Tullis: Uppsala. There was a graduate student from Uppsala, who was partially supported by the company that later brought dextran out, who was there working, because he wanted to understand fractionation principles. He said, "Oh, but dextran will do this, too." So we got into a whole thing, and I published a chapter in a book on the relationship of molecular size, shape and charge to the precipitation of, the lining-up and rouleau of red cells. So something would come up that way and different people with different backgrounds would make great contributions on it. The next time we might talk about surfaces, and why platelets were destroyed by rough surfaces like anodized aluminum, but not by stainless steel; why plastics were non-wettable; why non-wettable surfaces didn't degrade lipoproteins, whereas wettable ones would. The next time we might talk on equipment or how one could theoretically separate blood atraumatically, because this was what one of our hang-ups was, unless you get blood in its true state in nature, there's no way properly to study the proteins or cells, because they're damaged, and if you collect it in a media with a chelate, you've already damaged it, you see! So we were interested in native blood in its native state in order to do studies that would have meaning. That was the driving force. But blood is, after all, a pretty diverse liquid, so we got into all aspects of it, from gas exchange to everything else.

Q: To your knowledge, did this type of interaction happen in any other labs dealing with hematology at that time, or was this--

Tullis: Not with hematology, no. I'm sure it did in other disciplines, but not with hematology.

Q: You mentioned earlier an exclusive intellectual club in Washington, D.C.

Tullis: The Cosmos Club. I know Cohn would go down about once a month to meetings with other scientists.

Q: And who would participate? Cohn, Marshall, and--?

Tullis: Many others. I don't remember who they were.

Q: Okay.

Tullis: I can't give you the details of that except that I know that's how they became so friendly.

Q: Okay. There were others at Harvard at that time, Nobel Laureates in hematology--

Tullis: Yes. [William B.] Castle and [George R.] Minot.

Q: And [William P.] Murphy?

Tullis: Murphy. Yes.

Q: Murphy--was he there?

Tullis: Murphy? No. Minot and Castle and Murphy had their theater of operations, shall we say, at the Thorndike Laboratories at the Boston City Hospital. They were heavily involved in red cell work because of their original studies on pernicious anemia. They were so heavily involved in everything related to the red cell, and the development of the standards there, that they didn't participate in any of Dr. Cohn's work. They had their own separate interests.

Q: This was since the time of the liver fractionations?

Tullis: Yes, yes.

Q: There was no further--

Tullis: Even though Cohn had done the liver fractionation for him, there was no interaction later on, because Dr. Minot was getting elderly at that time and he himself was not involved, and Dr. Castle, who was running the laboratory, a man who was many years younger, was Professor of Medicine running a whole department of medicine there, and was deeply involved in that, and kept that as a separate activity. Moreover, the group at the Thorndike laboratories was more interested in the diseases of the blood; Cohn was more interested in the nature of blood as a biologic fluid. It was really quite an intellectual separation. Not that they didn't like each other or respect each other, or anything of that sort, it was just they were in different fields. Dr. [T.H.] Ham was, of course, down with Dr. Castle.

Now Murphy was purely a clinical practitioner of medicine. He never was a researcher nor was he interested in research, really. I think Dr. Minot, out of kindness, insisted that he be on the Nobel Laureate award, because he used one of Murphy's patients, and Murphy had given the injection to that patient. It was one of the first patients that they treated, and Murphy was here at the Brigham, and not down at the City Hospital, but he contributed some of the patients to Minot's original studies.

Q: How did you feel at the time, being involved in labs, as you're saying, that were directed more towards basic research, whereas there were separate labs working in hematology that would be—it’s just the--since your background was as a physician.

Tullis: Thinking back on it, it was strange, I guess, but I was so interested in what I was doing that it little by little began to get reoriented toward diseases. As I got more and more into the physiology of separating platelets--I began to study the platelet diseases, and got into studies of remostasis as I separated the clotting proteins, with Dr. Cohn's help, and we made the first concentrated prothrombin and then different things of that sort: an accelerator globulin, and Factor VIII, for hemophilia, the first fibrinogen, and so on. This got me more and more into the disease phase, so I didn't lose my interest at all in clinical medicine. As I told you earlier, I insisted from the beginning I would maintain that, and then in 1964, I was asked to come over here to the Deaconess Hospital and head up a new department in medicine and it worked out very well.

Q: How would you characterize the work that you did yourself at that time? This is the late 1940s, early 1950s, are in the--

Tullis: Characterize it in terms of what it was, or what?

Q: In the sense that you see the papers that are read, that you published at the time, dealt with morphology--

Tullis: Yes, that's right.

Q: --very much. And in accounts often given in the history of biochemistry right now, they talk about the change from morphology, as practiced in the nineteenth century, to the new experimental scientists, and make this differentiation which I find strange between morphology and experimental sciences. And here you are, in a leading lab of experimental science, doing morphology! So I was wondering if you could comment on just the styles of research?

