ASH Oral History: William Bosworth Castle

Q: Dr. Castle, could you tell me a little bit about your family background?

Castle: Well, my father, William Ernest Castle, who lived from 1867 to 1962, was Professor of Zoology at Harvard and a pioneer in experimental mammalian genetics at the turn of the century. [See L. C. Dunn Biographical Memoirs, National Academy of Sciences, 38; 33-80, 1965.] My mother, Clara Sears Bosworth, 1870-1940, was the daughter of a farmer living near Wellsville, Kansas, whose wife insisted strongly on college education for their children. Clara graduated from the University of Kansas at Lawrence and married my father in 1886. In later years, her considerable talents led to the production of amateur plays and interesting accounts of early life in Kansas. In 1897, I became the first born of three sons: William; Henry, who died while in his second year of Harvard College; and Edward, subsequently Professor of Physiology at Harvard College.

I was born at 10 Ash Street Place in Cambridge, Massachusetts, in one of a few single-family houses with backyards situated on one side of that quiet non-thoroughfare. Its other side bordered the lawns and gardens of the Greenleaf Estate. A good place for a child to learn to respect the prior rights of tolerant gardener Murphy and his floral borders.

In 1907, the family, now of five, moved to a newly built house at 186 Payson Road, Belmont, Massachusetts. Our dwelling had no near neighbors and overlooked a quarter mile away the extensive market gardens, orchards, and greenhouses of the Hittinger Farm. With the friendly young Hittinger boy as our playmate, this offered the untutored learning experiences of a running brook, a shallow former ice pond, a barn, a blacksmith shop and, once only, a paper wasp's nest. My father now exhibited the knacks and talents of the farm boy that he had been by grafting hit trees and cultivating a kitchen garden bordered by phlox and iris. Unlike his youngest son, Edward, in adolescence, I was little interested in my father's attention-demanding animal breeding experiments, as I grew up, or in his agricultural enjoyments.

When in 1909 his animal work was transferred from Cambridge to Harvard's Bussey Institute, in another Boston suburb, Forest Hills, a tedious daily commuting trip became a necessity of his academic life. Salvation came with the purchase of a 1915 Model T Ford as suggested by Walter B. Cannon. This was not without its perils, as he was a slow learner at the wheel.

I was at once interested in the machine and its planetary transmission and being young required no more than a few hundred yards of open road to learn how to drive and shortly to make elementary repairs. After two or three secondhand Model Ts of my own in college and medical school, I purchased a Ford Model A Roadster, the only factory-new car that I have ever owned. It achieved fame with medical students and hospital house staffs and was loaned to at least two research fellows for their honeymoon travels.

In 1933, I married Louise Griffin Muller, a lovely public school music teacher from a suburb of Philadelphia, whose good nature and common sense have often put me in mind of "the lady from Philadelphia" of The Peterkin Papers. She had graduated from West Chester State College in 1929 and after our marriage in 1933 we lived in Brookline, Massachusetts. There she became, through membership in the League of Women Voters, interested in local public affairs and in 1960 was elected to the town's Board of Selectmen. The first woman to achieve such membership in Brookline, she served for nine years.

Q: Dr. Castle, what about your early education? Can you tell me something about how you first made any contact with science teaching in secondary school and in undergraduate levels?

Castle: In 1909, my father entered me in Browne and Nichols preparatory school in Cambridge. Our teachers were now all men who presided in their own rooms to which we went when the bell rang. I learned ungladly the required Latin and English and elective French. Also, regrettably, a year of Greek rather than German. Plane geometry seemed a labored effort to prove the obvious but algebra allowed the solution of practical problems when once clearly set forth. I yearned for a final fourth year when I could learn elementary physics by simple classroom experiments. With classmate Tom Cabot, I engaged in and survived after-school experiments with fuming acids, electric arcs and gunpowder in his home. And with Russell Cogswell, tried to understand the working principles of wireless telegraphy and the practical construction of a simple crystal receiving set. I could never learn to read Morse code.

