Oral Histories: Dr. John W. Gofman, M.D., Ph.D., Section 13 of 37

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Heparin and Lipoprotein Research With Human Subjects

HEFNER: Is there any connection with this heart research with heparin[22] treatment tested at that time?

GOFMAN: Yes. One of my graduate students, Dean Graham, had noted there was a paper by Paul Hahn from the University of Tennessee that showed that [when] he gave dogs heparin injections, their blood might have been cloudy from fatty globules, [but it] cleared up [after injection]. We had this elegant technique by then. We could study the lipoproteins in this ultracentrifuge.

Some of us took some heparin by injection. Dean studied the blood and he just cleared out some of the lipoproteins with the heparin infusion. Then we tried to do that in a test tube, and that didn't work. But if the person [was injected with] the heparin, [and we] drew the blood, then that blood would cause [test-tube] alterations in the lipoproteins. Bernard Shore, a graduate student of mine, finally proved that the effect of heparin was to release into the bloodstream an enzyme which is called lipoprotein lipase.

We thought that the heparin story [was of] obvious importan[ce] [for] the whole question of management of lipoprotein. Endothelial cells,[23] [under] heparin, [activated release of] the lipoprotein lipase from the endothelial cells. We were hopeful of really doing some management of the whole problem of abnormal lipoproteins with the heparin, but it was not that easy. I probably injected myself 150 times [during] heparin experiments we did on ourselves.

HEFNER: Why don't you comment about that, too? Here we are in [the] context of this interview [about] human radiation experiments, and you've drawn a pretty stark contrast of today's human use standards versus then. Why don't you [comment on the] contrast?

GOFMAN: Max Biggs, who later came back to Livermore and took over the Medical Department for me, was doing a Ph.D. thesis [(dissertation)]. He had his medical degree [from Harvard and did some work on] people with these abnormalities of lipoproteins. He did do some tracer work with tritium-labeled cholesterol in those patients.

I can't remember whether Biggs had to go through any committee at all. I don't think we did at that time. But we did an awful lot of experiments on ourselves. Hardin Jones and I, we were interested in what happened acutely after a fatty meal; we were interested in what happened for 24 and 48 hours after giving yourself a heparin injection. We did an awful [lot of] experimentation on ourselves. Max Biggs' work did involve giving some tracer to some of these patients with lipoprotein disorders. Donald Rosenthal did some of that, too. Those were [the] only things where we were using tritium as a label for cholesterol.

HEFNER: We found some information about patients at Stockton, [California] and Napa, [California].

GOFMAN: We worked a lot with the people in Psychiatry. How that happened was that Mary Lasker, who died last year, of the Lasker Foundation, helped me a great deal with my work. She once said, "If all this work of yours on heart disease is correct," (she didn't doubt it at all), "shouldn't it apply to stroke and cerebral arteriosclerosis[24] ?" I said, "Well, Mary, it should, [but we have only] checked this out on the heart disease." We studied hundreds of people with heart disease. That didn't involve injecting them; we got blood from them. I said, "I don't know the answer about cerebral disease." She said, "Well, couldn't you find out?" I said, "Yeah, we can start doing some studies on the correlation between heart disease and brain disease." [She said,] "Well, what will it cost?" I said, "About $75,000, maybe put in about $25,000 a year for 3 years." I wanted the program; she sent me a check for doing the work. That was Mary.

To do the whole story, I contacted Alex Simon, who is a professor of psychiatry at UC here in San Francisco-he's a wonderful guy; and Nathan Malamud, who worked on cerebral pathology. He [(Malamud)] was also in Psychiatry. [I] went over and talked to him. One of the studies we arranged to do was to get tissues from heart and brain of consecutive deaths. They get people who died in the mental hospitals. I don't know what they had to get, in the way of permissions, to take these tissues. I just don't know, but they arranged that and we did some studies that were published in the American Journal of Cardiology. Nathan Malamud and Wei Young, a Ph.D. student of mine, and I, published a series of three articles in the American Journal of Cardiology on the relationship of cerebral and coronary arteriosclerosis.

Out of that, we were wondering whether people who had strokes in the mental hospital would show anything. We did some studies of the blood and some of the people in Stockton and Napa got interested in the possibilities [that] these lipoproteins might be involved in mental disorders. We [did this] through Alex Simon's contacts in those places. We arranged studies in both Stockton and Napa State Hospital-[no radiation studies].

GOURLEY: What were the studies? What did they involve?

