ASH Oral History: Louis K. Diamond (5/7)
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Q: This was a question, actually, of control over the blood supply?
Diamond: That's right. They did a tremendous job. Their medical director, Dr. Herbert Perkins, is a genius at running a good blood bank. They supply all the hospitals in this area, and outside too. He does a lot of good research. Anyway, that's the story of the Red Cross.
Q: Dr. Diamond, could you comment on the problems of funding for your hematological research during this time period?
Diamond: My Hematology Research Laboratory was funded first by small grants obtained by Dr. Blackfan. During the War, of course I had the support of research going on with Dr. Cohn. Although I didn't get money directly from him, he could give some money for a technician or something of that sort. After the War, the Hood Foundation gave us money. Although the first grant was for five years, they gave me some more money, and I continued supporting the laboratory that way. They were very generous to me.
After the War, of course, came the National Institutes of Health, which supplied funds. During the War, we had the OSRD, the Office of Scientific Research and Development. They supplied money to research laboratories having something to do with the War effort. When OSRD closed down after the War, the NIH took over. The NIH set aside money -- several million dollars -- to support hematology research laboratories all over the country. I was one of the first to receive a five-year grant, renewable every year, to do research on blood groups and on hematologic conditions in children. This money gradually was increased to the point where it not only took care of my laboratory needs, but began to support research fellows. Then they set up a research program, research fellowships -- particularly in hematology. They supported laboratories, which appointed research fellows for, usually, two or three years. There, too, I was one of the first.
So I started training fellows. I had trained them even to a small extent before the War. But after the War, beginning about 1947, 1948, I had money enough to train two or three fellows for periods of one or two years, and sometimes even for a third year. To make a long story short, from the time I started in the early 1950s, until 1968, when I retired from Harvard -- I trained 75 fellows.
Q: Dr. Diamond, I was wondering if you could talk about your blood research that led to your work with the Rh business.
Diamond: This development that arose at the Children's Hospital, and the Boston Lying-in Hospital, where I was a consultant for hematologic problems in infants. Over a period of five or six years, we had had about 20 cases of newborn infants who developed anemia, jaundice, and a lot of nucleated red blood cells in their peripheral blood. This had been first called "congenital anemia of the newborn." Children who did not show much anemia right after birth, but in the first week became very much anemic and required transfusions to survive. These have been reported as single cases, or as cases -- two or three -- that any doctor might have had. But it was a fairly rare condition in the newborn nursery.
Back in the late 1800s there had reports of cases of generalized swelling, or edema of the fetus and of the newborn. This was called hydrous fetalis. This too tended to run in families. It was blamed on various congenital anomalies. Some of them were born very anemic, with big livers and spleens. The pathologist often pointed out that their circulation was full of nucleated red blood cells. A pathologist in Germany said these were erythroblasts, meaning young red blood cells, and called it erythroblastosis fetalis, meaning
erythroblast in the fetus. Such children usually did not survive.
Also in the late 1800s, several obstetricians and general practitioners described children - infants -- that developed severe jaundice within the first few days of life, and often died of that and of anemia. Had about a 50 percent mortality. Some of them recovered entirely spontaneously. Those that developed anemia were given transfusions and recovered. This was called icterus gravis, meaning severe jaundice. This was recognized as being different from the transient jaundice of the newborn baby that a lot of infants have about the third to fifth day, and clears up by the fifth or sixth day. Icterus gravis was recognized to produce severe nerve damage in children, if children survived the jaundice.
Now in Boston, such children, whether they were born with jaundice or with anemia often were referred to me. We recognized that in some families, some children were born with hydrops and in the same family some were born with severe jaundice. I was able to collect, in 1932, 20 of our own cases, and in the literature over 200 references. We published a paper. Dr. Blackfan, and Dr. Baty and I. After 1932, reports in the literature called this "EF" and realize that it was one disease.
In 1939, Dr. Phil Levine made a discovery which we had missed. The cause of EF was a new blood factor, present in the infant but absent in the mother. She developed antibodies against her infants' red cells, which led to EF. This new blood group became known as the Rhesus Factor, or Rh for short.
End of Session.
November 18, 1986
Q: Interview with Dr. Diamond continued, November 18.
Dr. Diamond, I was wondering if you could elaborate upon the significance of the work that was done in hematology, especially from the research angle, at Children's Hospital in Boston.
