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Oral Histories

Radiologist Hymer L. Friedell, M.D., Ph.D.

Foreword

Short Biography

Early Training and Research

Pre-War Radiation Therapy

Pre-War Experience at the University of California

Amount of Information Provided to Patients

Prominent Researchers Working at Berkeley

The Army Medical Corps and the Manhattan Project

Work at the Chicago Metallurgical Laboratory

Inspection of Manhattan Project Facilities and Proposed Sites

Search for Data on Human Exposure to Radiation

Purchase of a Cyclotron; the Manhattan Engineer District's Early Biomedical Program

Plutonium Injection Studies

Patient Consent in the Plutonium Injections

Advisory Role in the Early AEC Biomedical Program

AEC Isotope Distribution Committee

Pre-War Experience at the University of California

MELAMED: It was after that that you went to the University of California [at San Francisco] and worked with Dr. Stone?30
FRIEDELL: Because about that time, we were beginning to hear about other artificial radioelements: radioiodine, radiophosphorus. So I thought: "I'd better," since I had this opportunity to find out about it, and I wrote to Dr. Stone and asked him if he would accept me. And he did. So I came and became a member of the staff.
FISHER: At the University of California.
FRIEDELL: At the University of California. I think the hospital's name was then the Moffett Hospital, as I remember correctly. I used to go everyday across to Berkeley31 to work on the cyclotron.32 Then, there were a lot of people working on various things, and I sort of thought that maybe I could do something with radiophosphorus and patients.
FISHER: What did you do at the cyclotron? What was your work?
FRIEDELL: My work on the cyclotron was really, first of all, learning what the stuff did and how you produced it. And, secondly, I began to learn about how we could make appropriate measurements of the intensity of the element that we were working with. My interests at that time were primarily phosphorus and strontium-89, in radiophosphorus. I don't quite know how I got started in this.

Oh, I should add one more thing. One of the other things I observed is the treatment of neutron treatment in patients. We, [meaning] Dr. Stone and Dr. Larkin, actually treated, it's published—we were then pursuing studies on cancers. I think they were probably cancers that were difficult to cure, if I remember correctly. I think I recall abdominal tumors of various kinds, some chest tumors. And I don't believe they wanted to treat highly sensitive tumors, like lymphomas or things of that kind, with this; I can't be sure. I don't remember it that well. I was really not a part of the team. I was really an observer and occasionally I participated because Dr. Stone was away, or for some reason Larkin wasn't available, or something. I actually treated some of the patients.
FISHER: Did they bring patients to the cyclotron?
FRIEDELL: They brought patients to the cyclotron. Patients were treated at the cyclotron. I sort of was looking at radiostrontium. And what I did there was, first of all, study some distribution studies by injection of animals. I think we used a colony of mice and rats. Then we would simply assay33 the studies. We didn't do much radioautographs at that time; which later we got to be well-developed. I don't recall myself doing any.
FISHER: Autoradiography?34
FRIEDELL: But we did do studies on bone, and primarily other tissues, to see what the distribution was at various periods—and some of the stuff may have been published with others. But I never really got to publish the actual material that I did, because my interests were towards the clinical surface, [and] because I was really on the staff at the hospital. One of the things we found of interest was: to perhaps consider treating some of the diseases that hadn't been attacked previously with radioelements.

First of all, radioelements theoretically had one important advantage. If you somehow had an element which had preferential deposition in tumors, or in the vicinity of tumors, it might be useful. And so it occurred to me, and others, that perhaps radiophosphorus might be very good. Because, first of all, phosphates are part of the DNA complex, and so they might be picked up in the tumor.

