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Q: In coming to Boston University, did he place any particular emphasis on certain areas for basic research?
Ross: I think he was eclectic. He placed emphasis in all these areas: cardiovascular disease, hematology, gastroenterology, nephrology, endocrinology, infectious diseases, immunology and even psychiatry!! He brought good, aggressive, interested, young physician investigators in each of these areas; he gave them full support. Chester was an Infectious Disease man, and he figured that this was his area, but he hired Rammelkamp and Weinstein, who were in the same field, and they complemented his wisdom with laboratory investigation and a different approach. Chester was a very wise man, and he did a very great deal not only for his associates and B.U., but for the whole of medicine.
Q: Was there any attempt to set up more academic areas in conjunction with Boston University academic departments, such as biochemistry, or joint departments in physiology?
Ross: Well, he was quite successful in modifying the clinical departments of the school: surgery, obstetrics, psychiatry, and pediatrics. He didn't have the same success in the basic sciences, because the people who were there had tenure appointments, had been there for a long time, and they were set in their ways. They weren't going to take these changes from Dr. Keefer, or anybody else. So, unfortunately, the basic science departments really never progressed at that time, to the same extent that the clinical departments did. I would say it was not at all uncommon for the clinicians to work more closely with representatives of basic science departments at Harvard, and M.I.T., than it was with the basic science departments in their own school of medicine. That was unfortunate, but that's the way it worked out. This is not to say that the people who headed these departments were not fine people. They were fine people, but they were of a different era and a different concept, and they weren't going to change, and he couldn't change them.
Q: What was the status of hematology? There was a division of hematology created under Keefer with you as Head?
Ross: None of these subspecialties of medicine had existed at the B.U. medical school. When Chester went there, he created all these de novo, and brought people in to head them. There was a nice gentleman who was an old-style homeopathic clinician, who had taught the course in what was called clinical pathology. He was strictly a cytological hematologist, and he was a very good doctor, but he didn't do very much research, and wasn't very aggressive. He was superseded by me. There had not been a Division of Hematology before I came, and hematology at Boston University subsequently progressed, I think, quite satisfactorily. After I had been there several years we brought in another fine man named Charles Emerson, Jr., who also worked in the field of hematology. He made interesting contributions to make. He succeeded me when I left the Evans. When I went to Boston University there was a very small blood bank which had been started by a surgeon named Frank Barton. And I guess under Keefer's stimulus, I supplanted Dr. Barton as the head of this endeavor. I became very much concerned with the development of blood banking and transfusions. In the past, blood banking had not really developed to the point where large numbers of transfusions could be very appropriately carried out. And having seen a series of deaths from d mismatched transfusions in the institution from which I came, I thought it was tremendously important to have adequate controls, which we instituted. In the work that I subsequently did relative to blood preservation, it was very helpful to have available the blood bank to complement the more basic research that we were doing on storage of red blood cells. This was very helpful indeed! We developed a real good blood bank, and we never had any fatalities from transfusions when I was there; I don't suppose they've had any since.
Q: This is in terms of the work that developed after the start of World War II?
Ross: That's correct.
Q: Okay. Perhaps you could elaborate on that.