GOFMAN: [They] involved the study of lipoproteins in their blood. Never any radioactivity involved at all. No tracer studies at all.

HEFNER: How about any research with Langley Porter [Clinic in San Francisco]? Were you involved in any research [there]?

GOFMAN: [Just pathology studies on] a hundred hearts and brains. It's a classic study. I think it's the best study that had been done at that time. I don't think that anyone has done any better studies since of the correlation of the amount of arteriosclerosis in one of 16 cuts of heart arteries with each other. Then the correlation [of the] cerebral arterial system of one cerebral vessel with the other, [and] then the intercorrelation between the cerebral and the coronary. In answer to Mary [Lasker]'s question, "Does this apply?": We concluded that there were two things: one is a lot of interrelationship between this disease in the brain and the heart; and, [two,] there is also a lot of independence, meaning that there is a local factor in the vessels that partially determines [what] happens, as well as the general factor such as lipoproteins. The group that I contacted to do that was Nathan Malamud, the pathologist, and Alex Simon, who were professors of psychiatry at Langley Porter.

HEFNER: Do you have a sense of informed consent at that time, how it would be structured?

GOFMAN: You mean to just get the arteries and the brain sections [from deceased persons]?

HEFNER: Yeah.

GOFMAN: I have no idea. My only thing was, Alex Simon was a guy who was a doer and Nathan Malamud, a shy guy, but a superb pathologist. They said, "Yes, we can get the hearts and the brains." They did. Wei Young, the Ph.D. biophysicist working with me, he did all the sectioning and staining of the tissues and all the measurements on those hearts and brains, result[ing] in that series of three papers. I never asked anybody for permission. I didn't know of any-

HEFNER: -any use for internal review board?

GOFMAN: No, I don't remember anything about it at all. I just said, "Alex, can [you] do this?" He said, "Sure, we'll get the hearts and brains." And they did. I haven't the vaguest idea whether they had to go [to] anybody. It [is not] the way things are done today-I can tell you that.

HEFNER: That's true. It is good to contrast the two, to see where we've come.

GOFMAN: The things I did with a lot of people, we were a referral center for the people with these bizarre blood lipoprotein patterns from all over the world. Sometimes, for some of them, I wanted to know whether they would alter their diet.

Bill Donalds was the head of the Cowell Hospital, the head physician; he was a good friend of John's and Ernest's. I wanted to know a lot of things about diet and lipoproteins. I went over to see Bill Donald and said, "If I can get some cooperation from your dietitian, we could [do] some interesting studies on arteriosclerosis problems." Bill said, "Sure."

He introduced me to Virginia Dobbin. They set up a diet table and I had between four and eight people eating lunch and dinner at the Cowell Hospital. Virginia did all the menus. I would tell her we would like to have a high-cholesterol diet or a low-cholesterol diet, a high-fat diet or a low-fat diet, or a high-animal-fat diet or a low-animal-fat diet. Alex Nichols-at that time (he's a professor in the Division of Medical Physics) [he] was a graduate student of mine who got his Ph.D. with me-co-handled that whole diet study.

We did do a lot of human experimentation in this sense. We had both some students and some of these people referred from around the world. We would have them on one diet or another and we'd study their blood every week-[of course, all these people knew these were experimental studies.] And we didn't get any permission from anybody to do it but they never got any radioactivity.

We had that diet table running at Cowell Hospital for a few years. We had excellent cooperation from Virginia Dobbin, and my wife, and Hardin's wife and Tom Lyon's wife. Tom was the cardiologist in San Jose who worked with us, providing us clinical material. The [wives] wrote a book on the low-fat, low-cholesterol diet in 1951.

HEFNER: The staff wanted me to ask you about that.

GOFMAN: You want to see it? I have it here and it's been revised a few times. It's still selling. Let's see, from '51; that's 43 years. That's a long time for a book. At least they get some royalties every year under that book. When Alex and I made some major discoveries about carbohydrate and various fats of the diet, he and I and Virginia Dobbin wrote a book on dietary prevention and treatment of heart disease which was nowhere near as successful as the low-fat, low-cholesterol diet. But it's a damn good book.

I don't know if I know anything more about the John Lawrence thing. There were some underhanded things, actually some efforts to try to destroy the division, which was the reason I went to see Mrs. Hearst. I asked her to set up [an event] honoring John Lawrence, and she did. [The] regents sponsored [a] dinner and made a big to-do about the Donner Laboratories and all the good things that were done there. It was just a kind of slap in face to the medical center, which was not being very nice.