Q: Then how did medicine become a career choice?

Castle: I entered Harvard College early in the month after the distant "Guns of August" were heard in 1914 and for the first time lived away from home in Gore Hall, one of President [A. Lawrence] Lowell's new freshman dormitories on the Charles. Meeting and making new friends from other schools and other states was heady stuff. Night-time bull sessions that I think explored the subject freely rather than merely scored debater's points were intellectually rewarding, at least to me. I took courses in chemistry, biology, and physics, including an elective on the nature of matter at a subatomic level by Theodore Lyman. Lectures by Professor [Elmer] Kohler on inorganic chemistry were often related to industrial use, but I first heard of and saw the periodic table of the elements in his course. Far from its present completeness, it gave exciting evidence of a fundamental order in the universe. The experiments of Jacques Loeb with plants and animals seemed to obey the same laws. The human politics of the World War was a shocking contrast. During parts of summer vacations, I took demanding month-long courses: surveying at the Harvard Engineering Camp on Squam Lake and quantitative inorganic chemistry in Professor Theodore W. Richards' laboratory. The problem assigned was to determine the atomic weight of sodium, a meticulous exercise for me in how not to spill salt in the process. I also worked in a shipyard in Bath, Maine, helping to build Liberty Ships and spent July 1917 in Officers' Training Camp in Plattsburg, NY.

I decided upon a medical career as a result of educational experiences in Harvard College that showed me that I was not bright enough to be a physicist or biologist and that success in most professions leads to a desk job with domination of or by others. It seemed to me that this was not necessarily so for a career in medicine, where, for example, in contrast to law nature, not man, is the adversary. Indeed, I saw that if a doctor wished, he could remain always and usefully in direct contact with the object of his endeavors, the sick man, woman, or child. Moreover, three of my closest college friends were planning to go to medical school: Tracy Mallory, Grantley Taylor, and Howard Sprague.

It was easy to get into Harvard Medical School in 1917 after three years in Harvard College. More doctors were expected to be needed for the war in Europe. Many faculty members were already in military service in hospital units or as special consultants, though most were released by the end of my second year. The curriculum was the Flexnerian type [named for Abraham Flexner, who published an influential report on medical education in 1910]: two years of lectures on preclinical sciences with related student laboratory exercises and physical examinations mainly of normal heart and lungs. Then a third year of lectures on clinical subjects relieved by occasional CPC's by Richard Cabot himself. He had elsewhere expressed the opinion, unpopular with the general medical profession, that there were only twelve drugs with therapeutically demonstrable efficacy. In the final fourth year came the clinical clerkships in medicine and surgery at the major teaching hospitals and the opportunity to complete the required dozen obstetrical deliveries on the district (slums) of Boston. This was described by Fritz [Frederick C.] Irving, Professor of Obstetrics at the time, in the "The Ballad of Chambers Street."

In retrospect an extracurricular event was for me of special interest. This was the Cutter Lectures given at the medical school in the fall of 1917 by the young Dr. E.V. McCollum of Johns Hopkins. He described the growth requirement for small amounts of a "water-soluble B" and a "fat-soluble A" substance by young rats kept on simplified diets. Restoration of normal growth was promptly achieved when minuscule amounts of A or B were provided. Thinking of the striking cure of oriental beriberi by restoring the husks to a diet of polished rice held out prospects for discovery and relief of other human disorders by a "newer knowledge of nutrition." At the moment, finding a medical internship if possible in Boston seemed of more importance.

Q: Dr. Castle, can you tell me a little about what the internship was like at the Mass. General Hospital when you went there?

