Q: Dr. Castle, what about Hale Ham? What was your working relationship with him? What went on?
Castle: Well, [Thomas] Hale Ham came to the Thorndike in 1934 after having graduated from Cornell Medical School in 1931 at the top of his class. Meanwhile he had interesting experiences as a medical intern in the old New York Hospital. By the completion of his internship he had already shown an interest in clinical investigation. After two years of medical residency he was recommended to us by Eugene DuBois, who ten years previously had recommended Soma Weiss to Francis Peabody, from a similar background of Cornell education and Bellevue clinical experience. Hale, while an intern, had made over a thousand ambulance calls and in this way saw a very human cross-section of medical need and urban poverty. He meanwhile taught himself to do white cell differentials on blood films that he had made and this turned out to be the beginnings of his interest in hematology.
At the Thorndike, Hale was at once a natural friend of all comers, patients, staff and hospital employees. He was thoughtful, kind, competent and soon showed himself to be an ingenious clinical investigator. He believed in and practiced what he later wrote about at Case Western Medical School, "The Student as Colleague." At the Thorndike he was as much interested in the learning progress of his junior colleagues in research as in the success of their experiments, always designed in careful written protocol with his help. He persuaded the Works Progress Administration (WPA) workers at the City Hospital in those Depression days to make essential laboratory furnishing that was impossible to get from the hospital authorities. A bank of electric lights under a galvanized iron hood gave much needed illumination for a laboratory bench. Someone wrote on it in large letters with red glass crayon, "What I am, I owe to Ham." That was very true of that particular item and a lot of other things that Hale managed, with his tact and understanding approach to people at the City, to achieve. He described life at the City Hospital as "worth it but just." And he certainly made the most of the opportunity by his adaptability to the City Hospital, which was not possible for all. Hale was interested in natural history. One day when a small green frog appeared in his salad in the doctors' dining room, he was pleased to give bystanders a lesson.
Hale helped me in furthering the evidence for an essential normal so-called intrinsic factor lacking in the gastric juice of patients with pernicious anemia. His own initial research was on the factors involved in the so-called sedimentation rate of red cells in blood rendered incoagulable byoxolate and standing in a narrow glass tube. Fibrinogen increase was shown to be the principal determinant of the relation of infection to an increased sedimentation rate. Soon thereafter, Hale showed the effect of slight acidosis in vitro as well as in vivo in causing increased hemolysis in paroxysmal nocturnal hemoglobinuria. It was prevented in the patient by nocturnal insomnia or by hyperventilation in a Drinker respirator, presumably by producing mild alkalosis. In vitro a rise of ph prevented the complement sensitivity of the red cells of the condition from expressing itself in hemolysis. This research initiated his interest in other varieties of hemolytic anemia including the role of orychrostasis in the spleen and elsewhere and the hemolytic action of oxidative drugs studied with Charles P. Emerson, Jr. Hale's curiosity was aroused by hemolysis in vivo in which no hemolysin was demonstrable in vitro, for which an explanation was not found until some years later by Jim Jandl and his colleagues. A few years after his arrival, Hale was placed in direct charge of the house staff at the City Hospital for whom he became friend, counselor and guide. He then followed Henry Jackson, Jr. as director of the second year course in laboratory diagnosis at the Medical School. There he introduced, after the whole class lectures, section work for individual students at the laboratory bench that clarified the clinical problem through procedures related to an individual patient. This correlation was a strong point in the course and each student's results were put on the blackboard and analyzed statistically before the end of the exercise. As to the relationship between the individual patient and the essential laboratory studies, Hale said, "Nothing is less interesting than an anonymous urine specimen." Clinical description of diseases and their related laboratory procedures were eventually collected in a paperback syllabus that became available to generations of medical students as the Culver and Page hardcover book. Hale insisted that his original edition should have a paperback cover so that it would be kept readily available on the laboratory bench despite the risk of damage by reagents.
Hale left Harvard in 1950 to become Professor of Medicine and in charge of curriculum reform at Case Western Reserve University School of Medicine. There his persuasiveness and patience resulted in great benefit to the education of students with the loss of only one or two professors who preferred research to more teaching responsibilities. In part due to Hale's influence post-graduate teaching of hematology in connection with national meetings of the American Society of Hematology became an important process and continues to this day.