As a matter of fact, Dr. John Lawrence35 was then busy treating various hematological36 problems: leukemia and excessive red cell formation; the name escapes me. Anyway, he was treating patients with radiophosphorus. It occurred to me that maybe we could try this on widespread carcinomatosis,37 particularly in carcinomas of the breast, because you would find—
FISHER: Polycythemia vera. Now did you participate in some of the first studies of phosphorus-32 in the treatment of polycythemia vera?38
FRIEDELL: I participated with Dr. Lawrence, but I was not—he had already been doing this for some time. Oh, yes, you see, I treated that and leukemias as well.
FISHER: How successful was this?
FRIEDELL: It was very successful. Obviously, you could knock the hematopoietic system39 down, and you at the same time suppressed the white cell count. And you had to be careful about how much suppression you did. We knew that you could suppress the hematopoietic system with relative ease. And one of the things we were thinking about is using radiostrontium, because radiostrontium [deposited] primarily in bone, and therefore, the energy was enough to get a fair amount in the hematopoietic40 system.
FISHER: Why was radiostrontium preferred in the treatment of, say, bone tumors, over radioactive calcium?
FRIEDELL: I think—I don't know that there was any preference. I don't recall right now, but radiocalcium—I think there were problems in the preparation of radiocalcium. There were mechanical reasons. Theoretically, if you're going to get it into the bone, why not use calcium? I don't know. I've forgotten know what the energy was. It's been such a long time, I haven't looked at it. There was a reason why radiostrontium had some advantages. First of all, it was a much longer half-life, if I remember. Do you know?
FISHER: [About] 50 days.
FRIEDELL: Radiostrontium was about 90 days. Strontium-89—what was it?
FISHER: I think it's about 50 days. Strontium-89–chloride has just been reapproved.
FRIEDELL: What was radiocalcium?
FISHER: I don't remember. I don't have that chart.41
FRIEDELL: It's not important. But anyway, for some reason, calcium could not—there were mechanical problems—otherwise they would have used that. We didn't really pursue radiostrontium with any weight.
FISHER: It could be produced in a cyclotron?
FRIEDELL: It could be produced in the cyclotron. So is radiocalcium, because there was a fellow by the name of Pashce who had sort of outlined that this area worked for him. If I remember correctly, he was a Frenchman and had been working in the Donner Lab42 before I was there, before I came. For reasons that are not clear to me . . . Anyway, radiostrontium really wasn't used very much. Actually, radiostrontium was done in a desultory sort of fashion, because it didn't look as if it was very promising, if all you got was radiostrontium all over the skeleton, which was troublesome.
FISHER: Because it didn't localize specifically in tumors?
FRIEDELL: No. And of course, the idea was tumors proliferating rapidly, It might indeed have some preferential uptake.43 But the differences were very modest. And you had a long-lasting radioelement, reasonably long-lasting. You'd be irradiating bone marrow pretty vigorously.
FISHER: Do you recall, at that time—I've read your paper on the six cases that were injected with strontium-89, some prior to amputation—do you remember if strontium had been used previously to that, or prior to that, anywhere else in the country in studies of bone tumors?
FRIEDELL: First of all, there weren't too many places where they could have radiostrontium. They would have to have a cyclotron. I think there was one in Boston, and possibly one—this was in the very early '40s, maybe 1940, something like that, '40 or '41, just before [our entry into] the war. The [U.S. entry into the] war started in December of 1941 [with the bombing of Pearl Harbor on the 7th], so this must have been 1940, late '40 or early '41.

We were pretty vigorous. We were doing a lot of work that seemed impossible to me now, that I ever got involved in so many things. But we did it. The things that we pushed most were radiophosphorus and carcinomas of the breast. As I pointed out, one of the things that was intriguing about it was one: you could follow it, because you could take x rays of the skeleton and see what had happened.
FISHER: Were these with phosphorus plaques, or applicators, or was it injected?
FRIEDELL: No. It was intravenous radiophosphorus.
FISHER: It was administered intravenously [(into a vein)]?
FRIEDELL: Yes. I think it was sodium phosphate. We would prepare this. Of course, there was a system for preparing it already, because, as I pointed out, John Lawrence had used it a couple of years before. As soon as that cyclotron was operating, they were beginning to make radiophosphorus, and John Lawrence was already treating leukemia and polycythemia. The material was available. Of course, you could have done it through the alimentary tract,44 but it was quicker and easier to do it intravenously. That's what we did. And so we actually showed many many patients—we would say, it probably didn't cure anybody. But I did have one patient that lived for 10 years with no metastases to the bone, identifiable by x ray.
FISHER: From breast cancer?
FRIEDELL: From breast cancer. The lesions calcified. That meant—the reason why there is desolation is because the tumor has interfered with bone deposition. As soon as the tumor disappears, bone deposition would occur. Sure enough, we had this in many patients, I would say in maybe 20 percent of the patients, maybe as many as 30.

The limiting thing was: how much phosphorus could we use, without suppressing the blood count severely? We had one patient in which we pushed the surrounding site count down to about 10,000 [white cells per microliter] from 300,000, and there was very little bleeding. We were surprised. Either ourcounting systems were no good, or for some reason the patient had no severe bleeding consequences.

