Q: This was a nationwide society?
Conley: It wasn't a society. It was a board of the US Pharmacopoeia. But there was no other way. No animal assay.
Q: Who originally organized this board?
Conley: I can't tell you. It was organized by the United States Pharmacopoeia. I presume it was done in the 1930s but I really don't remember. It was very much a going concern when I joined. But every patient who was treated with liver extract received USP liver extract which was designated in units. One unit was that amount which, when injected daily to a patient with pernicious anemia in relapse, produced an optimal reticulocyte response. So you see, I was very interested in pernicious anemia and when B-12 became available, we were among the first investigators to be provided with vitamin B-12 and specifically with radio labeled vitamin B-12. We did the early experiments on the absorption and excretion of vitamin B-12. The observations that we made here on the urinary excretion of B-12 formed the basis for the so called Schilling Test.
Q: Was Hopkins one of the few sites where actual pool of patients was-
Conley: No-- you see you had to have untreated patients. Our pool consisted of patients who were treated. Patients came in every month to get their injections. For the assay you had to have new patients who came in with anemia. In those days, you did not get informed consent. You just went ahead and gave the stuff. The drug houses, of course, were scouring the countryside trying to find doctors who were willing to do this. And if the doctors were willing, then they were paid so much for doing it. And when a patient with pernicious anemia came in, they'd notify the drug house. The material would be provided and they would submit the necessary forms to the USP-- to our board which would then certify the preparation as being up to snuff.
Q: Were you primarily responsible for organizing this pool of patients?
Conley: No, No, No. All we did was receive the data.
Q: You just received the data? And this was something--
Conley: Yes, the drug manufacturers had to find the doctors who would test the material, get the results and submit them to the board.
Q: But they were doctors at Hopkins--
Conley: No they were doctors anywhere. No one institution would see enough patients with pernicious anemia --
Q: So the data that you had came from everywhere?
Conley: Everywhere.
Q: What would be some of the other areas of early concern? You had pernicious anemia, you have--
Conley: My personal situation was that I suddenly became head of a non-existent division with no training in this at all. There was no hematologist here. So I had to really learn by doing. And this is one of the few places where that could be done, because we had such a wealth of clinical material and such a close inter-relationship among doctors. There was no jealousy, and I was welcome to see anyone who came along. Very quickly, I built up clinical experience. And with every new case that came along, I was quick to read the literature. I had to. Not just a textbook, to really read original papers. And in doing this, of course, my curiosity was wetted. Instead of being as a current investigator would almost necessarily be, having interest confined within narrow limits, my interests were very broad. So I was involved in all kinds of things.
Q: Did coagulation remain--
Conley: That was my primary interest for, oh, five years, I guess. But then my colleagues who came along and I had some very distinguished ones, took over and increasingly did the work and finally supervised it. I became less and less the authority on blood coagulation, to the point where in recent years I have been totally out of it.
Q: What was some of the early work you did in coagulation? There was work for example in hemorrhagic--
Conley: Well the very first paper that we published here was published with William I. Morse, who was here as a fellow in general medicine working in the outpatient department. I met him and asked him to come and work with me in the laboratory and he did. We discovered that in doing the prothrombin time test, the non-specificity of the test was such, that there was no way to compare the results of a test done here with the results of a test done at the Mayo clinic. This turned out to be very important, and has been, in very recent years, re-emphasized so that now in Europe, in particular, a standardized thromboplastin preparation is used. But that was the first thing we did.
And then we became very interested in patients, I've already mentioned our studies of how blood clotting was initiated, and the discovery of a plasma factor that we did not identify but was involved with surface induced clotting reactions. We became very interested in anticoagulants that occurred in the blood of patients, and discovered what came to be known as the "lupus anticoagulant." That's had quite a big flair in recent years. So these turned out to be important things that we were doing, diddling in the laboratory, with our hands and a few test tubes. And that's the way it went.