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Q: Dr. Castle, when did John Harris come to the Thorndike?
Castle: John Harris came to the Thorndike in 1948 and remained there until 1952, when Hale Ham recruited him for his group at Western Reserve. John was a graduate of Harvard Medical School in 1943 and was on the medical services of the Harvard Medical Unit as an intern and resident from 1944 to 1947, after which he moved to the Thorndike and began his own research career. John is a man of quiet competence, an excellent teacher and clinical investigator quick to learn new techniques. His research originally was to help in exploitation of Lionel Berk's discovery in 1948 that Vitamin B-12 then just isolated by Merck from liver extract was also active as the so-called extrinsic factor when given daily in 5 microgram amounts by mouth with normal human gastric juice, without which no hematopoietic effect occurred. Harris devised a biological assay for Vitamin B-12 using the growth of Eugyena gracilis in vitro. This was applied to pernicious anemia serum and usually showed less than 100 micrograms of per ML as opposed to several hundred in the normal individual.
The study of a patient with sickle cell disease stimulated Harris's interest. On the basis of Ham and Castle's demonstration of the increased viscosity of deoxygenated sickle cells, their birefringence under a polarizing microscope by [Irving] Sherman in 1940, and the electrophoretic differences of sickle cell and normal hemoglobin by [Linus] Pauling and [Harvey] Itano in 1949, Harris decided to study the viscosity of crude hemolysates of normal and sickle red cells. When normal hemoglobin was deoxygenated, the viscosity was not significantly altered. But when the hemolysate of sickle cells was so treated there was an obvious increase in the viscosity of the hemoglobin. I've never forgotten the visible change from a freely-movable crimson liquid to a molasses-like, deep red deoxygenated sickle hemoglobin solution that John showed me in a small Erlenmeyer flask. He then got in contact with David F. Wall at MIT and thus had access to a phase microscope and a good collaborator in physical chemistry. Wall at once recognized that under the phase microscope the viscosity increase was accompanied by the formation of what he called "tactoids" resembling sickle red cells in shape. The tactoids were also, like the deoxygenated hemoglobin, birefringent under the polarizing microscope. An article by Harris was published in the same month in 1950 as another by [M.F.] Peruts and [J.M.] Mitchenson in "Nature." The rest is history. Harris joined Hale Ham at Case Western Reserve School of Medicine in 1952.
Q: Dr. Castle, you mentioned the Pauling observation. There is sort of a legendary tale that you had a very important conversation with Pauling on a train ride, about sickle cell disease. Can you tell me about that?
Castle: Yes, the train ride was in 1945 in connection with preparation of a committee report to Vannevar Bush on the need for support of scientific research in medicine after the war. And eventually this was published by Bush for the Committee as "Science-The Endless Frontier".
During this train ride I was able to ask simpleminded questions of Dr. Pauling about why, for example, gelatin was not a good antigen. And also, I recalled the recent observations of Sherman, who had shown that when sickle cells were deoxygenated they became birefringent in polarized light. I told Pauling that this suggested to me some type of molecular orientation and that I thought it might be the kind of thing that he was interested in. I did not remember at the moment that [E. Vernon] Hahn and [Elizabeth B.] Gillespie in 1927 had stated that sickle cells deprived of their hemoglobin would no longer sickle upon deoxygenation.
Q: So what happened then? Dr. Pauling listened to all this and then what happened?
Castle: Well, this was in 1945, and in 1948 Pauling studied hemolysates of sickle cells and normal red cells electrophoretically and found that there was a distinct difference in their behavior. He and his associates showed that in the trait the hemoglobin was composed of a normal hemoglobin and an abnormal hemoglobin, whereas in the sickle cell anemic patient, there was no evidence of a normal hemoglobin and only the abnormal hemoglobin was present.
Q: Well that was a productive train ride for molecular biology. Dr. Castle what about Jim Jandl? When did he join you and start to work on hemolytic anemias?
