Q: Hageman, after the patient that--?
Conley: Yes, Oscar Ratnoff had a prepared mind, of course, because he had worked here and was convinced, that glass contact activated a plasma factor.
Q: Could you supply some more information on what types of equipment and approaches would be required to find a soluble component with the plasma itself?
Conley: I can tell you research equipment was very primitive in those days. This was before research grants. I met the president, I guess the owner, of a local ice cream company, and he gave me an ice cream freezer which we used for our refrigerated centrifuge. And I borrowed a centrifuge that we put into this freezer. That was our original refrigerated centrifuge. I found investigators who were using rabbits for their research. When the rabbits were discarded we cut off their heads to make thromboplastin. We were so lacking in funds, that I actually redistilled the acetone that we used to extract the thromboplastin rather than buy a new bottle. You can't believe how tough times were in those early years. I obtained my first NIH grant in 1948.
END OF SIDE ONE, TAPE ONE, BEGINNING OF SIDE TWO,TAPE ONE
Conley: The first research grant that I received from the NIH in 1948 was still being supported when I retired in 1980, and, beyond that I had many additional grants. But that first one was must be one of the longest term grants that the NIH issued. With some financial support we were able to have designated fellows. Thereafter, I had a training program which was very much research oriented. We had a small program in which we would take, at the most, two or three fellows per year. Everyone who was appointed recognized that he was going to spend a large fraction of his time doing research. During my tenure, we never had a clinical hematology program. The fellows learned clinical hematology by osmosis but not through a formal structured program.
Q: Was Max Wintrobe's book used, CLINICAL HEMATOLOGY?
Conley: Max Wintrobe's book was used by every hematologist extensively, in large part for its extraordinarily complete bibliography. Since I was a newcomer to the field, every time I encountered a patient with a disease I didn't know much about, I would not only read Dr. Wintrobe's chapter, but I would go to the library and read all of the original references. I built up a substantial collection of reprints over the years. Soon after we had fellows, we started having a journal club. In those years, it was possible to review the hematologic literature in total in a once-per-month session. At those meetings we would send for reprints and so I rapidly built-up a large reprint collection.
Q: How would hematology at that time be defined? Who would be counted as a hematologist?
Conley: That is a very good question and a very important one, because there was almost no such thing as a hematologist. There was no hematology organization. There was no journal of hematology until 1946, when Blood, the journal of hematology, was founded. Hematologists included all kinds of people, who were interested in the blood. And at various informal meetings, and many meetings were informal, participants included non-clinicians: biochemists, and biologists. This is one of the marvelous things about hematology, its multiple interfaces. Hematology was considered to be the queen of the clinical sciences, in fact the first branch of clinical medicine to have a solid scientific basis.
Q: Who is it that considered hematology as the queen of the clinical sciences?
Conley: I don't know who first introduced that term but it has been often repeated. And it was certainly true. There are certain reasons for that. Everyone mentions the availability of the blood. Something that you can get and study much more easily than you can other tissues or organs. But hematology, meaning examination of the blood-- blood counts--were done routinely by all doctors. In this medical school, in the second year, there was a major course in what in those days was called clinical microscopy. And for many, many hours, students learned to perform blood counts, to examine the urine, to examine other body fluids and so forth. And they had to do this because when they went on the wards, they were entrusted with this responsibility. So every medical student learned a lot of hematology. In that era, students were less involved with cardiology or gastroenterology.
Q: What about other areas such as bacteriology?
Conley: Bacteriology, of course, was taught as a formal course in the pre-clinical sciences. But in terms of clinical medicine, the clinical microscopy course was taught by clinicians to students who were going to be using these methods to examine patients.
Q: Was the emphasis in this clinical microscopy more of a morphological?
Conley: It was more on methodology as it started out, but as information evolved, as it rapidly did, pathophysiology was incorporated into the teaching. Then as pathophysiology became interesting in other branches of medicine, and particularly after students no longer did routine blood cell counts, hematology was squeezed out and largely displaced. So whereas students, had a couple of months of hematology, now they got maybe ten sessions.
Q: Perhaps we could return to that question of how hematology got squeezed out, a little later on. But I was wondering if you could identify more of the content of hematology at that time. At what point did there seem to be a shift from morphological studies to this what you're calling pathophysiology?