In any event, we treated a lot of patients. It looked a rather promising, good-tallied approach and, as a matter of fact, when I came here after the war, we pursued this study and had the same kinds of responses then.
FISHER: At Case Western?
FRIEDELL: At Case Western Reserve University, then Western Reserve University.
MELAMED: One of the things we've seen in some of the documents is a kind of discussion of the line between treatment and experiment. All of this work you did was really to treat patients. Or was some of it, once you determined a patient, to do some investigation as to effects?
FRIEDELL: Our investigation then, probably we did some investigation. That is, we could get postmortems on some of the patients, and then we would try to assay the tumors and the bone, and kind of correlate it with the dosage that the patient had received. We tried to do some distribution studies. But I would say that most of our studies were done on animals—because to control patients, it's extremely difficult.45

Approaches then was that we were really responding to their clinical needs. After all, these patients were very ill. What we were doing was to see whether indeed we could renew, that we [could] produce serious changes in the tumors. We wanted to see whether indeed we could really prolong their lives a little and make them more comfortable. One of the things, one of the problems of course, is control of pain. All of these appeared. As a matter of fact, I think there is still a place for the use of radioelements, [although it] has now become rather awkward.

In a way, radiologists aren't the first line for the management of patients. The physicians, usually internists, who see them first are the ones who work with them. There is, of course, ample evidence that you can suppress tumor growth by various chemotherapeutic46 elements. As a radiologist, my general observation is that I haven't got much faith in them. As a matter of fact, I don't have a terrible lot of faith in radioelements as well, unless you can make them specific. Because, they don't have specificity [(the ability to selectively kill cancerous cells while sparing normal cells)].

Chemotherapeutic [treatment of] patients, however, does it by interfering with it [or] by doing cross-linking neucleotides,47 or by interfering with some protein—hasn't any way of selecting the tumors from other rapidly dividing cells. The chemotherapeutic agent usually goes around: in my facetious way I say, "Who's dividing today?" You see? Now if you don't have synchrony, you now have another problem and you're aware of that.

I'm frankly puzzled by how much credence is put in chemotherapeutic agents. I think they can suppress this all right, but why [they are] so effective is pretty hard for me to understand rationally. Because, unless you [have], say, normal cells, seriously depleted and great propensity for recovery . . . I also am uneasy about what you're doing to them, perhaps modifying them in such a way that they may show unusual growth in those tumors. It may be that I'm not cognizant enough of this. But, what it really meant was that the x ray or radiation approaches would gradually reduce in interest as the chemotherapeutic agents took over.
FISHER: Did you ever use either phosphorus or strontium-89 for reduction of pain?
FRIEDELL: We never used radiostrontium. Because, in a way, that was abandoned pretty early.
FISHER: Why was that?
FRIEDELL: It didn't look very promising. We were uneasy about it. First of all, radiophosphorus—what is the half-life, 14 days or something like that?48 That gave you a little bit better control. Secondly, radiostrontium wasn't the real thing. It was a substitute for calcium, if you will. It was an analog of calcium. I think that the results weren't terribly promising. So we said, "Why do this?" It seems to me, I recall correctly, "I do this and we stick with radiophosphorus."

Amount of Information Provided to Patients

FISHER: One of the questions that comes up in the 1990s about work done in the 1940s, has to do with: how much did the patient know about the procedures that were done on them? Can you kind of help us with this?
FRIEDELL: I would say that our approach at the present time is much more rigorous. We never really did any purely metabolic studies49 on normal patients, for example. There may have been. But if we did, we would calculate the dose. At that time, there was kind of a, how shall I say, a level which was called the tolerance level; a sort of acceptable level, really based on radium standards. Therefore, if we used tracer50 studies, we usually ignored the possible potential hazards, which obviously have to be very small.

When you look at it, the kinds of dosages that were used, even though they theoretically, by whatever means you use (if you're linear or the other one)51 have to be small, compared to all the other hazards that arise. If you assign, say, one rad to a potential cancer in one time in a thousand, something on that order, you could go another decade. Patients, primarily without any other impact, would have about [a] 20 percent chance of dying of cancer.
FISHER: Naturally.
FRIEDELL: That's the survival. The incidence is probably 30 percent. When you cure someone, if you look at the hard statistics, 20 percent. That means that, out of 10,000 patients, twenty [percent] will die, 2,000 will die. If you have 100,000 or something in that order, you see, you change the odds very little.
FISHER: Did patients in the 1930s and 1940s have a difficult time understanding the concept of radiation?
FRIEDELL: I think they were much more receptive to the physicians' assurances. We would say, "This isn't going to be any problem to you, not at all." They would generally accept it. I think the whole approach to radiation has been inordinately . . . Nobody ever talks about radiation anymore, except they add a certain adjective. It's lethal radiation or dangerous radiation or fatal radiation. They never say it's a lethal Buick, or a fatal Chevrolet. The risks are somewhat simpler.
FISHER: You hear the word "deadly" radiation quite often in the news. "Deadly," that kind of thing.
FRIEDELL: Well, true. Radiation could be deadly. So now, the approach is very diffident. Once you mention radiation, never mind that radiation is streaming in here from cosmic rays.52 And never mind that you go up in the airplane and you receive a few millirads if you fly enough, there is a different approach. In those days, I think the patients relied more on the doctor's assurances. After all, there were no immediate responses. They could observe that themselves. If you gave radioiodine to patients,53 and you gave it for diagnostic purposes usually, you would measure it over the thyroid;54 and they had no problems.