Diamond: As part of the program of training hematoloaists at the Children's Hospital in Boston, as each new trainee came on and learned something about various hematologic problems, and broadened his knowledge and understanding of the hematology that we were encountering, after a period of indoctrination -- sometimes a few months, sometimes half a year, sometimes even a full year -- the individual would settle into a research program with a special interest of his own so that he could -- he or she, we had women as well as men as fellows.
Q: Two questions. Where did the fellows come from?
Diamond: They all had had previous training in pediatrics or internal medicine. They applied for this Fellowship, which had become well established and pretty well known around the country since it really was the first of its kind after the War supported by the NIH. We had a number of applicants every year, and could only appoint two or three per year. But each, as she or he became proficient in general hematology and in pediatrics, would take on a research project of some sort. For example, two of them became interested in clotting problems and hemophilia, of which we had quite a number of patients. They worked in this area. They helped stabilize Fraction I, the first fraction of Dr. Cohn's isolation of plasma fractions. We began to use Fraction I as an anti-hemophilic fraction. It contained other materials than anti-hemophilic factor, which even to this date has hardly been purified completely.
Q: Dr. Diamond, could you expand upon some of the projects that were undertaken such as the work in hemophilia and in iron-deficiency anemia?
Diamond: There were several of my fellows who were studying the large number of patients with iron deficiency and other nutritional deficiencies as a cause of anemia. Iron deficiency was the most common and made up the largest number of patients that we had in one single category. There was also folic acid deficiency which we learned about later. In addition we had hemolytic anemias, blood destroying anemias, to work on. In the Boston population, where there is a large population of Italians, Greeks, and Mediterranean peoples, we had what was called thalassemia, or Mediterranean anemia. We probably had more such patients than any other city on the east coast short of New York. Then we also had sickle cell anemia because we had a fair number of children from the black population. So that there were any number of projects for researching.
Q: Could you say something more specific about the work being done on thalassemia, as well as on sickle cell anemia? How it is identified, why it's seen as an important problem, and what techniques were developed to deal with it?
Diamond: One of the individuals that came to work with me in Boston is very important in the study of thalassemia and of sickle cell anemia. That is Dr. Y.W. Kan, a doctor who came from Hong Kong. After Boston, he moved to California. He is one of the world's leaders in detecting the gene and the chemical basis for thalassemia. He has discovered how to isolate that particular gene and recognize it even in utero, and now it is possible to make this diagnosis at two or three months of gestation and advise on interruption of pregnancy if desired.
Q: Then did Dr. Kan first start working on this problem with thalassemia?
Diamond: Probably sometime in the late 1960s, early 1970s. He has continued on this, and has set up a large laboratory here. He is one of the people supported by the Howard Hughes Foundation, which guarantees his laboratory support. Dr. Kan is an example of a man who became interested in one particular project after he had rounded out his hematologic training, and has pursued this in depth to the point of uncover in a really, the genetic basis for thalassemia.
Q: This raises another question, which is the use of genetics itself within hematology. There are other instances earlier perhaps we'll talk about in a short while.
Diamond: Sickle cell anemia, of course, early on was recognized as a genetic defect -- heritable -- and was worked out by several people. Particularly of course by Linus Pauling finding the defect, for which he got the Nobel Prize, in the type of hemoglobin that caused sickling. Anyway, as these Fellows became skilled in general hematology, they did develop an interest in particular projects. I've mentioned at least four areas -- nutritional anemias, clotting defects, the hemolytic anemias, and the anemias of the newborn, which included erythroblastosis -- in which these men became proficient. Usually, after two, three, four, sometimes as long as five years, would leave for advanced positions in other schools. Of the 75 Fellows that trained in Boston with me, fully two-thirds of them eventually became professors of pediatrics or heads of hematology labs. In fact, five of them became professors and chairmen of departments of pediatrics. But the advance in knowledge in hematology came from the training that these Fellows received, and spread all over the country.
Q: Did you work out a specific method for training since this was a new medical experience, setting up the pediatric hematology services?
Diamond: No. The individuals -- all that came -- were trained or all previously trained in pediatrics. They couldn't come unless they had had one, two, or three years in pediatrics before they became interested in hematology. Then, at first they just helped us with patients with hematologic problems and learned hematology that way, and then they could start to work on problems of their own and publish papers of their own. There was no set program. It depended on case material. But there was always so much case material that in the course of a year or two they certainly would have covered all the important types of hematologic problems. Then, of course, when they became interested in a particular subject it was necessary to go back in the literature. In working up papers, they'd spend a lot of time in the library, and working with others, too.