HEFNER: Was there anybody else trying to destroy-

GOFMAN: In Berkeley?

HEFNER: Yes, in Berkeley.

GOFMAN: Yes, that was a lot later. Some of the biologists there didn't particular[ly] like the Division of Medical Physics. In the reorganiz[ation], it was shifted [to the] molecular and cell biology thing. The Division of Medical Physics became a department, then was abolished in the biological reorganization.

I think there was a lot of arrogance on [the part of] some of the people in molecular biology. They [thought they] were the greatest thing since the wheel and everything else didn't matter. I think they considered some of the goings-on as to why Berkeley Rad Lab [should] not work on heart disease. Just offshoots of our work and it's gotten to be rather well accepted. But I think that to some of the molecular biologists-this is before they grew up-they regarded this as too practical, and therefore of no interest in a great campus with fundamental science. You get stupidity on campuses sometimes-[that] has no equal and sometimes equals most of the stupidity elsewhere. Nothing secret: I'll tell them that, too.

HEFNER: On the off chance, do you know anything about experiments conducted by Will Siri or others on the San Francisco 49ers, the whole-blood-volume study?

GOFMAN: I do know this. Will Siri was at the Lab when I joined the Lab in 1947. He's an extremely bright guy. He wrote the first book on applications of tracers[25] in biology. He was working for his Ph..D. and I was on his Ph.D. committee. He could not take an [oral] examination: he simply blocked completely. We talked to him and said, "Look, maybe we [can] do it in writing." He refused. He never got the Ph..D degree; he was helping John Lawrence with all their work with radioactive iron and iron metabolism. That's all I know about.

John was so interested in polycythemia vera, the disease that he successfully treated with radiophosphorus. It's a disease of too many red blood cells. They were interested in that and altitude effects [in other] continents. I think Will went with John Lawrence down to South America in connection with some of that. I never knew details, except that I had a very high respect for Siri, and I still do.

I tried like hell to make some progress to get him to get his Ph.D. He just could not stand examinations. Having written the first book on radioactivity and applications of artificial radioactivity, you'd ask him a question on his exam and he couldn't answer. The guy obviously was one of the world experts. That's all I knew about him.