Generally, people assign hazard to more-or-less immediate responses. Once it was established that radiation could produce oncological55 impact at high enough doses, then you see there was a whole new examination of this; particularly the patients that didn't realize that their exposure was very high to cancer anyway. As I pointed out, 30 percent of the population is going to have some cancerous changes; and 20 percent of them, actually 18 percent, are going to die of cancer. That's the milieu in which you look at radiation now.

In those days that didn't occur. We probably were pretty sloppy, put on a little extra radiation here and there. It didn't impress us at all, because we did studies. And I am doing some of my studies, particularly in radiostrontium. [I] was looking for very sensitive counters, and Emilio Segrè,56 who was then working at the lab—one of the best—I cajoled him into letting me use his [radiation detection equipment] because his was the best. Of course, he was very careful about this, because he didn't want any contamination.
FISHER: He was at Berkeley?
FRIEDELL: He's a Nobel winner. I'm the guy that contaminated his counter. He will never forgive me. So I have this distinction.
FISHER: At Berkeley, you would have been about 29 or 30 years old? A young physician.
FRIEDELL: I was then about 29 or 30.

Prominent Researchers Working at Berkeley

FISHER: Who were the physicians of prominence that seemed to lead out and make the decisions on human studies at the University?
FRIEDELL: Joe Hamilton57 was there. John Lawrence was there. Larkin was there, because he was working with the neutrons. There were other physicians who were actually working there. I think I was one of the few. I can't recall any; I'm trying to think of any. But the ones that come to mind—[Bert] Low-Beer was there.58 But Low-Beer didn't do anything in radioelements until later.
FISHER: What did he do?
FRIEDELL: He was working in diagnostics. I'm not sure I got it straight. I may be wrong about this. Low-Beer came from either Czechoslovakia, or somewhere. Low-Beer may not have had a license to practice. He may have been working in research. He used to work with [and married] a girl by the name of Anne Treadwell, whose name appears in some of the studies. He may have been doing some research, but not on humans.
FISHER: At the cyclotron?
FRIEDELL: With the cyclotron. But I never saw him at the cyclotron. I only saw him over in the hospital in San Francisco.
FISHER: Did you recruit your patients mostly from the hospital in San Francisco, to come over?
FRIEDELL: No—except those that we were going to be treating with neutrons. We treated all our patients in the hospital. We had radiophosphorus and brought it over. All the patients were treated there. The other interesting thing about the hospital was that they were the first ones to have a million-volt x-ray machine. One of the scientists, I've forgotten his name for the moment, built the machine.
FISHER: For therapy? Orthovoltage?
FRIEDELL: Supervoltage.
MELAMED: Were the patients you treated—was there any way to characterize them? Did they come from a very different kind of [stratum] and economic levels, or did you get more charity patients? Is there any theme there?
FRIEDELL: I think they came from all levels. Because the one patient that I recall so well, that had such a good response, sort of followed me over the United States. You may know that I came from Minnesota. She got in touch with me, and she discovered that I was visiting my family in Minnesota; and my uncle was a doctor. She arranged to come, and I examined her and saw her in Minneapolis. She was a fairly well-to-do patient.

There were all kinds of patients. We didn't make much distinction in those days;—that's not true: we did make distinctions. But we treated all of the patients. I would say that many of the patients that came to see Dr. Lawrence were well-to-do patients. They wouldn't come to see me in preference to Dr. Lawrence if they had leukemia or polycythemia.
MELAMED: And in the work Dr. Hamilton was doing, as well?
FRIEDELL: Dr. Hamilton's interest in patients was rather modest, clinically. He was doing research more than anything. But exactly what research he was doing, I wasn't particularly aware of. At that time, it was very interesting. There was real freedom, as we extol the virtues of freedom. Everybody did anything they wanted to do. There wasn't any real surveillance. The only surveillance that I had was from Dr. Stone. If I told him I wanted to do something and I outlined it in general, he would say, "Go ahead, do it." I don't think John Lawrence really had a kind of committee to take a look and see whether this was an appropriate approach as far as over here, for example.