Now, the question of the cause of erythroblastosis fetalis, or hemolytic anemia of the newborn, I've already touched on. I'd like to develop that further, because it's a good example of how knowledge accumulates.
Now, the antibody in the animal or human plasma is of two kinds at least, which we now know as IDG and IGM. The IGM is an antibody that acts in the saline suspension perfectly well, and causes clumping of red cells by the antibody in the dilute saline solution. IDG does not, but we didn't know that. When we set up the mother's serum in a case of hemolytic anemia of the newborn against the red cells of the husband, or of any individual, or of the baby, the IDG full of antibody which is present there did not clump in saline suspension. That's why we missed it all those years. The diluted the red cells in saline and the only antibody that might show up was an IGM, and that is not the type of antibody originally developed by individuals that develop antibodies against a blood factor.
However, I mentioned that in 1932 we cared for this baby with hemolytic anemia of the newborn (erythroblastosis fetalis), which was transfused with its father's blood. When we happened to try some of the mother's serum against the baby's red cells in a dilute saline suspension but not quite as dilute as two percent--ten percent I'd say--there seemed to be some clumping. However, on showing it to an expert serologist it was declared an artifact, not true clumping.
Now, Levine in 1939 had this patient whose baby had died of erythroblastosis at birth. She needed a transfusion. She received her husband's blood, and almost had a fatal reaction from it. Levine set up her serum against the husband's cells, in saline, and he saw no gross clumping. But in one area he thought there was some small clumps and when he studied it further, he found that she did have some sort of antibody against the red cells even in saline suspension. She was an unusual person, in that most of her antibodies against the factor on her husband's red cells were of a type that do not act in saline, but do act within plasma suspension. Most women who become sensitized through their babies have only this type of antibody. Once he had found it, we began looking for this kind of antibody. Everyone then realized that there was a new blood group factor to which the women had become sensitized through their babies, during gestation, and that this was the cause of the hemolytic anemia.
In the meantime, Landsteiner and Wiener had been injecting rabbits and guinea pigs with Rhesus monkey blood, which was Landsteiner's way of detecting blood group antibodies. They thus had found the M, N and P Factors on human red cells, but these were clinically unimportant. Because Wiener had used Rhesus monkey blood to inject the guinea pigs and rabbits, he called it a "Rhesus factor," and found that it did react in a very peculiar way against human red cells too. Then Levine proved that this was the antibody similar to, though not exactly the same, as Landsteiner's and Wiener's Rhesus antibody. Therefore Landsteiner and Wiener, and Levine too, called it the "Rhesus factor" in human blood. As Levine proved years later, it's not the same, though quite comparable.
Q: There was almost a twenty year period between the time that Levine first isolated this Rh factor and the time that he proved the non-identity between the Rhesus factor and the human.
Diamond: But by that time there'd been hundreds, if not thousands, of published articles calling this the Rhesus factor. Therefore it was difficult to change the name; it should have been called the "Levine factor" or Lord knows what.
Q: But this twenty years was also a period of very rancorous debate between Levine and Wiener. I was wondering if you perhaps could comment on that.
Diamond: It was more a one-way debate, because Wiener insisted on calling it the Rhesus factor, and insisted on several other ideas of his that were not quite acceptable to everyone. He wanted to name it the way he had devised Rh 0 for the most common factor, whereas the English -- through the skilled work of Race, and with the help of the great geneticist Dr. R.A. Fisher--found that several subfractions of what we call the Rh existed and eventually developed a very logical nomenclature for the Rh blood groups system.
Q: Could you, perhaps, comment upon what affect this work of Wiener had on the development of the research around erythroblastosis?
Diamond: It would be more the work of Levine. He set up a laboratory for blood grouping, at first in his own small quarters at the Newark Beth Israel Hospital, and then when he accepted a position with the Ortho Laboratories -- a pharmaceutical company in Raritan, New Jersey -- he solicited and received unknown serums from all over the country and all over the world. He developed one of the largest repositories of unusual blood group serums in the world. The rivalry between Levine and Wiener unfortunately was the result of Wiener insisting that his nomenclature -- Rh 0, Rh prime, and Rh double-prime, capital Rh, small Rh, and other such confusions -- should be the established international nomenclature. Most people preferred the C, P, E nomenclature of Race and Fisher and Levine.