Ross: Well, you see, I came to the Evans in 1940, and the Japs bombed Pearl Harbor in December, 1941. That completely changed the whole direction of our research endeavor, because it became apparent from studies that I did on blood that had been stored in the usual fashion, just in saline solution, that erythrocytes and stored them in the usual blood-banking solutions, and transfused them into experimental subjects. The labeled cells all vanished within a matter of eight to ten hours after they were injected. At that time, along came a named Thalhimer who thought that if you put the blood into corn syrup solution, it would prevent red blood cells from aging. The reason this was believed was because the corn syrup solution prevented hemolysis of red cells, and the supernatant fluid did not become pink. Well, when we put blood with radioiron labeled red cells in that solution, they too vanished just as rapidly or more rapidly than if it had been stored just in salt solution. At that point, at the Battle of Casarine Pass, in North Africa, there was no blood for transfusion. They had plenty of plasma, but when a boy lost his leg, or his arm, or got shot through the lung, and lost blood, if he was just given plasma, that didn't help him very much. The physicians who were there recognized the need for whole blood. There was no real mechanism for taking blood for transfusions in the army hospitals. So they would draw blood from the medical people that were in the back lines, and since there was no citrate for anticoagulation or any way to preserve it, they would defibrinate the blood by stirring it in a flask with a glass rod and would use that definibrated blood for transfusion! And Dr. Elliot Cutler, chief surgeon there, sent back numerous communications to the War Department saying, "For God's sake, get us some blood for transfusions!" Because the plasma, which had been developed in large measure by Edwin Cohn at Harvard, just wasn't doing the job! Well, at that point, the use of corn syrup as a blood preservative, because it preserved the appearance of the mixture, was advocated. It was necessary to put 500 cc of corn syrup solution with every 500 cc of blood, which created a problem because it doubled the weight and the mass of the stuff that had to be shipped overseas. There was a considerable disputation about these various preservatives in the Surgeon General's office. The Surgeon General was a surgeon named Rankin, and he wasn't convinced that anything was necessary except the corn syrup blood mixture that was being sent. However, Dr. Conant, who, at that time, was the Director of the Office of Scientific Research and Development [OSRD], had recognized that there were problems, and a Dr. Newton Richards, a distinguished physician, was head of the medical branch of this organization, and got together a group of people and provided government funding from the OSRD to start studying blood preservation. I was one of the investigators who did these studies, working with me at the Evans was Dr. Clement Finch. This work was done in close cooperation with Dr. Robley Evans and a Dr. Wendell Peacock at the Massachusetts Institute of Technology--
Q: It's Wendell Peacock?
Ross: Wendell Peacock. Do you know him?
Q: I had his name down.
Ross: Wendell Peacock. He was a physicist. Also there was Dr. Jack Gibson III, and at Harvard and the Peter Bent Brigham Hospital. We all worked together in Boston, trying different ways of preserving red blood cells so they would survive longer in a bottle. There were other people working on the problem in other places, as, for example, Dr. Max Strummia in Philadelphia, and some people working in Canada. Together, over a fairly brief period of time, it was discovered that there were ways to keep blood cells happy in a bottle for a longer period of time. And, as frequently happens, there was a roundtable discussion as to what was going to be considered "satisfactory," in terms of percentage survival and duration of storage. It was decided that "satisfactory" would be 70% survival at the end of three weeks. That was accepted as the sort of standard, and we had a solution to do that which was adequate to store blood, so that 70% of the cells would survive at the end of three weeks. By that time, the necessity for whole blood for the treatment of battle casualties became readily apparent, particularly in the South Pacific, where there were no facilities for transfusion. It was necessary to devise a technique of delivery. This was done by getting a plywood box with six compartments constructed with an ice container in its center. This box with its stored blood could be dropped by parachute behind the battle lines. Hundreds of thousands of units of blood were taken from the civilians of this country, shipped to battle areas, and dropped by parachute to first aid casualty teams behind the lines. This saved the lives of lots of troops. This fact was recognized by General George Marshall who, in some of his writings, commented about the tremendous contribution that had been made to the war effort and to the medical care of troops with the use of this technique for preserving blood. As a consequence of this, the Medal for Merit Board recommended to President Truman that recognition should be given for this research. Robley Evans, and Jack Gibson, and I were given a special commendation by Harry Truman, the President of the United States! This was pretty exciting, and very gratifying! It was nice t 'know that what you did trying to help mankind was recognized by the president! Following this, my estimation of Harry Truman went up quite considerably. I now think he was a very great man and president! !!
Q: Was all this work funded under the O.S.R.D.?
Ross: All of this work was funded under the Office of Scientific Research and Development, through the Committee on Medical Research, headed by Dr. Newton Richards, who was a very good friend of Chester Keefer's and also a very fine and wise gentleman! The investment in this research paid off! This research was not funded by Chester and the Evans Memorial funds. All costs for this research were paid for by the government. This was the first government grant that anybody had gotten at the Evans. It made possible the employment of technicians, the acquisition of better radioactive detection devices, and the funds to pay subjects to whom we would give the blood that we had preserved. This transfusion procedure was a cause of problems at times; to find out if the stored blood was really any good, we had to transfuse it into somebody. We gave this to technicians and medical students, and, unfortunately, on one occasion, some of the blood wasn't all that good, and it made one of my technicians and one of the medical residents quite ill for a brief period of time.
[end of side one of tape three; beginning of side two of tape three]
Q: Tape three, side B, interview with Dr. Ross.
Ross: I commented that we transfused some of this preserved blood into a couple of individuals who got fever and got sick and scared the hell out of me!! But, fortunately, they got better without any other problems. One of my colleagues, however, was not so fortunate. He gave a transfusion to somebody and killed the boy, and that was a terrible, terrible tragedy.