Now, if you want to do something that hasn't been done before, there will be a committee that will approve—that will decide whether this is worthwhile. And there will be all kinds of elements in it. There were tremendous differences. I would say the further west you went, the less controls there were. I can't really characterize Joe [Hamilton]'s actual research, but I do know that he and Mayo Soley[, M.D.] were the first to use radioiodine. Mayo Soley was an endocrinologist. He was also dean of the medical school [at UC Berkeley, and later at the State University of Iowa].59 I think they did some work together. Later on, I got to know Joe very well. I got to know him particularly well when I got into the Manhattan Project.
FISHER: What year would that have been when they first used radioiodine, as you recall?
FRIEDELL: I think it must have been late '30s.
FISHER: Were you ever involved with the teaching program at the university or over at Berkeley?
FRIEDELL: Theoretically, I maybe started out as a teaching fellow. But I would say that my teaching would be limited to house officers. I participated in conferences. There were regular conferences; and they were teaching exercises, if you will. The students attended, but it was not a rigorous or arranged curriculum. These were regular conferences that had to do with oncological approaches or certain diagnostic studies, and the students would be there. You could say that was my teaching experience.
FISHER: Dr. [Glenn T.] Seaborg60 mentioned to us that he recalls incidences where either Dr. Lawrence or others, in demonstrating the principles of radioactivity, self-administer[ed] radiosodium to show its rapid uptake in the mucosa of the stomach [by holding a Geiger counter next to the palm of his hands to demonstrate activity in blood circulation]. Do you remember any of this?
FRIEDELL: I don't really recall this, but I think if anybody did it, it would be Joe Hamilton. I would guess it would be Joe to do it.61 I don't think it would be any of the other—well, it might be John Lawrence as well. But I never did it.
FISHER: Did you ever administer yourself with any radioactive solutions?
FRIEDELL: I think I probably took some radioiodine in my mouth for demonstration purposes.
FISHER: Uptake in the thyroid?
FRIEDELL: Right. I've taken the thyroid. I may even have done it after taking up doses of iodine to show that it didn't—I could block the radioiodine from appearing.
FISHER: Block it with some cold [(stable)] iodine?
FRIEDELL: Yes, potassium iodine or something.

The Army Medical Corps and the Manhattan Project

MELAMED: Pick up what you were saying about getting to know Joe Hamilton and how you were working in the MED, in the Manhattan Engineer District.62 Were you working together at that time?
FRIEDELL: Afterwards, I got to know him very well. I suppose it's useful for me to tell you how I got into this. This is a little—some problems, here that should be look[ed] at if you want history completely. I was a reserve officer. And I had been a reserve officer for maybe four or five years, maybe six years, since I graduated from the University of Minnesota. I retained that reserve status for a long time. Then, when I got to California, the war was impending and they were beginning to call up reserve officers. And I thought, surely, they'd call me any day. When at Pearl Harbor, which was December 6 [(December 7, 1941)]—I thought—I hadn't received—

. . . As a matter of fact, I thought surely they were going to call me. I was saying that I lived in a house that I rented from an individual, who had been called up. So they were calling up everybody at that time. I expected that I would receive a call any minute. And I wondered about it. I kept saying to Dr. Stone, "You know, I'll be called anytime now." He didn't respond very well. I don't think he was evasive, but he didn't talk to me much about it.

Then I discovered that they had identified what they called an "essential list," which was being respected by the military forces for teaching purposes; so I wouldn't be called, as long as I remained on that essential list. I discovered that I was on this essential list. I thought about it after a bit, and I felt that I just couldn't continue on the list, even thought it had been extremely desirable to stay out of the war. Because I'd been this reserve officer, all my friends were being called up, and I didn't think it was quite right. So I asked them to remove me from the essential list. And they treated this as a, somewhat, I would say—without serious attention.
MELAMED: Was it Dr. Stone who had seen that you got on this essential list, do you think?
FRIEDELL: After all, it was the dean's responsibility. I never had direct access to the dean; I usually went through Dr. Stone. I finally said, "I must be released. Otherwise, I'm going to have to resign and take my chances." As a matter of fact, I was already beginning to make contacts with some friends of mine who were in the Air Force. Because I thought if I'd go in, maybe I could get into the Air Force.
FISHER: Were you interested in joining?



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