Q: Why did Wiener push so hard for his nomenclature?
Diamond: Because he had named it first, he thought. Levine had accepted his naming it at first, until Race and his group in England showed that it was easier to deal with c,d,e -- that is little "c," little "d," and little "e" -- rather than "Rh prime," "Rh double-prime," "Rh 0," "Rh sub" Lord knows what.
Q: Do you think that this rivalry instigated by Wiener had any effect on the research programs of various labs?
Diamond: Just confusing.
Q: There was confusion.
Diamond: That's right.
Q: How long did this confusion last? Was it the work of the geneticist, R.A. Fisher and his group?
Diamond: Actually, people found that they preferred to use the C,D,E system.
Q: Dr. Diamond, could you please comment on the influence that Wiener ostensibly had with the NIH, in terms of his fight over nomenclature, the Rh factors?
Diamond: Dr. Wiener was a recognized world authority on blood transfusion and blood group factors, and had written the best book on this subject. This book was accepted all over the world as the bible for blood transfusions. Wiener wrote several good papers on transfusion reactions and a few on erythroblastosis. All his papers of course used the Rh 0 name. He insisted not only that his own papers bear this nomenclature, but he was a very aggressive writer. If anyone, particularly the English, dared use the C, D, E nomenclature, he was sure to write a few letters -- personal letters -- censuring them for doing that. He tried to persuade Dr. Levine not to accept the C,D,E system, to insist that it be the Rh 0 and prime, and insisted that the NIH back him in this. For a while the NIH did use that nomenclature only, but eventually they used both nomenclatures in preference to one or the other.
Q: What role did Karl Landsteiner play in all of this? He was mentor to both Levine and Wiener.
Diamond: He accepted the Rh 0 system. In fact he died before the C,D,E controversy had gone very far. So that he had no reason to enter the fight in any way.
Q: Could you peRhaps comment on the role that the work on Rh Factor played in development of the blood banks?
Diamond: The Rh Factor was the stimulus to re-awaken interest in blood group factors in humans. Thereafter using these newer methods of detecting antibodies present in plasma of sensitized individuals, numerous factors were discovered in humans. As a cause of transfusion reactions, and as a cause of hemolytic anemia of the newborn due to maternal antibodies against the fetus, and against the newborn baby. More than three hundred different blood group antibodies have been discovered in human beings. The English, particularly Race and Sanger -- in London -- working in their Serology Laboratory--became internationally famous for detecting some of these rare blood groups. Then the next development from that, the realization that blood group antibodies were mostly of the IgG type that did not react in saline, led to a further extension for the blossoming of the research on antibodies and the extension of immunology as a tremendous field for research and for practical clinical developments in the field of immunology and genetics. Departments of genetics, departments of immunology just opened up all over the world as a result. Although it wasn't the sole reason for development of immunology and genetics by any means, it was one of the factors that helped boost the interest in antibody research.
Q: Could you comment on the particular role that the identification of Rh factor and blood-typing played in the development of blood bank systems?
Diamond: Blood banks after the war became established as a necessity for the treatment of numerous conditions -- not only replacement of blood, but hemolytic anemias where blood destruction went on, and other areas in which immunology was vital factor in the understanding of disease processes. Blood bank directors, blood bank technicians, blood bank scientists were established in routine laboratories in all large hospitals. True, the American Association of Blood Banks and the Red Cross in many cases supplied the blood through their established organizations, but even in these hospital blood banks, research work in immunology was pursued. For example, here in San Francisco, Dr. Perkins, who was the scientific director of the Irwin Memorial Blood Bank that supplies so much of the blood in San Francisco and in the whole area, has several good research workers and in fact is also on the faculty at the U.C.S.F. medical school and helps guide some of the research in immunology, and in blood banking. We have our own blood bank here in the hospital, but we get all our blood from the Irwin Memorial and we just distribute it here and make sure it goes to the right people and so on. So that this was a tremendous boost to the field of immunology and to the field of genetics, which certainly would have taken years to develop if not for the stimulus of new blood groups and blood banks, where such material had to be very carefully analyzed in order to avoid serious transfusion reactions.
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