Next | ToC | Prev

Heparin and Lipoprotein Research With Human Subjects
HEFNER:	Is there any connection with this heart research with heparin[22] treatment tested at that time?
GOFMAN:	Yes. One of my graduate students, Dean Graham, had noted there was a paper by Paul Hahn from the University of Tennessee that showed that [when] he gave dogs heparin injections, their blood might have been cloudy from fatty globules, [but it] cleared up [after injection]. We had this elegant technique by then. We could study the lipoproteins in this ultracentrifuge. Some of us took some heparin by injection. Dean studied the blood and he just cleared out some of the lipoproteins with the heparin infusion. Then we tried to do that in a test tube, and that didn't work. But if the person [was injected with] the heparin, [and we] drew the blood, then that blood would cause [test-tube] alterations in the lipoproteins. Bernard Shore, a graduate student of mine, finally proved that the effect of heparin was to release into the bloodstream an enzyme which is called lipoprotein lipase. We thought that the heparin story [was of] obvious importan[ce] [for] the whole question of management of lipoprotein. Endothelial cells,[23] [under] heparin, [activated release of] the lipoprotein lipase from the endothelial cells. We were hopeful of really doing some management of the whole problem of abnormal lipoproteins with the heparin, but it was not that easy. I probably injected myself 150 times [during] heparin experiments we did on ourselves.
HEFNER:	Why don't you comment about that, too? Here we are in [the] context of this interview [about] human radiation experiments, and you've drawn a pretty stark contrast of today's human use standards versus then. Why don't you [comment on the] contrast?
GOFMAN:	Max Biggs, who later came back to Livermore and took over the Medical Department for me, was doing a Ph.D. thesis [(dissertation)]. He had his medical degree [from Harvard and did some work on] people with these abnormalities of lipoproteins. He did do some tracer work with tritium-labeled cholesterol in those patients. I can't remember whether Biggs had to go through any committee at all. I don't think we did at that time. But we did an awful lot of experiments on ourselves. Hardin Jones and I, we were interested in what happened acutely after a fatty meal; we were interested in what happened for 24 and 48 hours after giving yourself a heparin injection. We did an awful [lot of] experimentation on ourselves. Max Biggs' work did involve giving some tracer to some of these patients with lipoprotein disorders. Donald Rosenthal did some of that, too. Those were [the] only things where we were using tritium as a label for cholesterol.
HEFNER:	We found some information about patients at Stockton, [California] and Napa, [California].
GOFMAN:	We worked a lot with the people in Psychiatry. How that happened was that Mary Lasker, who died last year, of the Lasker Foundation, helped me a great deal with my work. She once said, "If all this work of yours on heart disease is correct," (she didn't doubt it at all), "shouldn't it apply to stroke and cerebral arteriosclerosis[24] ?" I said, "Well, Mary, it should, [but we have only] checked this out on the heart disease." We studied hundreds of people with heart disease. That didn't involve injecting them; we got blood from them. I said, "I don't know the answer about cerebral disease." She said, "Well, couldn't you find out?" I said, "Yeah, we can start doing some studies on the correlation between heart disease and brain disease." [She said,] "Well, what will it cost?" I said, "About $75,000, maybe put in about $25,000 a year for 3 years." I wanted the program; she sent me a check for doing the work. That was Mary. To do the whole story, I contacted Alex Simon, who is a professor of psychiatry at UC here in San Francisco-he's a wonderful guy; and Nathan Malamud, who worked on cerebral pathology. He [(Malamud)] was also in Psychiatry. [I] went over and talked to him. One of the studies we arranged to do was to get tissues from heart and brain of consecutive deaths. They get people who died in the mental hospitals. I don't know what they had to get, in the way of permissions, to take these tissues. I just don't know, but they arranged that and we did some studies that were published in the American Journal of Cardiology. Nathan Malamud and Wei Young, a Ph.D. student of mine, and I, published a series of three articles in the American Journal of Cardiology on the relationship of cerebral and coronary arteriosclerosis. Out of that, we were wondering whether people who had strokes in the mental hospital would show anything. We did some studies of the blood and some of the people in Stockton and Napa got interested in the possibilities [that] these lipoproteins might be involved in mental disorders. We [did this] through Alex Simon's contacts in those places. We arranged studies in both Stockton and Napa State Hospital-[no radiation studies].
GOURLEY:	What were the studies? What did they involve?
GOFMAN:	[They] involved the study of lipoproteins in their blood. Never any radioactivity involved at all. No tracer studies at all.
HEFNER:	How about any research with Langley Porter [Clinic in San Francisco]? Were you involved in any research [there]?
GOFMAN:	[Just pathology studies on] a hundred hearts and brains. It's a classic study. I think it's the best study that had been done at that time. I don't think that anyone has done any better studies since of the correlation of the amount of arteriosclerosis in one of 16 cuts of heart arteries with each other. Then the correlation [of the] cerebral arterial system of one cerebral vessel with the other, [and] then the intercorrelation between the cerebral and the coronary. In answer to Mary [Lasker]'s question, "Does this apply?": We concluded that there were two things: one is a lot of interrelationship between this disease in the brain and the heart; and, [two,] there is also a lot of independence, meaning that there is a local factor in the vessels that partially determines [what] happens, as well as the general factor such as lipoproteins. The group that I contacted to do that was Nathan Malamud, the pathologist, and Alex Simon, who were professors of psychiatry at Langley Porter.
HEFNER:	Do you have a sense of informed consent at that time, how it would be structured?
