ASH Oral History: Louis K. Diamond (3/7)
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Q: When did Sprunt and Evans do this work?
Diamond: It was done in 1926.
Q: It was quite current.
Diamond: Yes. It was very new -- maybe 1925, 1926. In fact, glandular fever was not known to most people. Excepting that there had been this epidemic. The gist of it was that I looked this up. Sure enough, the white cells were typical of what Sprunt and Evans had described. The fever and glands were typical. This is the first case of infectious mononucleosis recognized at the Children's Hospital. Dr. Blackfan was very pleased that he had made the diagnosis. This was February or March of 1927, before I graduated. Dr. Blackfan had me present this case to different groups, and special clinics. I became adept at presenting this case. Therefore, when I approached Dr. Blackfan after I got the appointment to New York hospital and told him I'd like to come to Children's, he said "Okay, we'll put you on the list." Well, toward May or June I was wondering what I'd do with the nine months I had to wait for my appointment. I asked Dr. Blackfan if I could work in the laboratory on blood conditions. He said, "I'm interested in blood conditions. I'd be glad to have you work on blood diseases in children, see what you can find." I worked up some good cases, including one case of the atypical hemolytic anemia which occurred in a little Greek boy. Dr. Blackfan, who always remembered. things, said "You know, Dr. Cooley in Detroit has collected four cases of hemolytic anemia and enlarged spleen in some Greek and Italian children. They're now calling it Cooley's anemia." He's called it von Jachsch, which is wrong. Von Jachsch was a German, and no German had Cooley's anemia. Cooley's anemia became established as a peculiar hereditary anemia in Greek and Italian children from around the Mediterranean region in particular. The great Dr. George Whipple named it thalassemia, meaning the sea --the Mediterranean Sea. Anyway, Dr. Cooley asked Dr. Blackfan if he could include our case of Cooley's anemia with his four and publish the first article of five cases of Cooley's anemia. Dr. Blackfan was very pleased with this. Although we contributed a case our name wasn't on it. But by that name we had four or five cases in the Children's Hospital -- Italian and Greek children. Dr. BlackFan said, "We ought to study these. Maybe you can study them while you're waiting for your appointment." Blackfan said, "I'll help you start a laboratory for the study of hematologic diseases in our Children's Hospital laboratory building, right next to Dr. McKhann and Dr. Gamble." Well, we had so many cases in short order that I couldn't tend to them all and continue medical school. We had so many peculiar blood conditions, too, and children with nutritional needs. Dr. Blackfan said, "If I get some money to establish a hematology laboratory, how would you like to take it on and give up your [blank] Instead spend a year here at New York Hospital studying in this blood laboratory. We'll count that your year internship and then you can have the appointment in pediatrics, guaranteed." Who could ask for anything more? So that's how I became a hematologist. There was no money. Dr. Blackfan got money just to buy a scope and to hire a technician. Then, he steered me to Dr. Wolbach and Dr. Minot. I became a research fellow under Dr. Minot, to make rounds with him and to take care of hemologic problems at the Children's Hospital. My appointment was actually in the Department of Pathology, and Dr. Wolbach gave me a fellowship there. That's how I became a pathologist too, for that one year while I set up the hematology laboratory.
Q: What were the sources of Dr. Wolbach's money? Would you know?
Diamond: He had fellowship funds. So that's how I established the hematology lab at the Children's. The following year I became assistant resident from October 1928, then senior assistant resident from 1929 to 1930. Then Blackfan offered me the chief residency, which was a three-year appointment. Dr. Blackfan had been chief resident of Hopkins for 12 years that was the Hopkins system.
Q: If we could return to this question of establishing a hematology laboratory. This would have been one of the first specifically designed laboratories for hematology?
Diamond: In children.
Q: For children.
Diamond: That's right. There wasn't, to my knowledge, such a laboratory in this country. There were abroad.
Q: So you had to decide on what sorts of equipment and what sorts of problems were to be worked on?
Diamond: No. We worked on all of the blood cases that came in -- outpatient, inpatient. Once we were established, Dr. Blackfan was able to get money. In fact, we got a grant from H.P. Hood Milk Company to run a hematology laboratory that took care of the expenses of a technician. They'd promised it for five years and equipment--microscopes, and so on.
Q: Why would the Hood Milk Company be interested in--
Diamond: They had a foundation that gave money for the benefit of children. They still have. They've been doing that now for well over, well, forty years. Because it was established in 1934 or something like that maybe 50 years.
