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.
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