This endeavor, as I say, was fruitful. In the pursuit of this, I would like to emphasize that there were other groups working on this. There was Dr. Max Strumia, working in Philadelphia. He was a pathologist. There was a Canadian named Orville--I can't remember his last name. And there were one or two others that I can't remember right now, but they all worked together, and corroborated the findings of the other investigators, a very wise idea! There were two people doing the same research and checking out what the other one did. This accelerated the solution of the problem! We also had some contact with Edwin Cohn, who was fractionating plasma. He thought we were blunderbusses, because we were doing most of our work on human subjects, and he didn't do that. I tried to crystallize radioiron labeled hemoglobin in his laboratory using some of his equipment, and facilities, in collaboration with some of the people who worked with Edwin Cohn. I wanted to find out how the hemoglobin released from destroyed red cells was re-utilized. I never succeeded in crystallizing hemoglobin; Dr. Conant had done
this, but he was a far better chemist than I. But, again, this was an interesting example of intercooperation among scientists of different disciplines, working in different places who were trying to solve the same problem.
Q: It's been said that Cohn himself ran his labs and the plasma fractionation project almost as a business manager, that it was a combination of both scientific skills and management abilities that allowed the development of that fractionation process, and pilot plant. I was wondering if there were similar individuals who contributed to blood work in other groups.
Ross: Not to my knowledge. What you say about Edwin Cohn is certainly very true. He was an excellent manager; he was an excellent promoter, and he was able to attract good people to work with him. He stimulated them to do a lot of work, and he was able to get funding to support them to do the work. I would say there was a conflict between Edwin Cohn and A. Baird Hastings, professor of biochemistry at Harvard Medical School, and this, again, probably, was a good stimulus for each of them. There was a nice fellow named Pete Hughes who worked in the plasma fractionation process, and also a fine gentleman named John Ferry. They were able to tolerate Edwin Cohn's yoke and did extremely good work.
In the field of red cell preservation, there was nobody comparable. There was no industrial approach to this. This was all pretty much clinical research by people who were dedicated to trying to solve the problem of transfusions for military personnel. They each worked pretty much independently, although they all were supported by the Office of Scientific Research and Development, but they cooperated very well. But there was no industrial firm involved in the work relative to the preservation of red cells.
Q: There had been, however, a number of earlier attempts at building blood banks.
Ross: Blood banking really developed independently of the attempt to develop a method of preserving blood. A surgeon would recognize the importance of trying to have blood available to transfuse patients who had lost too much blood in the operating process. And many of these surgeons, as at Boston University, had started by surgeons, blood banks in their institutions. They were not particularly adept at trying to find out better ways to do it. At B.U. initially we had a refrigerator for the blood bank, that had been used to store meat, and it was quite all right, and we continued to use it for quite a while. The developments that I have described were supported by the O.S.R.D., although not oriented to blood banking really put blood banking on a firm foundation. [?] collection and storage of large amounts of blood and the ready availability of blood when needed. This was really made possible by the work that was done by the group supported by the O.S.R.D. This work made it possible to keep blood for a fairly prolonged period of time and to make it available for transfusion in every hospital in the country. The preservation process, which was developed during the war by the 0.S.F.D.-subsidized research groups with little modification, is still used to this day. The survival of stored red blood cells, has been extended to four weeks from three. Actually, I believe it's much better to give blood as fresh as possible rather than transfusing stored blood of which there is only a 70% or 60% survival at the end of three or four weeks. On the other hand, such blood is adequate to take care of problems, when it is the only blood available.
There's now a technique for freezing blood cells and keeping them for months, It's extremely expensive and, again, I think, except in cases of national emergency or unforeseen circumstances that fresh blood or blood not stored for more than a week is probably better than the frozen blood.
But blood banking in this country now is a tremendously important and a very large commercial endeavor. Most of this is done by the American Red Cross, which have excellent facilities for the collecting, storing and dispensing of blood to hospitals. There also are independent organizations that collect and dispense blood.
But the fear of God has been instilled in them as a consequence, of the possibility of transmitting hepatitis or AIDS. And I really believe that for most transfusion it would be best to obtain from people that are known to the prospective recipient who probably are free of hepatitis or AIDS. I don't know the actual total volume of blood transfusions in this country but except for antibiotics, and, possibly, analgesics, blood and blood products are the most frequently used therapeutic modality.