Castle: The 21-month medical internship was a progressive experience divided into seven three-month periods. First was outpatient medicine--neurology or dermatology--under supervision of part-time practitioners. Then a period of simple laboratory procedures on blood, sputum, or urine of individual ward patients. Next a period of collecting blood and other samples for examination by other hospital department laboratories such as bacteriology, biochemistry, or pathology. At long last with one's arrival at the level of junior house physician, one began to share in the work-up and care of ward patients and often to attend morning ward rounds with the residing physician of the month. Progressively from there on one assumed more responsibility in the management of patients with the limited therapeutic means available--few drugs, bed rest, and excellent nursing care. Skill was acquired in the succinct presentation of individual patients to idiosyncratic members of the visiting staff who made rounds for an hour or so in the mornings of weekdays. They were also available for after-hour consultation by the senior house staff when necessary as were members of the visiting staffs of surgical or other services. We interns were also aware of the informal research activities of one or two recent graduates of the internship who had small laboratories in the basement of the Bulfinch building. Arlie [V.] Bock was there too, carrying out experiments for L. J. Henderson on the fitness of the physical chemistry of the blood.

Q: Did you get an interest in hematology during your internship and residency or did that occur after you went to the School of Public Health? By the way, you were there for two years--can you tell me a little bit about that School of Public Health experience?

Castle: There was no residency available to me at the MGH and the normal course of life for a medical intern graduate was to go into an apprenticeship with an older physician, or if academically inclined, to find an appointment in a preclinical department of a medical school. My interest in hematology had been aroused by contacts with Dr. George Minot while I was in medical school, but in the fall of 1921 he developed diabetes and struggled bravely to continue limited medical work with dietary management little short of starvation. In January of 1923 Dr. Eliot Joslin was able to obtain small amounts of insulin for him, and Minot's life was extended to1950.

My appointment in the Harvard School of Public Health was simply because the academic appointment and laboratories of Dr. Cecil Drinker were there. In Dr. Walter Cannon's absence in Europe, he was acting head of Physiology in the medical school. I had in my first year of medical school undertaken some student research under Drinker's guidance and now in 1923 was fortunate to receive an appointment as Assistant in his department. What I did there was to work with Dr. Harold Himwich, who had come from Yale School of Medicine well-grounded in metabolic medical science. Harold was interested in the finding of certain European physiologists that the unitary respiratory quotient of excised muscle, both amphibian and mammalian, indicated that only carbohydrate was oxidized. With my help in preparing an isolated self-perfused gastrocnemius muscle in living decerebrate dogs, we were able to show that the average respiratory quotient of the resting muscle was not 1.0 but rather 0.71 or close to that of the expired air of the dogs. Like the whole animal, it was using both carbohydrate and fat as a source of energy.

This experience taught me that experimental work requires strong motivation, long hours, and hard work. It also convinced me that I preferred to study patients, if possible, in a scientific mode in a hospital setting. And so when near the end of a second year I was invited to consider an appointment under Francis Peabody at the recently-opened Thorndike Memorial Laboratory at the Boston City Hospital, I gratefully accepted. At that juncture I told Dr. Walter Cannon, who had returned from abroad to head the physiology department in the Harvard Medical School, as was proper, that I was to go to the City Hospital that fall. He remarked, "Ah, another brand for the burning." That is a metaphor of which I have been unable since to find the meaning, but have concluded that it was not congratulatory.

Q: So you went off to be "burned" at the Thorndike. Can you tell me a little about those early days under Peabody? What the Thorndike was like as an experience? How did it function?

Castle: The importance of the Thorndike opened in 1923 was that it contained a comfortable ward for the study under controlled conditions of patients selected from the medical services. Thus it was surrounded by the rest of a large municipal hospital with a wide variety of patients. Those chosen for study in the Thorndike were being cared for by young men who were much interested in their work and did not forget that the patient was the valued object of their scientific and humanitarian concern. Thus there was opportunity for concentrated research effort provided by the Thorndike ward and its closely affiliated biochemical, hematological, and physiological laboratories all, in the same building. There was also a small animal house on the roof.

