge of the leukemia cases. One of my men, one of my trainees, took over the responsibility for this treatment that Dr. Farber's anti-folate, methotrexate, was used on. That's how that developed. Lederle Laboratories still, of course, manufactures methotrexate, which was one of the first drugs.
Q: So what we're actually seeing here is a process that might have begun as early as the 1930s with Hood Milk Company, and perhaps earlier. But especially during the 1940s and 1950s, we see a definite interaction between university-based research and different interest relationships.
Diamond: That's right. Slowly developing and expanding, so that now there are dozens and dozens of such joint ventures.
Q: So it's not as contemporary a phenomenon as is often suggested. It's not something just of the 1980s or the 1970s.
Diamond: Oh no. It really goes back, if you want to start it, way back in the early 1900s when serology and immunology and bacteriology really began to blossom.
Q: So this hybrid field of hematology actually played a central role in this development.
Diamond: I feel so. Now, let me go on to the further development, which I think is important, of erythroblastosis fetalis. After Levine showed that the so-called Rh factor was the basis for it, we of course began using only Rh negative blood for the transfusion of the infants with erythroblastosis, or hemolytic disease from the action of maternal anti-FH on the infant's Rh positive blood cells. The way to treat such children, obviously, was to give them only Rh negative blood because some of the maternal antibody against the Rh positive cells of the infant would have carried over and be present in the infant's systen, and would remain there until it was used up--which took a matter of two, three, four weeks or so of gradually diminishing. Meantime, Rh negative blood was necessary to protect the infant's circulation against the reaction of this anti-Rh which the mother had given it, in-utero. Now, the best way -- Dr. Wiener, as well as we -- decided was to remove the infant's Rh positive blood and the serum containing the infant's plasma containing the Rh antibody acquired from the mother, and replace it with Rh negative red cells which could not be damaged, and which the infant could live on until the anti-Rhwas all gone. Then the infant's own Rh positive cells would not be destroyed. Dr. Wiener dissected and cut an artery in the newborn infant's wrist to withdraw blood, and at the same time put blood in -- Rh negative blood -- into a small vein in the other arm. This was a traumatic, difficult procedure. Me in Boston, in my laboratory particularly, decided that we wanted to do this using one of the very prominent, obvious veins in the umbilical cord -- the stump of the umbilical cord. First, we tried using rubber catheters, but these didn't work too well because the blood would clot in the rubber. About that time, plastic material became popular. Our neuro-surgeon, Dr. Frank Ingraham--I-N-G-R-A-H-A-M had developed a plastic material, manufactured by some plastic manufacturer that was non-clotting surface. In other words a smooth surface on which blood did not clot. He suggested maybe I should try this for blood. I did. He had shown that blood didn't clot too quickly -- it took fifteen, thirty minutes before clotting took place. So we tried a plastic catheter in the umbilical vein, threaded that in, and it worked beautiful. We could do a complete exchange transfusion in an hour or so, withdrawing ten ml, or twenty ml, at a time and replacing it with 10 or 20 ml of Rh negative blood. This exchange transfusion, or replacement transfusion, became the standard method of treating erythroblastosis fetalis -- by exchange transfusion. Of course you could use it more than once, even a half-a-dozen times if the baby needed half-a-dozen transfusions, using the umbilical vein.
Now that led to an interesting and important development. That is that in newborn infants, where they need blood repeatedly to measure oxygen, C02, and any number other factors, now instead of drawing blood by a needle every time, they thread an umbilical catheter into the umbilical vein, or cut down on another vein if the umbilicus isn't available. This has become the standard method of monitor in a blood changes in the newborn, and in older children too -- using plastic catheters and leaving them through small needles, or just cutting down on a vein and threading in a catheter and leaving it there for one, two, three, four days or more. These catheters can be sterilized and used without fear of contamination. This has been an important development in the management of newborns and of small infants--and particularly in premature infants, where you're dealing with tiny veins that would be difficult to catheterize ordinarily. It has made a great difference in the mortality of premature infants and of sick babies in the first few weeks of life.
Q: How long would it take for such a technique to diffuse through medical --
Diamond: Remarkably fast, because -- originally it took somebody like Wiener to do an exchange transfusion using his cut-down method. A fellow named Wallerstein developed a method of doing transfusions using the sagital suture, sagital vein in the head. But this too was dangerous. So, this diffused to the point so rapidly that house officers were doing the same transfusions. The time was reached when instead of my special Fellows, who for the first three or four or five years were called on to do these same transfusions, this was done by residents on the service Eventually, the pup, or the lowest resident, was the one who had to do the same transfusion because it was such a chore. It would take an hour, an hour and a half, to do gradually, of course. It's standard technique. I should think all this really spread within five or ten years. All around the world. Maybe within five years, really.