Tullis: I don't think I can make much of a contribution in that regard. One can see this, I think, more in Japan than in the United States, because the early Japanese scientists and physicians had all been trained in German schools. German schools were where morphology reached its height. They went back to Japan, and all they were interested in was microscopic appearance of blood cells and things of that sort. They were really hung up on this, and then, after World War II, with the American influence coming in, more of the physiologic approach to the analysis and pathologic approach to pathophysiology of cells, and that sort of thing. Then they totally changed and now they're leaders in molecular biology and things of this sort. But they had to undergo this, I think, more dramatically than you saw in this country. I think the reason that I published on cell size, shape morphology and things of this sort was in part the appointment that Cohn first gave to me. He said, "I want you to be a Special Associate in Cytology to the Department of Physical Chemistry." Well, you know, here I was, I was a physician. I was none of those things, but I had felt an obligation to give real attention to cytology. So I did. I studied the blood cells, and the shapes, and all this sort of business under different pathologic conditions. But, little by little, as I'm sure you saw, I got more and more into the clinical aspects of diseases of blood, rather than just the chemical approach to it.

Q: Could you talk more specifically about the actual research that you did as a specialist in cytology within a physical chemistry lab?

Tullis: Yes. As a specialist in cytology in the physical chemistry lab, I first studied surfaces to determine which surfaces would best support normal morphologic appearance of cells, and then, later, biochemical integrity of the cells. Next, I got into studies on the kinds of media that would support viable cells, ex vivo, in various storage states. Next from this, I got into the long-term storage of red blood cells, because the equipment, which by then we--Dr. Cohn and I--had designed, and which I had then named, although he was deceased, I named it the Cohn Fractionator in honor of him--that work had to do with equipment that made it possible to put--well, let me give you the story--put glycerol in. Let me give you an interesting little aside on that.

Q: Do.

Tullis: In 1951, Dr. Cohn and I had designed a prototype of a separating machine which a lot of people degradingly referred to as a "washing machine," where we could collect blood over an ion exchange column to decalcify it, so we wouldn't be putting a chelate in, and directly into equipment that, as the blood flowed out of the body, would separate the plasma. One of the projects that Dr. Cohn suggested theoretically in one of the luncheon meetings we should design was a way of collecting blood so that it would not be damaged in the collection. Up until this period of time, one collected blood through a rubber tube into a citrate solution in a warm bottle and essentially everything that was labile was already denatured by the time one got it separated to study it in the laboratory. So we started with simple concepts of pH control, temperature control, et cetera, and he said, "Now, we'll have to design some way to do this." So the first thing we did was have blood flow over a resin column that decalcified it, so that one did not have to add an anticoagulant solution. Then it flowed into a bowl where we would siliconize the inside of the glass bowl to make it non-wettable to protect the lipoproteins and platelets which, by then, I had found out what nature to make it--glass--and with control over the temperature, and so on, and separate the cells from the plasma as it flowed through, eventually ending up with a concentrate of white cells and a concentrate of platelets and a concentrate of red cells and then cell-free plasma. All this could be done with the red cells flowing back into the body. It sounds easy, but, believe me, there were many years of hard biomechanical engineering that went into this.

I want to pause to give a word of grateful thanks to a Mr. Robert Tinch, a superb young black scientist who came to work with me in 1947 as a summer graduate student from M.I.T. and who just died in October of 1984. He worked with me his entire scientific career, and he was a superb contributor to this early mechanical equipment development.

Anyway, we had gotten this to the state of making the first prototype in our own laboratory shop over there at the Department of Physical Chemistry across the street in the Medical School, and Dr. Cohn said, "Well, we've got to show this someplace." He was a great showman. He believed in demonstrations, and so on. So he said, "There's a meeting”--and it was either the first or second meeting of the International Society of Blood Transfusions--"and it's going to be in Lisbon. Let's go show the equipment." Later, I may tell you of the errors that occurred in the show that I had to put on. But, anyway, at the program, the day that we were to put our demonstration on for all of the congresses, the paper right before us was by Audrey Smith. Now, Audrey Smith was a young woman biologist at Mill Hill, in England, which was their state supported medical research laboratory just south of London.

Right after World War II, the cattle industry was essentially wiped out, in England, because they'd had to eat all their cows, and so on, during the war because they didn't have enough provisions to feed them. So they wanted to re-stock their cattle industry with good, genetically strong bulls, and the cost of shipping a bull from Australia to England was rather prohibitive. So they began experimenting with sending testicular biopsy specimens of semen of Australian bulls to England. And Audrey Smith had suggested, on the basis of thinking about why her radiator didn't freeze in her Ford car in the winter in London, that maybe ethylene glycol or propylene glycol or even glycerol would keep the sperm from freezing. So she had had them collect some needle biopsy specimens of the bulls in Australia, put them in glycerol, freeze them, and send them to England. She had found that when she warmed the specimen up, the sperm wiggled away and seemed to be perfectly normal. She also made the observation that some of the red cells of the bull that had contaminated the biopsy specimen weren't lysed when it was frozen. Well, we all knew if you froze blood, the red cells busted wide open from the presumed hypertonic effects that took place when the ice was melting, you see. Yet here were some red cells. So she had suggested that they just take a tube of blood and put glycerol in it, and freeze it, and thaw it, and they looked at it morphologically, and the cells weren't broken.