Q: Was there any interest shown by some of the pharmaceutical houses I or other commercial interests during this World War II period in the preservation of blood, in blood banking, or these other areas?
Ross: There was considerable interest in red blood cells! The production of plasma and plasma fractions by such companies as Squibb--and I think Parke-Davis--left huge amounts of red blood cells which were thrown down the sewer, which was a perfectly frightful waste! One of these companies developed a concept of saving these cells, drying them and using them as a powder to stimulate the healing of wounds. Interestingly, this was really quite effective. For example, if a patient had a huge ulcer on the shin, and this blood cell powder was applied to it healing was stimulated. But this therapy has not been pursued vigorously because of the possibility that the dried cells might transmit infections. However, industry was not particularly interested or concerned in the preservation, the storage and the marketing of whole blood products. This has been done primarily by the Red Cross and by physician-directed associations of blood banks and hospitals. So I would say that from the standpoint of whole blood, industry has not really gotten involved in this. Maybe that's just as well.
Q: Is there a reason why industry would be interested in the plasma fractionations as opposed to whole blood?
Ross: Sure. They can make money. It was possible to do this without attention so critically to time, the duration of storage. Since storage time was not so critical they were able to develop fractions of the plasma proteins, which are extremely valuable therapeutically and prophylactically: [?] anahemaphilic fraction, the fibrinogen fractions, the gammaglobulin fraction, and [?]. Plasmofractation lent itself much more advantageously to industrial exploitation than does the marketing of blood cellular elements that have a finite lifetime and are much more difficult to handle and process. I know that some commercial concerns were marketing whole blood, and cells, at one point, but I don't think this turned out to be particularly lucrative, and, as far as I know, they don't do it any more.
Q: Was there any problems with the development of quality-controlled blood products, whole blood products?
Ross: Oh, yes, indeed. They are a terrible problem! The quality control from a chemical standpoint was, I think, solved quite well, but the quality control from the standpoint of potential infections, still is not completely controlled, although it's greatly improved. It is possible to detect the presence of some hepatitis viruses in blood, and to exclude such blood from use. Presumably, it's possible to detect the presence of the AIDS virus. But most of these are only 95% to 98% accurate, and if you get a large quantity of blood that's contaminated with just a small quantity of virus that's slipped through, you can infect hundreds and, potentially, thousands of people. This is one of the ways in which children who have hemophilia have been given AIDS consequent to receiving anti-hemophilic concentrate from large volumes of serum. It is a very great problem and I think its solution depends, again, on fundamental developments and ways to detect the possible presence of disadvantageous agents.
Q: Was there any other work that you did under O.S.R.D. auspices during the World War II period?
Ross: My work under O.S.R.D. was related entirely to the preservation and transfusion techniques for the blood. I did not do other work under the O.S.R.D.
Q: Did funding continue from previous sources on other work during this World War II period?
Ross: The only sources that we had, as I say, were the Robert Dawson Evans Memorial Fund. That continued to provide support. At the conclusion of the war, it became apparent that the government was
going to provide support for medical research.
[recorder turned off and on]
Q: Dr. Ross, you were at Boston University Medical School for fourteen years. I would like now to talk about the developments of hematology as a specialty, subspecialty, at the Boston University Medical School. Could we, perhaps, start off by talking about the teaching of hematology?
Ross: Very good. The instruction in the field of hematology, except in laboratory procedures, really didn't exist at Boston University before Dr. Keefer came and brought me there. He developed a series of lectures for medical students on different types of medical, internal medicine subjects, and I was given the responsibility of developing and implementing a lecture series for medical students in hematology. These were quite fruitful, and interested many of the students into seeking subsequent work in hematology. From the clinical standpoint, the residents who were in the hospital were brought there specifically to work with one or another of these young investigators. There were two residents who were assigned to me, two to Ingelfinger, two to Rammelkamp, and so forth. Most of these residents came to work in these specialty fields because they were interested in the field. Additionally, they were doing general medicine as well as working in the specialty field of hematology, both in the laboratory and with hematology patients in the hospital.
Also, we developed for the first time at that institution an ambulatory clinic for patients with hematological disease. This was really quite successful. We started with one half day a week. We began to get so many patients that we had to have two full days of clinics a week to take care of the cases who came to B.U. These ambulatory cases provided many of the patients that subsequently were admitted and treated in the hospital. Many of them also participated as subjects in clinical investigations.