And then as times became more sophisticated, we did more sophisticated things. Dr. Robert C. Hartmann, who was actually the first fellow who got paid to be a fellow, carried on a lot of coagulation research. He was interested in the role of platelets in coagulation and other things. In his era we discovered the anti-heparin activity of the platelets, later designated "platelet factor 4." He went on to become head of the Hematology Division at Vanderbilt. His successor in coagulation was Dudley P. Jackson who continued, and was very important in demonstrating that living platelets, that is to say, metabolizing platelets were necessary for haemostatic function, and that dead platelets or platelet fractions were no good. And that was an important-
Q: Did he work with radiation injury?
Conley: Yes, he produced thrombocytopenia with radiation and then showed what it took to correct the hemorrhage, and nothing short of living platelets was any good. At that time, various people were giving ground up platelet extracts and all sorts of things and claiming that they worked. In fact, they don't. So that was a very important observation that Dudley Jackson made. And so it went. Dudley Jackson was here for quite a few years and went on to become the Chairman of the Department of Medicine at Georgetown.
Q: You mentioned earlier that you did some of the early work on circulating anticoagulants that was later, later had, or more recently has a greater interest in lupus for example.
Conley: An anticoagulant as a cause of a defect in blood coagulation had rarely been reported when we came along. I think there were no more than three or four reported cases in the world. We discovered that one of our hemophiliacs had one of these anticoagulants which is now thought to be an antibody. But at the time that we discovered it, there were only two published reports documenting this. And there was no report of the anticoagulant which is now known as the lupus anticoagulant which we discovered, which had different properties.
Q: Interest waned or never picked up on this until--
Conley: Oh no, it's attracted interest all along the way. But there has been a great flare of interest recently. The lupus anticoagulant is very well known. There is enormous literature on it, but I don't think many people remember where it was discovered. That was a long time ago.
Q: Would you like to say some more about it?
Conley: No, we discovered it and described it, and I became very interested in lupus. Lupus was a little known disease back in those days and the discovery of the LE [Lupus Erythematosus] cell at the Mayo Clinic is what crystallized interest in lupus because it facilitated diagnosis. And so in this institution, we very rapidly accumulated a large number of cases. I studied the hematologic aspects. We did the so called LE cell preparations in our laboratory and in fact invented a new and improved method for demonstrating LE cells. The big monograph on lupus that really brought clinical knowledge together was co-authored here by Dr. Harvey and a group of his associates including me. I wrote about the hematologic aspects.
Q: When was that monograph--?
Conley: That was published in Medicine, in 1954.
Q: So once again this is interest in doing research that arises from clinical concerns.
Conley: This has been my life. Having questions asked by patients that we go to the laboratory to answer. And I lived during an era when it was possible to do that.
Q: Do you think that's how hematology developed in other settings?
Conley: Oh, I think there's no question about it. That that's how it evolved, and it was possible in hematology, more readily than in other fields to do this.
Q: The work for example of Dudley Jackson on radiation injury, where did his interest in radiation injury come from? Was that from World War II?
Conley: He was graduated from medical school after World War II, but that was a time when all young physicians had to do military service. He was lucky enough to do alternate military service with Gene Cronkite.
Q: At ________________?
Conley: Cronkite was then in the Navy. So that's where he did the radiation work.
We had a large population of patients with sickle disorders, so I followed with very great interest the discovery of Linus Pauling's group of the electrophoretic abnormality of the hemoglobin. We were desperately anxious to use his methods. But between 1948 and 1952 the only person who could do this, really, was Dr. Itano, at Pauling's laboratory. And they used the tremendous Tiselius apparatus which meant very few specimens could be examined.
Then Ernest Smith in 1952, came to work with me as a fellow. Ernest Smith had had no prior laboratory training or experience at all, but he knew about the work Henry Kunkel and his colleagues had done on zone electrophoresis using filter paper. I had been to talk to our biochemists here, to chemists at Homewood, trying to develop a method by which we could do what Pauling's group was doing. They all shook their head, they didn't know what to do. And this young fellow with his own hands built electrophoresis tanks out of plastic. We put together a Heathkit apparatus and in no time at all were able to electrophorese hundreds of samples of hemoglobin with much more beautiful separations than you could get with the Tiselius apparatus. That led to one important discovery after another. Any number of new abnormal hemoglobin was discovered here. We found that hemoglobin C involved two percent of the black population. We described the clinical syndrome produced in persons who were heterozygous for both hemoglobin S and C. So this was a very exciting period here.