Soma Weiss, strongly recommended by his medical chief, Dr. Eugene Dubois of Cornell's New York Hospital, came to the Thorndike at the same time that I did in September 1925. Already appointed in 1923 were three Assistants to Dr. Peabody: Henry Jackson, Jr., Robert N. Nye and Joseph T. Wearn and a research assistant, a lady physician graduate of Columbia P and S, Dr. G.L. Muller. In 1924 Drs. Herrman Blumgart, Charles A. Doan and Perrin H. Long joined the Thorndike staff and Dr. Peabody became Chief of the Harvard (Fourth) Medical Service. There he and a mature Back Bay practitioner, Dr. Edwin A. Locke, together presented to the house staff a fine example of the integration of medical science with the care of the patient. Francis Peabody believed strongly that ward teaching experience was vital in the training of the Thorndike staff.

Q: Dr. Castle, did you immediately meet Dr. Minot when you came to the Thorndike and did you start working on the problem of pernicious anemia right away?

Castle: Dr. Peabody was the director of the Thorndike until his untimely death in 1927. Dr. Minot did not come to the Thorndike until 1928, but as a medical student I had already met him at the Massachusetts General Hospital. In my second year in medical school, I failed to pass the course in laboratory medicine partly because, I like to think, I honestly reported my inability to make the two areas of the counting chamber for red cells come out within the then required limits. Anyhow, I was asked by Dean Worth Hale to take a makeup examination which was supervised by Dr. Francis Peabody. He kept away from such technical matters and asked me questions about mechanisms of anemia, which I found not only interesting to try to answer, but educational. I also heard in medical school that it was known, especially from the work of Levine and Ladd at the Bringham Hospital and from the work of Arthur Hurst in London, that in pernicious anemia the stomach invariably lacks the normal ability to secrete hydrochloric acid. Also, that there is a neurological disorder that goes along with some cases of pernicious anemia. It seemed to me that--

Q: Excuse me Dr. Castle, the Levine you're talking about-- is that Samuel A. Levine?

Castle: Yes, Samuel A. Levine.

Q: Who became the famous cardiologist.

Castle: Later, at the City Hospital, I saw patients with scurvy and "alcoholic" polyneuritis, the latter considered by Dr. George Shattuck to possibly be related to oriental beriberi, a nutritional disorder due to lack of something present in the husks of unpolished rice. I hoped that there might be other opportunities for the discovery of reversible nutritional deficiencies in the clinic. When Minot and [William P.] Murphy demonstrated in 1926 that progress of an incurable disease, pernicious anemia, could be completely arrested by liver feeding, it suggested the possibility either of a metabolic disorder or of a nutritional deficiency. The problem was that there was nothing strikingly wrong with the diet of the patient with pernicious anemia, and that it was curious that it was necessary for pernicious anemia patients to eat liver but not for the normal individual. However, a simple connection seemed possible through the lack of digestion in the pernicious anemia stomach indicated by the consistent lack of hydrochloric acid, which from the work of [Arthur] Hurst was known sometimes long to precede the development of the anemia, and from a few surgical operations to follow total removal of the stomach. So it occurred to me that defective digestion of food of some sort in the stomach of the patient with pernicious anemia might deprive him of something that was present in liver. And that I attempted to prove.

Q: Dr. Castle, how did Minot's efforts tie into [George H.] Whipple's? What was the relationship, and was there some sort of community of scientist and clinicians communicating with one another on this kind of nutritional problem?

Castle: I think communication between scientific communities was something that didn't occur very often between practitioners of medicine and pre-clinical scientists. Whipple was head of the Department of Pathology at the new medical school in Rochester, NY. For several years he had been studying the quantitative relation of various food substances to hemoglobin regeneration in a colony of dogs subjected to repeated blood loss. Minot was a member of a group practice in Boston who had taught himself to count blood cells and to make accurate diagnoses from microscopic inspection of stained blood smears. He had a well-deserved reputation as a skilled hematologist and was the medical consultant of the Huntington Hospital, a small Harvard research institution. In 1925 Whipple and Robschsit-Robbins reported "the favorable influence of liver, heart and skeletal muscle" in their dogs. Liver was the most active. Minot and W.P. Murphy then decided to give it a try in 10 patients with pernicious anemia. By May 1926 200 grams a day had produced a prompt clinical improvement and sustained increases in red blood cells in more than 40 patients.