Castle: Jim Jandl came to the Thorndike in 1952. He was a graduate of the Harvard Medical School in 1949 and had been on the Harvard Medical Services of the Boston City Hospital from 1949 to '52 with, I think, an interval of service perhaps for a year in the Navy. He became a staff member of the Harvard medical unit in 1955 and continued there until the abolition of the Harvard and Tufts Medical affiliations by the City Hospital Trustees in 1973. Jim was a remarkable and brilliant person. He was professionally ambitious, a hard worker, brilliant in discussion, with a retentive memory and great facility in writing. He had a sure instinct for important problems in hematology and their ingenious solution. He attracted able people to his laboratory and stimulated and guided them well toward independent achievement. Among them were Harry Jacob, Jay Katz, Frank Bunn, Buzz Cooper, A1 LoBuglio and Neil Abramson. His own research interests were in hemolytic anemias and their mechanisms. He recognized that the red cell must somehow transport oxygen without being burned up in the process. This was a dramatic statement of its need for defense against oxidation by free-radicals, in which glutathione was involved. He also investigated the immune hemolytic anemias by examining the effects of complete and incomplete antibodies in causing red cell sequestration in man and in experimental animals with chromium 51 labeled red cells. Resemblances of the red cell sequestration process in the spleen were found with millipore filters with apertures of 5 microns. Incomplete antibodies inert in vitro caused hemolysis in vivo by the adherence of FC components of IGG to macrophages in spleen pulp that caused loss of red cell membrance and resulted in spherocytosis and lysis. This phenomenon was demonstrated with A1 LoBuglio by plated macrophages; and electron microscopic photographs made by pathologist Ramzi Cotran added graphic illustration of the loss of red cell surface membrane. With Frank Bunn, Jandl studied renal filtration of hemoglobin, whose molecule is so large that it is not possible for it to pass the glomerular filter intact. Accordingly it was shown that by the use of reagents that favored disassociation of the normal hemoglobin tetramer, alpha-2 beta-2 to alpha-beta dimers glomerular passage was possible and that with reagents that maintained the tetrameric form, filtration was inhibited. Jandl and Bunn also showed that the exchange of hemes between intact hemoglobins could take place in vitro under appropriate conditions.
With Harry Jacob, Jandl showed that congenital spherocytosis and its hemolytic anemia were associated with sodium leak into the red cell and consequent activation of its sodium-potassium pump. This demanded increased energy and explained the spheroidicity and increased osmotic fragility characteristic of these red cells. In other words they had to use energy faster than normal cells do because of their membrane defect in order to partially sustain the integrity of their electrolyte contents. With R.H. Cooper, Jandl studied the apparent macrocytosis and targeting of red cells seen in blood films of patients with liver disease. This results from transfer of plasma cholesterol and lipids to extend the red cell surface. The actual mean corpuscular volume is not increased. Thus the apparent macrocytosis is a phenomenon of the blood smear and is due to an increase in the amount of surface membrane relative to the normal volume of the red cells. Spur cells that appear also in blood smears of liver disease are the result of excess membrane lipid, which is conditioned in some way by the spleen from the excess material found at the red cell surface. With Jay Katz, Jim Jandl demonstrated the dynamics of the cycle of transferrin in the utilization of iron by young red cells in the bone marrow. And this for the first time gave quantitative value to the phenomenon and its components. So Jandl and his pupils contributed to a number of important areas in red cell hematology. He certainly was throughout a most stimulating person and an excellent teacher and trainer of other young investigators who went on to notable careers in hematology. As an observer of the hematological research achievements of the Thorndike from 1925 to 1968, I would add to the above the names of Allan Ersler, who first demonstrated the existence of erythropoietin, and Victor Herbert, who added so much to knowledge of the megaloblastic anemias of vitamin B12 and folate deficiency.
Q: Dr. Castle, one last question. Of the many things in hematology and internal medicine, what gave you the most pleasure?
Castle: Well, I can remember, most vividly, the night that I discovered that instead of the daily one to two percent of reticulocytes in the blood smear there were six percent. This was in the blood smear of the case of pernicious anemia who was receiving a combination of beef steak and gastric juice. Previously there had been no response to beef steak alone. So it was obvious that some kind of association was required for the production of a liver extract-like effect, a combination of an unknown in the beef muscle and an unknown in the gastric juice. Today, in the light of the subsequent remarkable contributions of so many others, my self-satisfaction seems premature.
Q: So the highest moments for you were the thrill of discovery really. Thanks very much Dr. Castle.
END OF SESSION
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