Q: So once again we see the introduction of new technique leading to a whole redefining of the working relations within a hospital setting. We had a similar case with the indirect transfusion, with the development of ACD system.
Diamond: Sure. Anybody could do it. Now anybody can tap a vein in a newborn, or an artery--arteries as well as veins are threaded with plastic catheters and left.
Q: Was there any resistance of the type that came up against the indirect transfusions because of the existence of pyrogens earlier. This was a much smoother--
Diamond: It was accepted as the standard, non-traumatic way to do blood transfusion.
Q: What did it do in terms of hospital supplies? This is a new product - plastic -- being used in a new area.
Diamond: Right. Then of course plastic bags instead of bottles for blood transfusion became popular. We too were the first to use these -- first in Boston -- and then all over the country. Fenwal Laboratories in Chicago began putting out plastic bags already connected with tubes, so you didn't have to clean tubes and wash them and cut down transfusions--made transfusion technique very simple and very non-traumatic.
Q: So this would also contribute to what we discussed earlier -- the development of central supplies in hospital.
Diamond: All blood -- all fluids are now given out in plastic bags that the manufacturer can produce much more cheaply in bulk, and can sterilize, and guarantee them by their testing that these are sterile, used over and over again. Surely, it's made it more expensive to give transfusions when you have to use a disposable bag and disposable tubing. But it's so much safer. If you ever have even a mild transfusion reaction, you never want to have another one. So this has changed the practice of medicine to a great extent. Can even be given in the home, rather than having to hospitalize a patient.
Q: If we were to break down the early blood banking system into a series of different techniques borrowed from contemporarily developed technologies, as we did with the development of plastic tubing, plastic bottling, which other areas would we be interested in researching? There would of course be the question of refrigeration, I would think. Preservation.
Diamond: Yes. Now, of course, preserving blood for emergency need in case of earthquake or atomic bomb attack, and so on. In thousands of units! First, of course, there is the use of new diluents and preservatives, so that blood can be stored for 35, 40 days or more. But that isn't enough protection -- in case of a disaster you want something that can be stored for a much longer period. Therefore the freezing of blood cells became an important field of investigation.
Q: When did this research develop?
Diamond: That's been going on ever since the 1950s. But certainly in the last ten years, maybe longer, freezing of blood cells -- especially preservative solutions -- is a standard practice. All blood banks now have stores of frozen cells.
Q: You mentioned diluents? Is that--
Diamond: Yes. The various diluents, or preservative solutions.
Q: Could you spell that please?
Diamond: Diluents? D-I-L-U-E-N-T-S.
Q: The research on these different aspects of the blood banking process was done mainly where? In research labs connected to universities, industry?
Diamond: Research labs connected to universities, and hospitals. Hospitals were, of course, most interested in this so they could have supplies of blood for an emergency. Like the fire in Boston that destroyed that night club, the Coconut Grove, and so on. They needed much blood then, and they had to go out and bleed people. Whereas if they'd had frozen blood they could have brought it in a hurry. They use frozen blood for emergencies, and also rare blood groups! Also, there are people with rare blood types who have antibodies against the common blood groups. For them, you have to have a storehouse of rare bloods. The AABB and the American Red Cross have established such repositories of rare blood. They keep it and ship it all over the country, all over the world if there is a demand for it. That sort of thing.
Q: Dr. Diamond, we talked already somewhat about the relationships between the hospital and medical school and corporations. I was wondering if you could talk about, in terms of your own experience, the relationships that were worked out between the hospitals and the university, and medical school.