At the time the basis of the response of the patients as well as that of the dogs was not understood. Even the Nobel Committee, which should have known in 1934, when it awarded the prize to Whipple, Minot and Murphy, didn't realize that they were dealing with two entirely different conditions. They assumed, reasonably perhaps, that there was something in liver that was fundamental for bone marrow function and so stated. Since liver had been used by both Whipple and Minot with success, it seemed appropriate that they should both be given the award. So it was certainly the right award for the wrong reason. And unfortunately, some things happen like that in life.

Q: So a great medical discovery was made by practicing physicians who could read blood smears?

Castle: Yes, and I think the American physicians understood that it could happen. Who couldn't understand it were some of the leading hematologists in Europe. They could not believe that these callow young Americans could have made a discovery that had been denied their scholarship. Actually Soma Weiss played an important role by going abroad in the summer of 1926 and visiting various clinics in Europe and telling them that this was a true bill.

Q: But what about Peabody's role in this? Didn't he note normalization of megaloblastic marrow with liver feeding?

Castle: Peabody was interested in bone marrow morphology because that might give a clue as to the immediate nature of the anemia. And he realized from what had been written that the tibial bone marrow might be representative of the process as a whole. Moreover, the effect of liver feeding on bone marrow could be examined. I helped to persuade a few patients to allow tibial trephine biopsy in the interest of science, but I was not very interested in megaloblasts or jaundice. In the event, Peabody's paper was not quite clear as to whether a nutritional deficiency was being corrected or a hemolytic anemia was being suppressed by liver feeding. But at any rate he did raise the question of what we call today ineffective erythropoiesis.

Q: How about then, you said you weren't interested in the jaundice or the megaloblastosis. But you did get very interested in gastric juice and its administration to the anemic patients. Tell me what was the route of that experiment and how did it occur to you?

Castle: Elementary, Dr. Watson! Here was a disease in which there was no acid in the stomach, the cure of that disease was liver feeding, and normal people did not have to eat liver to stay well. I think the conclusion is fairly obvious. But it took me a while to see that the patient with pernicious anemia has to eat liver because his stomach can't make liver extract. Now that, as I didn't know at the time, had been suggested in essence by Austin Flint, in 1860. And he had given up further effort to solve the problem because he said he was too busy. However, he wrote that when the difficult and laborious researches of someone have shown it to be correct, "I shall be ready to claim the merit of this idea."

Q: After the discovery of the activity of liver feeding, Edwin Cohn got involved with Minot in an attempt to isolate the active principle. Can you tell us something about that involvement?

Castle: When Minot discovered in 1926 that liver feeding was effective, he immediately, being Minot, wondered why. And he knew that it was not likely that he would be able to find out, that a chemist was certainly needed. Now he knew Edwin Cohn and he knew he was a physical chemist and he decided to ask Cohn to help him. Cohn did the obvious thing and began the chemical fractionation of liver: precipitate, filtrate, and non-precipitate. Then Minot could test the fractions on patients. But classical methodologies that were available to Cohn didn't allow real progress to be made. However, the first thing he did was to show that heating at ph 5 got rid of the bulky liver proteins. Then a precipitate with alcohol and ether called Fraction G was produced to become Eli Lilly's #343 liver extract. Soon [H.D.] Dakin and [R.] West began their fractionation attempts with liver, initially along somewhat the same lines as Cohn's. And later they tied up with chemists at Merck with superior technology. And Merck also got a strong boost from a lady bacteriologist, Mary Shorb, who was interested in the nutritional requirements of a certain lactobacillus for which she found a growth-promoting substance in a refined liver extract. That did it. They now had a bacteriological test for the active principle, and they knew about chromatography. The active fraction was red and contained cobalt. In 1948 vitamin B12 was identified as a cobalamin by Merck and at almost the same time by Glaxo in Britain. Randolph West showed that it was active in pernicious anemia in microgram amounts by injection.