Q: Would they maintain an archives that would be open for research?
Diamond: Oh they must.
Q: That would be interesting to look at.
Diamond: H.P. Hood Foundation. But that was the hematology lab. Also I began taking on a research fellow to assist me, and to train him in hematology, from about 1938, 1939.
Q: But hematology today is a very broad field. But back in the 1920s wasn't even self-defined as a field that might be some specialty.
Diamond: Yes it was. Wintrobe down at Baltimore, who then went out to Salt Lake City, Utah. Has written books.
Q: But his books didn't come for another -- his text wasn't until the 1940s.
Diamond: About then, yes.
Q: I mean in the 1920s, though, its not--
Diamond: Hematology was a recognized specialty with W.B. Castle -- certainly he was a recognized hematologist. Josephs down at Johns Hopkins was a pediatric hematologist. Carl Smith in New York at Cornell, who wrote a good textbook of pediatric hematology.
Q: When did that first come out? Do you recall?
Diamond: No I don't. It's in its fourth or fifth edition. That just so it was have come out -- oh, it was quite a bit after the war in the 1950s.
Q: How did you decide in terms of the equipment that was needed for a lab?
Diamond: Well in those days all we needed were microscopes, blood pipettes, and hemocytometers and glass slides.
Q: This raises an interesting question. It's one of the debates that I talked about earlier going on in the history of biology. Already at this time, Dr. Minot had approached the protein biochemist Edwin Cohn to use the latest research techniques in physical chemistry to try to figure out what this missing factor was in pernicious anemia.
Diamond: That's right. Dr. Cohn was a great protein chemist over at Harvard College. Cohn had suggested that he might purify the fraction of liver that contained the active principal. He was able to do that very quickly, then, of course it was taken over by the pharmaceutical industry. Then Cohn was invited to come to Harvard Medical School, and given laboratories there to continue pursuing his interest in the chemistry of proteins. This was during the War. The Navy asked him to do something about the difficulty of transporting bulk plasma for treatment of shock at the battlefront. He said, "Well, the active ingredient of plasma in treatments of shock was the albumin. I think I can purify and extract the albumin and thereby cut down the bulk from 500 cl to less than 100. In fact, to 25 ml." He proceeded to do that. As a by-product he synthesized purified gamma globulin, the antibody components of plasma.
Q: Dr. Diamond, I was wondering if you could comment on this possible transformation that's taking place among practitioners of hematology, the change from a basically morphological research style with microscope as your centerpiece of attention, to one that's to use up types of equipment of much greater analytic strength -- your centrifuges, etc. I was wondering if you could talk about whether you used the more sophisticated equipment in your lab, or you developed relationships with other labs that had this equipment?
Diamond: I had the advantage, as I indicated, of being in a small laboratory building of the Children's Hospital. It was a two-story building in the middle of the Children's Hospital complex -- the old Children's Hospital. This was devoted to research only -- research in bacteriology, in biochemistry, and in nutrition. Dr. Gamble did his studies on fluid balance in rats and rabbits, and carried over what was learned to the research on children. He had equipment of all sorts, and very soon we found that morphology of hematology did not help in analyzing all the hematological conditions that we encountered. In fact many of them, which were dependent on the size and shape of the red cell, its hemoglobin content, its fragility -- its membrane stability -- and measurements that one could not make by merely observing the cells under a microscope, although of course there was some hint of membrane defects when one saw odd-shaped red cells, odd-shaped white cells sometimes, and also variations in the size of the cells. Measurements of cell size was dependent on being able to measure the total volume of the red cell sediment, red cell centrifuge, and relate it to the hemoglobin, hemoglobin content, and so on.
With the equipment available in a well-established experimental laboratory, we had the advantage of being able to make such measurements. Early on, we started trying to study the red cell membrane. This became an important project in which we could get the help of the physicists as well as the biochemists that were in our own organization and around the medical school. Being right next door to the medical school gave us the advantage of being able to call on the experts there in various basic sciences.
Dr. Cohn, as I've all ready mentioned, transferred his protein laboratories from Harvard College in Cambridge to Harvard Medical School, and occupied one whole floor of a Medical School building, it was called the Laboratory in Physiologic Application of Hematology to Clinical Medicines -- some elaborate name of that sort. He very quickly built it up with skilled biochemists, protein chemists, and actually taught people that became leaders in the field in other parts of the country. Now his method of using combination of temperature and the control of the ionic environments -- the salt content -- and also alcohol as the precipitant of proteins, purifying proteins led to very rapid increase in the knowledge of the blood, of both the fluid portion -- plasma -- and the cellular portion.