Conley: I think the big influence was in changing hematology from a branch of pathology, where it had been and still is some places, where bone marrow and blood examinations were done by pathologists, not by clinicians. The driving force, I would say was the discovery of the treatment of pernicious anemia. The discovery that an anemia, which was incurable and fatal, diagnosable by morphologic methods could, in fact, be treated. This stimulated all kinds of interest in the mechanisms of anemia. And it interested people who were not just looking at dead, fixed tissues.
Q: But there is a gap of time between the late '20s when the liver factor was being isolated [not isolated at Harvard], for treatments in pernicious anemia and this later period that you are talking about.
Conley: Things were going on but hematology was not a block of science. For example, what preceded the discovery of liver therapy was the discovery of the vitamins. That goes back before the turn of the century. The big discoveries, in the early part of the century, were the vitamins. And those vitamins included folic acid. But preceding the discovery of folic acid, it was well known that patients with pellagra were anemic. Pellagra was rife in the rural South. When I went to medical school, we learned about the three p's -the pellagra preventing principle, the three d's -dementia, diarrhea, dermatitis, when pellagra was known to be a nutritional disease, but its cause hadn't been identified. So this was a very exciting era and this impinged on hematology, too, because these patients were anemic and it was known that certain concentrates, yeast for example, cured the anemia but it was not until 1946, that folic acid was identified.
In other areas vitamin K was discovered by Dam. K stands for coagulation's vitamin if you spell coagulation with a K as they do in Dam's country. When I was an intern, patients with obstructive jaundice who were going to be operated on were given alfalfa juice, because alfalfa juice contained vitamin K. You see, I've seen some of these things evolve.
The nature of the bleeding in jaundice, was explained by Dr. Armand Quick, who was able to do this because he invented the prothrombin time test. And you see, the discovery of the prothrombin time test totally opened up the field for anti-coagulant therapy.
So all of these things were going on simultaneously, but unrelated in a sense that most of the investigators were not hematologists. But all of this was hematologic. And at a meeting, where these things were discussed, there were groups of people with varied basic knowledge and interests, but all bringing together their knowledge on a subject. When it was proposed, years later, that a society of hematology be formed--Henry Stratton and Bill Dameshek and others said we ought to have a hematology society-- this was actually opposed by some. Dr. Carl V. Moore who was one of my idols and one of the great hematologists of the time, said we don't want a society. If we have a society, then we'll be defining what a hematologist is, then we'll be having boards. He so appreciated, as I did, the non-disciplinary, or inter-disciplinary nature of hematology that we hated to see that destroyed by creating, as it were, a walled-in specialty.
Q: I'd like to talk about that a little later too. There seems to have been very widespread opposition to forming a society. People such as Bill Castle-
Conley: Yes, exactly, Castle never joined. Castle is an honorary member but he never joined the Society. Wintrobe didn't join it, I think for several years. I didn't join it-- at first.
Q: It was based around this notion of keeping hematology open to basic research in an inter-disciplinary fashion rather than getting caught in the standardization of boards.
Conley: Let's take the one disease, the study of which has produced more basic information than any other. Do you know what that is? Sickle cell anemia. I have written an account of the development of knowledge about that disease because I'm so fascinated by it: the sequential developments and who made the great discoveries. It's a very remarkable story because most of the people who made the discoveries, were not people that you would have thought would have done so.
Q: This is a very interesting picture that is developing for early stages of hematology. We have people working in other disciplines or sub-fields contributing to a later stage of professionals becoming self-conscious and saying this is what we would consider research with hematology. But a more particular question arises then: in numbers of the cases that you were listing, such as the work that went on with pellagra, the work with pernicious anemia, these involve nutrition and vitamins--how important was the study of vitamins itself as a model for doing research within the hematology? In other words, were vitamins seen as almost a magic bullet for hematologic disorders? Did that attract people to look into it?
Conley: One of the big nutritional items in hematology is iron and certainly people interested in iron metabolism were interested in nutrition as part of iron metabolism. As a matter of fact, the nutritional aspects of iron metabolism, I think, have been greatly over-emphasized. But there is no question about its very important role. Iron deficiency is said now to be the most common deficiency in the world. But I don't think that Carl Moore, for example, who was a great student of iron metabolism, could be said to have been a nutritionist. He was interested in iron, per se.