Q: How was the program in sickle cell anemia research set up then?
Conley: It was initially a clinical program. But when Dr. Smith came as a fellow, he built this little apparatus. It didn't take as much room as this desk top. But it was marvelous. You just take drops of red cell hemolysates, and you could put a dozen of them on a single strip of filter paper, turn on the current, and four hours later you had these perfectly beautiful separations. We had people coming from all over the world to see this, you know. It was so simple. But for four years it hadn't been done.
Q: And the prototype for that was the Tiselius apparatus?
Conley: The original apparatus that was used by Itano in Pauling's laboratory was this big Tiselius apparatus. That was how electrophoresis was first done.
Q: So where did Smith get his ideas for it?
Conley: From Henry Kunkel's publications. They were separating serum proteins. The method was there, but it just hadn't been applied to hemoglobin. By the time the method was published, we'd had a tremendous experience in discovering new abnormal hemoglobins including a very important one that was called Hopkins II hemoglobin. It was the first hemoglobin that was not produced by a gene that was allelic with hemoglobin S. And that was the first evidence that there were two genes involved in hemoglobin synthesis. It turned out that there are two polypeptide chains, the alpha chain and the beta chain, determined by two non-allelic genes. But the first convincing evidence for that was the discovery of Hopkins II hemoglobin in a family in which there was also hemoglobin S. These two hemoglobins did not behave as alleles.
Q: On the methodological side, did the electrophoretic apparatus then diffuse back to biochemistry and chemistry departments here?
Conley: Oh yes, that method and subsequently its variants came to be extremely important across the board in enzymology and all kinds of protein analysis.
Q: So this is a case where clinical science actually _________ in basic research.
Conley: Oh, yes. Henry Kunkel was an eminent immunolologist. As a matter of fact, when I was the chairman of the Hematology Studies Section, he was a member. He would never have called himself a hematologist but his contributions to hematology were very great. And that's what hematology has been like, you see. Quick, who invented the prothrombin time, was in no sense a hematologist. He didn't know anything about anemia, I don't think, or leukemia. Warner, Brinkhous and Smith, who invented the two stage method for measuring prothrombin were pathologists at the University of Iowa. Brinkhous became the professor of pathology at the University of North Carolina.
END TAPE ONE, SIDE TWO; BEGINNING OF TAPE TWO, SIDE ONE
Q: Dr. Conley, we've been talking about how hematology was defined in your early years as head of the Division of Hematology at Johns Hopkins. I was wondering if you could perhaps recount some of the early split-offs, people who might have been considered as important to blood work, but did not end as hematologists.
Conley: In the 1940s, hematology encompassed all of what is now oncology, I think you could say, except surgical practice. The few chemotherapeutic agents that were then available were managed by hematologists. Blood banking, to the extent that it was academic, was done by hematologists, but it was not largely an academic specialty in those years. The performance of routine laboratory tests was handed down as medicine advanced from pathologists increasingly to hematologists. Then as developments took place, blood banking evolved as a very large clinical service, and the blood bankers were predominantly non-academic. They were providing blood and not terribly interested in hematology apart from that service function. There were, of course, distinguished persons studying blood group serology and that sort of thing, often not directly related to operating a blood bank.
As laboratory medicine developed, clinical pathology developed as an increasingly important branch and clinical pathologists took over the laboratory aspects of hematology that formerly had been done primarily by pathologists. So clinical pathology became a specialty within pathology. As that happened, hematologists began to lose a lot of their livelihood because hematologists prior to that time had been the physicians who ran hematology laboratories. In Baltimore for example, a distinguished physician had his laboratory to which his internist colleagues sent their patients for blood cell counts and various other tests. He was not a clinical pathologist; he was an internist, himself, a hematologist. So that the clinical pathologist increasingly took over routine laboratory work, to the very great distress of hematologists. And of course, it threatened their livelihood. It made being a practicing hematologist much less lucrative than it had been.