GOFMAN:	You mean to just get the arteries and the brain sections [from deceased persons]?
HEFNER:	Yeah.
GOFMAN:	I have no idea. My only thing was, Alex Simon was a guy who was a doer and Nathan Malamud, a shy guy, but a superb pathologist. They said, "Yes, we can get the hearts and the brains." They did. Wei Young, the Ph.D. biophysicist working with me, he did all the sectioning and staining of the tissues and all the measurements on those hearts and brains, result[ing] in that series of three papers. I never asked anybody for permission. I didn't know of any-
HEFNER:	-any use for internal review board?
GOFMAN:	No, I don't remember anything about it at all. I just said, "Alex, can [you] do this?" He said, "Sure, we'll get the hearts and brains." And they did. I haven't the vaguest idea whether they had to go [to] anybody. It [is not] the way things are done today-I can tell you that.
HEFNER:	That's true. It is good to contrast the two, to see where we've come.
GOFMAN:	The things I did with a lot of people, we were a referral center for the people with these bizarre blood lipoprotein patterns from all over the world. Sometimes, for some of them, I wanted to know whether they would alter their diet. Bill Donalds was the head of the Cowell Hospital, the head physician; he was a good friend of John's and Ernest's. I wanted to know a lot of things about diet and lipoproteins. I went over to see Bill Donald and said, "If I can get some cooperation from your dietitian, we could [do] some interesting studies on arteriosclerosis problems." Bill said, "Sure." He introduced me to Virginia Dobbin. They set up a diet table and I had between four and eight people eating lunch and dinner at the Cowell Hospital. Virginia did all the menus. I would tell her we would like to have a high-cholesterol diet or a low-cholesterol diet, a high-fat diet or a low-fat diet, or a high-animal-fat diet or a low-animal-fat diet. Alex Nichols-at that time (he's a professor in the Division of Medical Physics) [he] was a graduate student of mine who got his Ph.D. with me-co-handled that whole diet study. We did do a lot of human experimentation in this sense. We had both some students and some of these people referred from around the world. We would have them on one diet or another and we'd study their blood every week-[of course, all these people knew these were experimental studies.] And we didn't get any permission from anybody to do it but they never got any radioactivity. We had that diet table running at Cowell Hospital for a few years. We had excellent cooperation from Virginia Dobbin, and my wife, and Hardin's wife and Tom Lyon's wife. Tom was the cardiologist in San Jose who worked with us, providing us clinical material. The [wives] wrote a book on the low-fat, low-cholesterol diet in 1951.
HEFNER:	The staff wanted me to ask you about that.
GOFMAN:	You want to see it? I have it here and it's been revised a few times. It's still selling. Let's see, from '51; that's 43 years. That's a long time for a book. At least they get some royalties every year under that book. When Alex and I made some major discoveries about carbohydrate and various fats of the diet, he and I and Virginia Dobbin wrote a book on dietary prevention and treatment of heart disease which was nowhere near as successful as the low-fat, low-cholesterol diet. But it's a damn good book. I don't know if I know anything more about the John Lawrence thing. There were some underhanded things, actually some efforts to try to destroy the division, which was the reason I went to see Mrs. Hearst. I asked her to set up [an event] honoring John Lawrence, and she did. [The] regents sponsored [a] dinner and made a big to-do about the Donner Laboratories and all the good things that were done there. It was just a kind of slap in face to the medical center, which was not being very nice.
HEFNER:	Was there anybody else trying to destroy-
GOFMAN:	In Berkeley?
HEFNER:	Yes, in Berkeley.
GOFMAN:	Yes, that was a lot later. Some of the biologists there didn't particular[ly] like the Division of Medical Physics. In the reorganiz[ation], it was shifted [to the] molecular and cell biology thing. The Division of Medical Physics became a department, then was abolished in the biological reorganization. I think there was a lot of arrogance on [the part of] some of the people in molecular biology. They [thought they] were the greatest thing since the wheel and everything else didn't matter. I think they considered some of the goings-on as to why Berkeley Rad Lab [should] not work on heart disease. Just offshoots of our work and it's gotten to be rather well accepted. But I think that to some of the molecular biologists-this is before they grew up-they regarded this as too practical, and therefore of no interest in a great campus with fundamental science. You get stupidity on campuses sometimes-[that] has no equal and sometimes equals most of the stupidity elsewhere. Nothing secret: I'll tell them that, too.
HEFNER:	On the off chance, do you know anything about experiments conducted by Will Siri or others on the San Francisco 49ers, the whole-blood-volume study?
GOFMAN:	I do know this. Will Siri was at the Lab when I joined the Lab in 1947. He's an extremely bright guy. He wrote the first book on applications of tracers[25] in biology. He was working for his Ph..D. and I was on his Ph.D. committee. He could not take an [oral] examination: he simply blocked completely. We talked to him and said, "Look, maybe we [can] do it in writing." He refused. He never got the Ph..D degree; he was helping John Lawrence with all their work with radioactive iron and iron metabolism. That's all I know about. John was so interested in polycythemia vera, the disease that he successfully treated with radiophosphorus. It's a disease of too many red blood cells. They were interested in that and altitude effects [in other] continents. I think Will went with John Lawrence down to South America in connection with some of that. I never knew details, except that I had a very high respect for Siri, and I still do. I tried like hell to make some progress to get him to get his Ph.D. He just could not stand examinations. Having written the first book on radioactivity and applications of artificial radioactivity, you'd ask him a question on his exam and he couldn't answer. The guy obviously was one of the world experts. That's all I knew about him.