Q: I wasn't thinking so much in terms of actually developing a grand theory for hematology but having a working model. What are the sorts of things that you would do research on. The reason I'm asking this is that Dr. Nathan has raised this as an issue. That because of the similarities in bone marrow morphology between leukemia and anemia, it was thought in the early '50s that there might be a model, that there might be--
Conley: Well a lot of people, particularly nutritionists--
Q: Well, he thought people practicing in hematology also.
Conley: One of my medical school classmates was Bob Williams, and his father, R. R. Williams, was the man who isolated, identified and synthesized vitamin B1--thiamine. Dr. Williams had been in the Philippines, where he--he was not a physician-observed nutritional deficiency and became very interested in it. He came back to the United States and maintained his interest in nutrition. My recollection is that he was director of the chemical laboratories of the Bell Telephone Company. He lived in Summit, New Jersey and had a laboratory over his garage where he was doing his nutrition research. I had met Dr. Williams, actually we sailed together for several days, so I had a chance to talk with him. He was sure that nutrition was the key to disease and that we would find a vitamin that would be curative for everything. Not one vitamin that could cure everything, but that we'd find multiple vitamins, that disease had its origin in nutritional deficiency, and I think many nutritionists have had that feeling.
Q: But you don’t think this might have been a view held by people practicing as hematologists?
Conley: I don't think so. When you talk about practicing hematologists, that's something else again, because there weren't very many people who were designated, or considered themselves to be practicing clinical hematologists. There aren't very many people now, who practice hematology apart from oncology. As a clinical specialty, hematology, I think, is concerned mostly with the treatment of oncologic disorders. Initially, hematologists were the persons who used nitrogen mustards and folate antagonists in the treatment of leukemia and lymphoma. As chemotherapy became more elaborate and complicated, oncology split off as a separate specialty. Most neoplasms are not hematologic ones.
Q: Would it be fruitful to talk about the split between oncology and hematology as well as some of the other areas that--that ASH seems to have not had as much influence in as might have been suggested by some of its members? Perhaps together as a most definite topic of discussion. This time just continue with talking about the early training in hematology at Johns Hopkins.
Conley: Progress, of course, has its perils and disadvantages, but you can't complain about progress. It was possible in Dr. Wintrobe's day, to know all there is to know about everything, that touches on hematology. I told you that when I began, we could review the total hematologic literature--surveying all the journals across the world--in one meeting a month. Now you can't do that anymore. So a hematologist was expected to know about blood banking and how the blood clotted, and how to take care of patients with leukemia or polycythemia or anemia. But as knowledge evolved, there were a number of mitotic divisions.
For example, blood banking split off quite early on. What made blood banking become such a specialty? Several things, the existence of the blood bank per se. You needed a unit where blood was stored and somebody who knew how to handle it. But then blood bank serology became very complicated following the discovery of the Rh factor and the cause of erythroblastosis fetalis. When I was a medical student, there was a prize given to the student who wrote the best paper on erythroblastosis fetalis. Of course there wasn't anything to write about. And then we suddenly find the cause of what was previously an untreatable and fatal disease. In the mid-1940s the Coombs test, which made it possible to detect antibodies that previously had been undetectable, made cross-matching a science, and made it possible to detect all kinds of allo-antibodies that previously had not been recognized. So blood banking rapidly became a special field. And because it was largely a service function, it tended to become more divorced from academic medicine than other branches.
Q: But there were certain connections in the sense that you had co-fractionation for the, within the blood component.
Conley: It was the plasma that was fractionated. Dr. Cohn was the one who fractionated liver extract that Dr. Minot had found effective in pernicious anemia. It was Dr. Cohn who did the early fractionation of the plasma. So that's another aspect of hematology that was developing quite independently.
Q: Is the fractionation of--?
Conley: Yes. The fractionation of plasma. I don't know how Dr. Cohn got to be the first chairman of the NIH Hematology Study Section, because I would not have thought in that period that plasma fractionation would have been thought to be primarily hematologic.
Q: He also wrote the first article published in Blood-
Conley: He was a very important figure.
Q: He was apparently personal friends with George Marshall who for a year was President of the American Red Cross and during that time made various connections in Washington.