So she came and put on a demonstration of this right after our demonstration of how to separate blood cells. Well, that night, Dr. Cohn suggested he and I have dinner together. He had--again, showing crossing disciplinary lines--the vision to say, "Jim, that will not work with blood, because when you put the red blood cells back into an isotonic media like blood, there'll be a rush of water into the cell to equalize the glycerol pressure, because the red cell is more permeable to water than it is to glycerol. Water will come in faster than glycerol will go out. So, he said, "It's a shame this will never be applicable to human blood. I said, "Well, let's talk about this." So we sat there, talking about could we not devise a system whereby one could put a nonpermeable ion--and this goes back to my original work, you see--put a nonpermeable ion, like lactate or something of this sort, in the media, that would hold the water outside while washing the glycerol out.

Do you understand the science of this?

So here we were. We had just demonstrated this machine that day. So he said, "I think we could redesign this bowl, so you can wash the red cells at the same time in the same equipment." And he actually drew it on the tablecloth, and he said, "Now, go home and do it!" In those days, I was very much the subservient, way at the bottom of the totem pole, the youngest member of his department. I had to do what he said. So I had to stop all of my other work for a period of about four years and work on the extraction of glycerol from red blood cells, and this made it possible for us to develop a system for working with large volumes of blood.

Now, you could do this, even before we did it, in a test tube, by a slow process of dialysis, but you couldn't do it with a pint of blood for transfusion purposes. So, one of the other things I happened to be doing at the time was I served on the Defense Department's Medical Advisory Council. Now, the reason for that was that the chief of surgery in the Roosevelt Unit in World War II, was made the Assistant Secretary of Defense for Health and Medicine after the war, Dr. Frank Berry, a thoracic surgeon in New York City, at the Roosevelt, also at Bellevue and a couple other hospitals. Frank asked me to be on his advisory committee--why, I don't know; just because he wanted to, I guess. So one day on one of our trips, I mentioned to him what I was doing with frozen blood, and I said, "Frank, this has real implications for the navy and army," and so on. He said, "You're right." He said, "Let's go talk about it." So he took me by the arm and we went over-and talked with the Secretary of the Navy, who sent us to the man in charge of their research, and they said, all right, they would support research to see if this could be made clinically useful.

Q: What year would this be?

Tullis: That was 1956.

Q: Okay.

Tullis: They would support the research to see if it could be made clinically useful if I would promise to be the consultant to see that it worked and it didn't just bog down as an expensive exercise in futility. So they got organized about two years later, and then along about 1957 or 1958 they sent Mary Sprowl up here to spend the summer working with me. And then we went over to the Chelsea Naval Hospital here in Boston, and established the first laboratory for the long-term preservation of red cells. That's where it all began, with the Navy.

So that was an example of where cytology sort of was a diversionary thing. But it brought together lots of other things I had been involved in in the past.

That equipment, then, was later used for many other biologic applications, such as plateletphoresis, and leukocytophoresis, and so on.

Q: Could you talk about some of your other work that you were doing during that time?

Tullis: Well, the work I was interested in was not that. The work I was interested in was coagulation and platelets. I was interested in platelets because of their relationship to hemostasis and in clotting, because I was privileged to have had access to the first clotting protein concentrates to study. I've devoted my entire life since then to these, once I was over here at the Deaconess and independent, doing my own things. Because Dr. Cohn's laboratory was no longer officially funded when he died, that was the problem: what to do with the team he had brought together. The University considered it, and then declined to sponsor it as an institute--Harvard never had sponsored institutes, unlike Madison, Wisconsin, with its Alumni Research Foundation. Harvard didn't want independent--and they still don't want--independent institutes with outside financing operating directly under the umbrella of the university. So what they said was, "It's nice to have that group together. You take the Protein Foundation, because it's already created, it already exists, and use that as a holding mechanism for going out and getting grants and contracts. And you can have space in the University, but your appointments will all have to go through departments of the University." No longer will it be independent, you see, and this was smart, because it maintained the quality of the appointments. My appointment, for example, reverted to the Department of Medicine, and my promotions and everything had to go through the Harvard Department of Medicine, which is where it belonged. Biochemists had to go back through biochemistry, and so on. So once Dr. Cohn died, which was tragic, because he could have lived many years longer if he had been properly diagnosed, once he died, the group stayed together for a transition period of a few years. Then little by little we got back into our own original departments.

Q: He died in 1953?

Tullis: Yes, 1953 or 1954, I think it was '53. It was at lunch; he had a C.V.A. right at lunch. He just suddenly slumped down, dropped his spoon, and he was dead in an hour of a cerebral hemorrhage.

Q: Was there further contact maintained even though people went back to their respective departments?

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