Q: Well, I'd like to just ask you, was this in your mind from the beginnings of the relationship of the university with pharmaceutical houses, in a major way, at least in this country?

Castle: No, I was only interested in discovering what I could about pernicious anemia. I didn't realize the folly of trying to get a useful substance out and not patent it. And neither did the university because it insisted that the Lilly company, which was giving Minot $6,000 a year for his research, should give the patent to the public, which is the same thing as saying there's no patent. Whipple, meantime, was getting lots of money from Lilly in the hope that he would discover, with his dogs, a form of liver extract that would treat "secondary" anemia. It wasn't obvious until later that Whipple's liver extracts were effective because of their iron content.

Q: Dr. Castle, who was paying for all the work that was going on at the Thorndike? How was research supported?

Castle: Research was supported by a departmental salary budget of probably $40,000 from the medical school and by supplements by the City of Boston to the salary of the director, the associate director, and two or three staff members with a lower rank. However, the major contribution was the free care of patients in the Thorndike ward and the maintenance of that ward, and its associated laboratories. That was a great contribution.

Q: Well, how were you paid when you went over there?

Castle: I was paid first by a salary for the chief resident, I think, $2,500 from the City, with free board and lodging. Laterm, when I had a faculty rank I was paid a bit more than that derived from City and medical school together. Minot had great abilities at making little things go a long way. When the salary available for a research fellow seemed to be a little large, he would ask the recipient to share it with another. For the unmarried there was, often free board and lodging.

Q: And how about the technicians and all, or were there any?

Castle: Originally Joe Wearn had two volunteer technicians and there was a chemical technician paid by the City. Later some others were paid by the City and some by the medical school. New and expert technical help and knowledge of descriptive hematology came when Minot brought Geneva Daland with him from the Huntington to be his research technician. She trained several junior technicians over the years.

It wasn't until after the War and the help of Max Finland with his connections with the pharmaceutical industry that we began to get really considerable amounts for research, which he generously shared for the good of the whole. And he was smart enough never to take a quid pro quo. He would say we'd like to have so and so much. And, yes, we're working in this area that you're interested in and you can be sure that we'll let you know if we find things that we think will be of interest to you. But whether we do or not, we'd like to have the money. And so he was able to attract considerable amounts.

Q: How did you get involved in the Rockefeller Foundation Commission to study anemia in Puerto Rico?

Castle: Through George Shattuck, Harvard's Professor of Tropical medicine. We knew that sprue had certain resemblances to pernicious anemia. It had been shown, I think, by Bailey K. Ashford and young Dr. Ramon Suarez down there that the crude liver extracts, then only given by mouth, would improve some sprue patients. I had also read papers by Hamilton Fairley that suggested that the bone marrow and the blood picture were similar, in certain cases, of sprue and pernicious anemia. Some years before Patrick Manson had shown that liver soup was good for sprue and [C.] Elders, who had been in Sumatra, I think for a long time had returned to Holland and successfully treated a patient or two with pernicious anemia with the same diet that he had used to cure sprue in Sumatra. That diet had in it a lot of meat and milk. And that was a hint to me, for what I did in pernicious anemia. So there was a real connection. Meanwhile Shattuck had written up proposals for me to go to Puerto Rico. No takers.

In 1930 a German physician, Dr. M. Gansslen, surprised us all, including Edwin Cohn, by reporting that a nearly protein-free liver extract derived from only 5 grams of liver when given daily by injection was effective in the treatment of pernicious anemia. At that time effective treatment with Eli Lilly's #343 extract by mouth required material derived from 300 grams of liver a day. This suggested to us the possible use of a sterile, neutralized and filtered aqueous solution of #343 by injection. It was soon found that such an extract derived from only 20 grams of liver when injected would produce a maximal reticulocyte response and prompt clinical improvement in pernicious anemia. Moreover because sprue is an intestinal disorder it seemed likely that parenteral therapy would have other advantages.