Diamond: This was an interesting development. I don't know when it started. It must have been in the early 1900s when the new medical schools like that in St. Louis, Washington University, that at Hopkins of course, University of Pennsylvania, appointed full-time men in the clinical fields to take care of specialties in the hospitals. In order to use these men, and use the patients too, for teaching purposes of students that went through the medical school, the teachers in the hospitals had to be members of the department in the medical school. The chief of, let's say, pediatrics at Harvard's Medical School was the man who was also the chief of the clinical department at the Children's Hospital, or at the Massachusetts General Hospital of Pediatrics. He had the privilege of recommending not only the clinical staff at the hospital, but also the teaching appointment, so that he could teach the students from the medical school who would come over in the third and fourth year. So that the recommendations were joint recommendations for a position in the hospital as clinician in a special area, and as instructor, assistant professor, associate professor, full professor -- going up the ladder -- in the medical school. That would pass through the faculty, where of course the C.V.'s and the attributes of the man could be reviewed. For example, if I had a man whom I had appointed as a trainee in the hematology laboratory and he was very good and I needed assistance, as I did time and time and again for the increasing load of patients at the hospital, I would recommend him for an appointment as an instructor in the department of pediatrics at the medical school, and recommend him to my boss -- my professor and chief of the hospital clinical department--to put through for an appointment at the medical school. Generally, of course, we wouldn't put through anybody that we couldn't recommend and document very carefully. Of course very rarely--in fact I don't remember ever did we have one of our applicants turned down. Once a man had received an appointment at the lowest rank -- an instructor in pediatrics at the medical school, and an assistant physician at the hospital -- then in due time, when he produced good work and could document it, he would be recommended for promotion. At Harvard, promotion was very slow. An associate professorship was a tenure appointment. That is, once you became an associate professor at Harvard, in the department, you would only lose that by either moving elsewhere or by doing something awful, which never happened in my recollection. But associate professor was tenure appointment and then full professor, tenure appointment. Then the chief of the department had to make sure that there were funds to support that man from his budget or from special grants, permanent hospital appointment.
Q: What was the early basis for the funding?
Diamond: The medical school had its budget. I don't how many million dollars. Each department is allocated a certain amount of money. The chief of the department knew how much money he had to spare, and how much he could assign to different individuals. But he had to have the money! He couldn't put through an appointment without also showing where the money was coming from. In some cases the hospital, in order to have somebody take care of patients with certain diseases, would allocate money that it had. Either out through a grant, or through a permanent endowment for taking care of the man. Sometimes he got part of his salary from the hospital, and part of his salary from the medical school. But you always had to have the money to support a man that you recommended for a position. They wouldn't approve a physician for which there wasn't money available so that the man would suddenly be hung up. It happened occasionally! Then the man would have to move elsewhere. Or you'd appoint a man for five years, and say, "The end of that time you either will have to generate some funds one way or another--research funds -- with your clinical ability -- or you'll have to move elsewhere." That is bad for assistant professors. Assistant professors are not appointed for more than five years for that very reason.
Q: In the days before big government funding through the NIH and the National Science Foundation, what might have been the major sources of research funding that would have come in to your labs?
Diamond: The NIH had some of these permanent funds. They'd give research professorships.
Q: Beginning how early?
Diamond: Oh, I don't remember when it started. I think way back again in the 1960s they put money aside in their budget to fund the research professorship in medical schools all over the country. You had to apply for those, but once they gave it to you they guaranteed that it would come hack year after year. They were careful not to fund more than what they could put in to their budget.
Q: If we went hack to the 1930s, what might the resources have been.
Diamond: The only funds then would be hospital generated.
Q: This was from fees?
Diamond: From fees, or from donations. The Children's Hospital in Boston had a corporation of members, wealthy families that could be depended on year after year to give money to the hospital.
Q: How were these funds allocated? Was there any strings attached as to what the funds could be used for, or was it at the discretion of the institute?
Diamond: Occasionally it would be just for work in asthma, or for taking care of patients with certain diseases. But most hospitals would refuse to accept limited funds like that, because the time might come when they didn't have such patients, and didn't use up such funds, and had to have more generally allocated funds.
Q: Did this ever present a problem for the research that you were responsible for in Boston?
Diamond: It certainly did, from time to time the head of the laboratory or the head of the research project would have to get out and scrounge around for money. Generally, we tried to have a few places we could call on -- like the Hood Foundation -- for help, or individuals that we tried to persuade to give permanent money, so that it would be in our treasury and we could draw on the interest of that. It depended a good deal on the ability of the individual. Some people were much more adept at that than others.
Q: What about during the Depression years? Were there any particular problems, in terms of funding, during that period?
Diamond: And how. [laughs]
Q: Could you expand on that a bit?
Diamond: I remember, I was married in 1929, which was the heart of the Depression. If not for a working wife, and for a couple of fellowships that I was able to get one after another, we would have had to close up then. But we were able to get private funds, and we were able to call on hospital finances to help support us to some extent. I never did have to get support for the hematology laboratory from the hospital or medical school. I always was able to get some private resources.
Q: What was the main source of the private resources?
Diamond: Patients' families. Actually, eventually you know at Harvard that this was true, but when I came out here some of my old patients wanted to establish something that would be permanent. So they got together. Harvard demands an endowment of a million dollars for the establishment of a permanent chair. Here they would accept 500 hundred, or 350 thousand, to begin it. They established the "Louis K. Diamond professorship" here from patients and friends that gave money. Some of them promised to give monies several years in a row. But there is this professorship, and I'm pleased that Y.W. Kan is the Diamond Professor of Hematology.
Q: That's quite an honor.
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