Most of his efforts, of course, were in the fluid portion. He had isolated not only albumin and gamma globulin, but five fractions. Albumin was Fraction V. There was Fraction I, which was a clotting fraction; Fraction II also contained some clotting elements. He was able to purify these by his methods with very little adulteration. Some of them could then be tried clinically. For example, early on we used Fraction I, the fibrinogen faction, and a portion of it which contained anti-hemophilic clotting factor. The gamma globulin fraction contained some other globulins which had some endocrinologic value. So that this expanded the usefulness of blood a great number of times. In fact it used to him a standard joke that eventually they'd be able to use every portion of the blood plasma except the squeak that the patient usually let out when you put the needle in his arm. Dr. Cohn's vision was to be able to take a unit of blood from the individual, have this flow through a series of instruments, and have all the different fractions separated as it went through, and have them serve some great special purpose. During the war, albumin replaced plasma in some areas as the shock therapy of choice, particularly for the Navy where bulk was difficult to manage, and then the globulin fractions for use in various diseases where immunity was an important factor.
Q: Dr. Diamond, I was wondering if you could say some words about Dr. Nathan Rosenthal and some of the contacts which you had with him?
Diamond: Yes. Nathan Rosenthal was the leading hematologist of Mount Sinai Hospital, and had a large hematology consulting practice, most of whom had hematologic conditions that required blood transfusions. He was a very skillful transfusionist, and would pick up bottles -- bags of blood -- or arrange for the donor and the patient to be brought to a local hospital where he could take the blood and then infuse it very promptly by the indirect citrate method into recipients. He was a very skillful microscopist, too. So that if there were any questions about leukemia, for example, he could make diagnoses based on bone Warrow or blood examination at other people had missed.
The leading research laboratory for studying white blood cells in New York was up at Rockefeller Institute, where Dr. Florence Sabin, who had been at Johns Hopkins Hospital and Medical School for a long time as a research associate, had moved. She was the first woman, I believe, to be given the position of Associate -- which was like a full professorship -- at the Rockefeller Institute. She studied chiefly rabbits and pigeons, and studied the white blood cells about the time I first came to know her.
Having been at Hopkins, Dr. Blackfan, while he had been at Hopkins, had come to know her quite well. When she moved to the Rockefeller Institute he wrote her and asked if he could send one of his students down there to see how she studied living white blood cells with a technique she called the "super technique." This used a warm chamber -- a box, with a controlled temperature and a microscope inside the box. A slide with a drop of blood and stained with neutro red and janus green -- two vital stains which didn't kill the cells, but stained them, then one would follow the movements of the stained cells. Dr. Sabin showed a lot of interesting attributes of the living white blood cells, particularity the macrophages, the giant cells derived from monocytes that were so important in taking up and digesting foreign material like bacteria. The supravital technique became quite an achievement to study the growth of cells in pigeons, rabbits, and then to some extent in humans. Dr. Sabin usually had three or four Research Fellows who worked with her. They often became the leaders in hematology, like Dr. Charles Doan, who became professor of medicine at Ohio State and then Dean there. Dr. Claude Faulkner of New York, a medical school hematologist, and others. Dr. Blackfan arranged for me to work in Dr. Sabin's laboratory from June to September of 1927. There I learned her supravital technique, which I brought back to Boston Children's Hospital with me for our laboratory to study white cells in children.
One of Dr. Sabin's great contributions was the study of the activity of white cells in tuberculosis. She produced tuberculosis infection in rabbits and in guinea pigs, and then showed that the so-called giant epithelioid cells in the tuberculosis system that produced large collections of cells typical of tuberculosis in the lungs and elsewhere were macrocytes which had picked up the tubercule bacilli, and they in turn stimulated other cells, and eventually formed this large collection which is typical of tuberculosis. Her study of active tuberculosis in pigeons and then ours in humans, as well, was an advance in our knowledge of tuberculosis.
Dr. Blackfan and I published a paper in 1929, the first paper I published, on the diagnosis and the follow-up of the activity of the macrophage in active tuberculosis in childhood. This was the first project in our research laboratory in Boston.