As a result Shattuck, I think, got in touch again with Colonel Frederick E. Russell of the Rockefeller Foundation who had been at the Harvard School of Public Health. He talked about his and my interests. And I gave a talk about my work in pernicious anemia at the Rockefeller Institute one afternoon. All this apparently convinced Russell that a study in Puerto Rico would be worthwhile. So when I heard that there was some money to be had, I thought pathologist C.P. Rhoads would be a good man to go along and we recruited Dick Lawson from Providence, who had allowed me to study some of his pernicious anemia patients, and off we went. And Dusty [Rhoads] began immediately to have big ideas and we rapidly acquired research beds in the Presbyterian Hospital and a few more in the School of Public Health Hospital in Santurce, PR. We had eight female technicians at one time working for us.

I have already described the sterile parenteral solution of Lilly's #343 oral liver extract that we had used with great success in pernicious anemia in Boston. And that turned out to be the case in sprue in Puerto Rico. We now know it contained both vitamin B12 and folic acid.

The other thing we did, probably more important, was suggested by a social worker named Celia Nuiiez who lived in Cidra up in the country where they had hookworm disease. She had observed that when they took the hook worms out of very anemic people they often didn't really get better. However, there were quack medicine sellers coming through town who sold them "tonics" and she saw that some of these patients got better. She wondered about this and she told us about it. So we said, "All right, we'll take the hookworms out of some of these here in the hospital and see what happens." Well, nothing much did happen until we gave them iron by mouth. So we learned that with or without removing the hookworms they got better on iron. Well now, if you turn the primary public health effort away from getting the worms out and instead get your patients better first, then they can build a proper latrine, perhaps get a job and then the worms can be taken out more safely when the blood levels are up.

Q: It sounds pretty interesting to me. Then your administrative role at the Thorndike became increasingly complex. I guess you became professor of medicine in 1937. What was the sequence of events that led to all of that?

Castle: Minot was Thorndike's director until 1948. And my administrative life thereafter never really got to be that complex, as I have said many times because, I had Max Finland to get the money and Charlie [Charles S.] Davidson to run the services. And I could go on with research work and only minor administrative problems at the Thorndike. We made our decisions at noon on Mondays with three people present, Max and Charlie and I.

Q: But would you have left the Thorndike? I had heard a rumor that you might have gone to England.

Castle: Why yes, I was invited to consider becoming Nuffield Professor of medicine at Oxford.

Q: Would you have gone?

Castle: Not after I went and looked. A delightful historic town with many stimulating colleagues, but not the place for controlled clinical investigation in those days.

Q: Why?

Castle: At some heads of beds in the Radcliffe Infirmary was a three-inch high sign with a doctor's name on it! In Boston I had a laboratory and research ward going at the Thorndike. It would have been foolish to give that up. Furthermore, as John Fulton told me, "There is going to be a war in Europe."

Q: There is sort of a general question that I'd like to ask you and that is how you then perceived hematology as a discipline, as both a science and a clinical entity?

Castle: In the beginning I was interested because you could count something of direct relevance in hematology. And that was impressive. And in anemia the possibility of reversing the disease by nutritional therapy. There wasn't anything that worked as well in medicine, as far as I knew. Now white cell diseases had no such mechanistic physiology then. That's all come recently. And platelet problems were of no great importance compared to leukemia. We had lots of patients with iron deficiency anemia and either folate or B-12 deficiency anemia at the City. So I had no philosophical concepts about hematology that your question deserves to know.

Q: What about when professional societies began to grow, like the American Society of Hematology? How did you see that?

Castle: When I heard that Bill Dameshek wanted to have an American Society of Hematology, and wrote that "it would have a profound impact on hematology internationally," I said to myself, "Not for me." But in fact the Society has provided a valuable forum for research presentation and a novel extension of hematological teaching.

Q: Why did you feel that way? You were interested, you were President of the Association of American Physicians, so you weren't anti-society? What was there?

Castle: I have always been naive about medical societies. So I didn't realize when I became a counselor of the A.A.P. that inevitably if I lived, I would get to be president.

Q: So you were really opposed to the formation of the hematology society, why?