Conley: Well Dr. Cohn was very well connected; there was no question about that. He was a force unto himself.
Q: How much do you think, what role you think that plays, the connections that people have and the sources of funding that people have as opposed to solving problems of diseases or pathologies.
Conley: I don't think you can draw any conclusions, any generalizations about that. Some of the most humble people make the greatest discoveries. Look at Dr. James B. Herrick. You know his name, you know what he did? A practicing physician, he discovered two new and important diseases within two years: sickle cell anemia and myocardial infarction. That had nothing to do with his connections. He was just a very astute clinical observer.
Q: But in the sense of people coming to, at a later stage, coming to see themselves as hematologists or belong to a society of hematology, what would you feel would be more important, the sorts of connections that people had or the sorts of research that they did?
Conley: Well I would like to think that in academic medicine, certainly in a place like this, research accomplishment would be very important. I can't imagine that political connections are vital.
Q: We, go back to the original question that you raised. How did Cohn become head of the NIH session?
Conley: He was a very dynamic person and he was doing important things. His ethanol fractionation of plasma proteins was new. This was exciting work. How he got to be the chairman of the study section. Why wasn't Wintrobe the first chairman of the Hematology Study Section? Here was a man who was known around the world as a great hematologist but that didn't happen that way. I have no idea how that all worked out.
Q: What sort of relationship was there between Wintrobe and Cohn, do you know, at that stage?
Conley: Well I suspect there wasn't any. I doubt that their paths crossed very much. But I don't know.
Q: You were saying in a once monthly meeting, the sum total of literature published on hematology could be covered. Where this literature might be found? In the Journal of Clinical Investigation?
Conley: We reviewed all of the general medical journals, of which there were relatively few in those days, the important foreign journals as well as American ones. Scanned the titles, picked out papers that seemed pertinent to hematology. Each member of the group was assigned a group of journals. And then we could scan these or review them in detail, depending on their importance, in the course of a meeting. In this way it was possible for us to be really broadly knowledgeable across the board in hematology.
Q: So you must have had some knowledge of what goes into hematology. Would it cover things such as blood banking? Would it cover work in sickle cell anemia?
Conley: Oh yes, we tried to cover the waterfront. And it was reasonably possible. You know when I was a medical student; we all read original papers with great excitement. I remember reading Dr. Castle's papers when I was a medical student. But few medical students read an original paper now. That's not exactly fair. But the fact is that medical students now complain about reading textbooks. They all demand handouts. They want a summary. The infinite detail is so overwhelming that everything has to be condensed. And that's a fact of life. There is just that much more to learn than there was, and I guess I'm glad that I had my career when I did and didn't have to contend with this enormous morass. I think it was rather fun being broadly based which no one can hope to be now in the same way. I don't think in this medical school or any other, it's any longer believed that the traditional three-legged stool is feasible. You just can't do that. You're going to have people who do basic research, and you're going to have clinicians, who are going to talk to each other, but they are not going to be equally competent in each other's fields.
Q: What would have been the hottest areas in hematology, let's say, when you first began your tenure as head of the division here?
Conley: The quest for the missing agent in pernicious anemia. Vitamin B-12 was discovered in 1948. And that was soon after I arrived, and so I got deeply involved in vitamin B-12 research. We had a huge hematology clinic by then, with I guess more than a hundred patients with pernicious anemia. I for a number of years was the Secretary of the Anti-Anemia Preparations Advisory Board. When liver was used to treat pernicious anemia, you remember that Dr. Minot gave a diet rich in liver. And then Dr. Cohn by 1929 had produced a fraction which was infinitely more potent. But it took from then until 1948 to find out what it was in liver-- that turned out to be vitamin B-12. One of the reasons that it took so long was that the only assay for this material was administration to patients with pernicious anemia in relapse. So the drug companies that sold liver extract had to have their preparations tested. They had to find doctors around the country who saw untreated patients with pernicious anemia who were willing to use this test material to treat their patients. They would give an injection every day and if the patient got what we considered being the optimal reticulocyte response then we would, as a board, approve. The data would be submitted to this board on which Dr. Castle, Dr. London, Dr. Bethel, others and I were members. I was the secretary so I handled the paperwork, would review these data and if the patients responded optimally, then we would approve the preparation.
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