This also was of great value in teaching both medical students and residents. For example, the substance folic acid had been isolated and had been believed to be the essential extrinsic factor in the treatment of pernicious anemia. We had quite a few cases of pernicious anemia in our ambulatory clinic. I comment that in the ambulatory clinic we also had medical students working as well as residents and fellows. So we put these P.A. patients on folic acid, which produced a marked improvement in their hematological status, but pretty soon we noticed that a couple of them developed extremely profound neurological disturbances. It turned out that although the folic acid would rectify the problems with hematopoesis it didn't do anything for the central nervous system. One of these poor fellows had to be brought to the hospital because he couldn't move his arms or his legs. This eventuated in a report that folic acid might have some deleterious effect upon the central nervous system degeneration in pernicious anemia. We proposed a hypothesis as to how this might happen, which didn't prove to be correct. This caused great concern at Lederle Laboratories, the marketer of folic acid. They undertook to disprove what I have just reported to you about the development of civs deterioration, but they didn't succeed.
This experience was very informative as an instructional example to medical students and residents: that you had better be awful careful when you take care of people when you start to do various and sundry new things to them. Fortunately, the man who developed the profound paralysis subsequently recovered! We stopped his folic acid and gave him liver extract and at that point he greatly improved. It's now recognized that folic acid is not the best thing for the treatment of pernicious anemia! You really need to have cobalamine (vitamin B-12), which is the specific for P.A. as near as we can tell.
Also, clinically, we had several patients who had a profound aplasia of the red cell series of the bone marrow, and a tumor of the thymus gland, and thymoma. We were able to recognize and describe this as a definite clinical entity. We presented a report about the development of bone marrow aplasia in individuals who had tumors of the thymus gland. Subsequently, these have been recognized all over the world. It's a very peculiar disease which probably is related to abnormalities in the hematologic system.
These were very effective instructional case studies from the stand point of the teaching students and residents! We had full support for the in-patient hospitalization of cases for investigative studies. The funds in the Evans, and to some extent the funds that we had by that time from the Atomic Energy Commission, made possible hospitalization costs for patients who were hospitalized and couldn't afford the cost. This was extremely valuable!! It's extremely hard to obtain that kind of financial support today. It's going to be even worse in the future. These clinical activities were very helpful in the investigative and instructional endeavors.
Q: Okay. I was wondering if you could say something more about the development and your direct involvement in the outpatient clinics under hematology.
Ross: As I say, we went to two days a week. I was there at all times and we employed a technician to do the necessary laboratory. Now we can put blood samples into a machine and get the results in fifteen seconds. Then it used to take a technician a half an hour to an hour to do the studies that were essential for just one case, in which the results were critical for management of the patient. The clinics were staffed by me and another professor, Charles Emerson. We had two or three fellows who worked with us. Also, there were residents and medical students. It was very stimulating and a good show! But we felt it was imperative that somebody who was ultimately responsible be a participant in what was going on at all times and this was, I think, very advantageous from the standpoint of instruction as well as from the standpoint of patient care.
Q: The development of the hematology service in the hospital overall went through a surge in evolution in the period that you were there. Perhaps you could comment on that?
Ross: Well, it's of interest that the number of cases that were in the hematology sphere became really quite numerous, both in the clinics and also in the hospital, because at that time it became possible to modify certain hematologic neoplastic diseases with chemotherapy. The first of these agents was known as nitrogen mustard. So we began to have numerous patients that we brought into the hospital to treat with these new modalities. I can't give you the exact percentage number, but hematology patients comprised a very significant percentage of all hospital admissions. These patients were not isolated or localized in any specific area. They were distributed throughout the whole hospital medical service, which I think was most desirable.
We began using some of the newer agents and sometimes were confronted with very serious complications as a consequence, because not only do these agents interfere with the progression of the tumor, but they also interfere with the normal functioning of the body. We had a couple of cases that lost their entire enteric mucosa as a consequence of the drug they'd been given! Fortunately, we were able to carry them through and they regenerated their enteric mucosa and got better. Fortunately, also, their fundamental lymphomatous disease greatly improved as a consequence of all this treatment. However, that doesn't justify the terrible trouble that came from the side effects of the medication. However, that's the way we had to find out what these medications could do. Fortunately we were able to control the side effects and did not lose any patients from them! The whole hematology service prospered. At the time I left the Evans this was all turned over to Charles Emerson. It continued to grow and become an effective part of the Department of Medicine at Boston University.
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