Q: What years would this have been?
Conley: This was, I guess, well under way in the 1950s and had reached crisis proportions I think in the 1960s.
Q: But you've already had NIH study sections on hematology itself. What role did the NIH play?
Conley: Hematology, as the queen of the sciences, evolved as an academic specialty. And the noted hematologists that became known around the world were academicians. They were doing laboratory research. Although some laboratory research in early years was relatively unsophisticated compared to present day investigation, it was very important in revealing scientific principles. And it became increasingly sophisticated to the point now where many of the people who're doing the very finest laboratory research never see a patient. They don't know very much about hematology outside of their own very special fields. That has been the big change. Hematology was a significant clinical specialty, particularly after Dr. Wintrobe's textbook was written. Now I think of hematology as an academic specialty, really, i.e. hematology apart from clinical pathology and apart from oncology.
Q: Once again, is that a creation of the NIH for example and their funding policies or is a creation, more of the content matter of study?
Conley: There is absolutely no question that the availability of funding has made this remarkable research achievement possible. What happened in hematology very early on, was that hematologic research was really very basic science oriented whereas in gastroenterology or cardiology, it was mostly clinical studies. The NIH was very excited about funding basic research, which hematology increasingly became with the discovery of coagulation factors; the better understanding of how blood clotted; the serology of the blood groups; the abnormal hemoglobins; all of these things opened whole new fields; for literally swarms of investigators to do very important basic scientific research, which in fact, in many instances, had implications that ranged far beyond clinical hematology. So this gave hematology a great advantage, really, in competing for research funding and for making great scientific contributions. It's no accident that in mid-century, many chairmen of department of medicine were hematologists, despite the fact that hematology as a clinical specialty is minute in relation to gastroenterology or cardiology.
Q: You're saying this was because of the influence of the basic research--
Conley: Because these people were doing research and medical schools wanted people who were doing productive, innovative research and these were hematologists. So look, who were the chairmen of departments of medicine? UCLA, there was John S. Lawrence, a hematologist of great distinction in that era. Max Wintrobe became chairman of the department at Utah. Charles A. Doan, chairman of the department at Ohio State, a noted hematologist. Carl Moore at St. Louis. Who else. Any number of people. Sydenstricker at Georgia, he was a great pioneer of the study of sickle cell anemia. And I'm sure many others that don't come to mind.
Q: Well there is Lawrence Young.
Conley: Lawrence Young, of course, at Rochester, a very important figure whose work on hemolytic anemias, particularly hereditary spherocytosis, made him famous. So these were all people who were doing very creditable laboratory research. And it was hard to find people in other branches of clinical medicine who were equally pushing forth the frontiers of science, you may say. So this is why hematology was the queen of the clinical sciences in that era.
Q: And yet there are areas that go beyond the realm of hematology itself. We're talking about blood banking, which does not go into, reach into the academic niche that hematology found, but also areas such as oncology.
Conley: Well, oncology, of course, has evolved much later than clinical pathology and was the next great threat to hematologists. As soon as tumors other than hematopoietic neoplasms were being treated by physicians other than surgeons, oncology opened up as a special field. Oncology was initially done by hematologists but then rapidly expanded beyond hematology. And oncologists, in many instances, in most instances I think, are not primarily hematologists. I think there was a big split, and so classical hematologists, the people who were investigating anemias and treating non-oncologic disorders, don't have very much left. So there are relatively few hematologists, classic hematologists, who are now practicing.
At the annual meeting of the American Society of Hematology, a group of these people get together and rub their hands and sympathize with each other. But the fact of life is that there is no way to change this. It's the nature of the beast. So oncologists and hematologists have joined hands and they have now overlapping specialty boards. In many programs there is an effort for oncologists to learn some hematology, and hematologists to learn some oncology. But in the terms of the practice of clinical medicine, outside of academic medical centers, the practice is oncology and there is little opportunity for a non-oncologic hematologist to survive.
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