Castle: I wasn't opposed. I was just not personally interested, and I didn't think that forming societies with by-laws and one thing or another was really going to promote the advance of scientific hematology.

Q: And how do you feel about that now?

Castle: The great virtue of the ASH is that membership is open to anyone with a doctoral degree and manifest interest in hematology. It is not a society that spends much time on who gets in and who does not.

Q: Dr. Castle, can you tell us something about some of your associates, such as Maury Strauss and Hale Ham, John Hams, and Jim Jandl?

Castle: Indeed yes, and I am very proud of them. Maury [Maurice B.] Strauss was an early collaborator of mine and very important to the extension of our work on the relationship of achylia gastrica to the etiology of pernicious anemia. He got an MD from Hopkins in '28, and became an intern on the Tufts medical service and came to the Thorndike in 1930. He remained there on the full-time research staff until '39 when he became more involved in private practice, which led eventually to his appointment as a clinical professor of medicine at Tufts. He was a calm, reflective, pipe-smoking philosopher. In the last few months, as intern on the Tufts service, he began to feel unwell. His blood was examined by an expert, and he was told that he had acute leukemia. That was quite a shock and he was given the opportunity to go down and rest for a few days on the North Shore. There he noticed that he wasn't getting any worse and he got a hold of his microscope and made blood smears every day and soon came to the conclusion that he didn't have acute leukemia but rather infectious mononucleosis. This was not an infrequent misdiagnosis in those days. At any rate, he kept his cool with that episode and came over to work at the Thorndike.

During that period in the Thorndike he had some admired friends and role models, one of whom was Dr. Merrill Moore, the poet, who had written the "Thousand Sonnets" and published them. And John Peters of Yale who had written the extensive two-volume text on quantitative clinical chemistry, with Van Slyke. There was also Homer Smith, who was much to Maury's liking as a natural philosopher in a modern day.

In 1930, a German, M. Gansslen, surprised us all, including Edwin Cohn, by describing a nearly protein-free liver extract of which material derived from only 5 grams of liver a day was effective by injection in treating pernicious anemia. And this suggested the possibility that we might do something with the Lilly #343 extract that would allow us to use it parenterally. We found in experiments with cats that when a sterile, filtered aqueous, neutralized solution of this #343 extract was given, there was a sharp fall of the animal's blood pressure, but an almost immediate recovery. Within half a minute or less, the blood pressure was back to normal. That was encouraging and we went ahead and prepared the material for possible clinical use. Then Maury Strauss and F.H. Laskey-Taylor, our biochemist, gave it very slowly intravenously at first, and later intramuscularly and found that it was 60 to100 times as active in pernicious anemia by the parenteral as by the oral route. So the active principle, whatever it was, was clearly in solution and much more effective on parenteral use.

In 1932, C.W. Heath and Strauss made a fundamental observation on iron-deficiency anemia. It was not understood at that time by what mechanism oral iron therapy abolished the anemia of iron deficiency, obvious as that would seem to be today. There was consideration of some kind of a "tonic" effect. That it had actually a quantitative relation to the amount of iron absorbed had not occurred to anyone. However, Heath and Strauss showed in a number of patients that small amounts of iron given intramuscularly, daily, were almost on the average 100 percent effective in increasing the amount of circulating hemoglobin in terms of its iron content. Maury then worked on the inhibitory effect of lack of acid in the stomach in the iron-deficiency anemia of pregnancy and showed that in the last trimester of pregnancy, no matter how anemic or iron-deficient the mother was, the infant was successful in achieving a normal hemoglobin level at delivery. So this interesting young man had made several important contributions to hematology by the time he moved on to more of the practice of medicine. The war came and after that he became Chief of medicine at the Boston V.A. Hospital. Towards the end of his career he published, after five years of work, a large volume, called "Familiar Medical Quotations." This was in 1968. Its 7,000 references made it a fitting companion piece to the older "Bartlett's Familiar Quotations" also published by Little, Brown, I think.

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.

{Tape off}

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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