Q: Could you expand on two points that you've raised now. One, could you talk a bit about the citrate method of indirect transfusion, and then if you could say some words on the status of leukemia research at the time that you made contact with Dr. Rosenthal.
Diamond: About leukemia research first, there was no such research going on then. When the diagnosis of leukemia was made on a patient it was a death warrant. There was no way of doing anything about it. Not until many years later, in fact in 1950, under the stimulus of some work done in Boston by Dr. Farber, the famous pathologist at Children's Hospital, and me, and the use of a new drug which a chemist, Dr. Suberow from the Lederle Company, developed. Now it is called methotrexate. That was the first drug -chemical --to be used in treatment of leukemia. Starting with its use in children with acute leukemia, we achieved first a 50 percent remission rate. Now it is one of the chief drugs not only for leukemia but for many other malignancies. Until that came along there was really no treatment for leukemia that was at all encouraging. All we could do was transfuse the patients and hope that some of them would go into partial remission.
Q: So the main types of studies, once again, were morphological studies.
Diamond: Exactly. Now, this brings up Rosenthal's method of indirect blood transfusion, in which he was the expert. Not infrequently leukemia patients would go into remission after receiving blood transfusions. Dr. Rosenthal did all the transfusions originally by the direct method, that is; connecting the vein of the donor to the vein of the recipient and by use of syringes just pumping from one in to the other. There was always the problem of clotting which could not be overcome in any simple way. The introduction of sodium citrate as a means of preventing clotting of blood, the so-called indirect transfusion method became popular. It was simple enough so that even a house officer could do it. Whereas formerly there were skilled transfusionists, like Dr. Rosenthal, who did direct transfusions, and who commanded good fees for doing that because it was a difficult technique to do without trouble.
Q: Did the use of sodium citrate lead to the replacement of these expert surgeons?
Diamond: Right. The direct transfusion method therefore fell into disuse. There was little advantage to it, and there was always the hazard that blood would clot in the syringe and would be lost, or that the catheter in the vein, or the needle in the vein, would clot and so on. So when citrate came in, transfusion became easy.
Q: There was a gap of time, wasn't there, between the period when Lewison first began to popularize the use of citrate and--
Diamond: Right. People didn't buy it too easily; they were afraid citrate was toxic, and if they didn't use the right amount of citrate they'd get reactions, and they could get reactions from poorly made up citrate and pyrogens in the fluid. As a matter of fact Rosenthal proved that most of the transfusion reactions that they ran in to, something like 10 percent reactions, were due to bacterial or other protein contaminants of the transfusion equipment or in the citrate solution, particularity if they used the same bottle and the same tubes over again and hadn't cleaned them thoroughly. Some protein material left would cause febrile reactions, and very serious ones, so that the indirect transfusion method, the citrate method, became popular and was generally used.
Q: How were the actual reactions overcome, if that was the problem with adapting the citrate method, and then was shown that there could be bacterial contamination?
Diamond: It was a matter of being sure of sterility of the equipment, thorough washing if you used equipment -- rubber tubes and bottles -- over and over again, which they usually did. Of course, they couldn't afford to throw away the bottles, and various people had their own type of bottle. In Boston we had what was called a Fenwal system devised by a Dr. Carl Walter (who's still alive), a surgeon who did very good transfusions. At any rate, the matter of cleaning the tubes and cleaning the bottles, avoiding contamination was what led to a very low percentage -- less than one percent -- transfusion reactions, in the hands of skilled people.
Q: Hospitals today have a central supply--
Diamond: Central supply labs and departments.
Q: They didn't exist at this time, or is this when they start to come in?
Diamond: No. Everybody supplied his own tubes and needles and bottles and equipment. We didn't trust a central supply room to do this. We felt it had to be done by somebody who would handle only transfusion equipment that was the usual way it was done.
Q: At then at a certain point central supply rooms became acceptable.
Diamond: Oh sure. Yes.
Q: When was this? Is there any particular --
Diamond: Oh, as far as transfusion equipment the central supply must have been popular in the late 1920s and early 1930s. But they took over blood transfusions when we began to have blood banks, and blood banks did not start much before the late 1930s. First there were plasma banks, where they discarded the red cells and just kept the plasma. They could freeze the plasma and reconstitute it afterwards. So plasma banks became popular at the beginning of the War.
Q: Where would the supply for sodium citrate and the other materials come from at that time?
Diamond: Chemical companies.
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