Advisory Committee on Human Radiation Experiments, Interview with DR. William Sweet, by Gil Whittemore, Achre Staff, 08 April 1995

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ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS OF: MARTIN, MAGNUSON, McCARTHY & KENNEY REPRESENTING DR. SWEET AND MASSACHUSETTS GENERAL HOSPITAL [Corrected approved by interviewee on J u l y 5, 1995.1

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MR. WHITTEMORE: This is an interview on 9 9 5 , with Dr. William Sweet by Gilb rt Whittemore of the Advisory Staff. Also attending the meeting is Raymond Kenney, who is a lawyer representing both the hospital and Dr. Sweet. MR. WHITTEMORE: As I have been explaining to Dr. Sweet, the purpose of the Committee in general, and one purpose of these interviews is to try and record the recollections of those who were active during this Maybe we could begin if you could just briefly say something about your own training and when you first became interested in radiation. DR. SWEET: I'm glad to do that. My interest in radiation was kindled by my association with the Chairman of the Department of Biochemistry at Harvard. The way that association developed is this. Professor Hastings was not the Chairman of the Department of Biochemistry when I was a medical student. He succeeded that man, and rapidly developed

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a tremendous stature in the field of biochemistry and broadly speaking, a good many other features of biology. During the War, he made several trips to London and Europe, strictly concerned with duties in connection with fighting World War 11. I, at the time, was working in a British hospital. I went over there before we were in the War, and stayed at this job during the rest of the War, the Acting Chief of the Neurosurgical Service at the University of Birmingham, England. Come the end of the War, my wife was looking around for a place for us possibly to buy or rent in Boston, because I knew I was coming back to the Mass. General. She wrote me a letter saying what the house was like and also mentioning that the next door neighbor was a biochemist she thought at Harvard, called Hastings. I cabled back, "Buy the house. I* [Laughter] Which was the most astute decision I ever made, because it turned out that Professor Hastings did not care to drive a motor car. So I drove him to the Harvard Medical School on my way to the Mass. General most every morning of the week for years.

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H e was one of the few members of the Haward faculty who spotted the fact that radioisotopes are terrific from the standpoint of biological investigation. He persuaded me that that was the I, with some difficulty, had gotten a grant from the Rockefeller Foundation to do stereotactic neurosurgery. I gave the money back to the Rockefeller Foundation in due course to get grants via the Atomic Energy Commission to work on radioisotopes. The first isotope that we had available for biological work was Phosphorus 32, which was used to label the phosphate ion. We were looking for something that might concentrate in brain tumors as compared with normal brain. These marvelous means of detecting radioactivity in extremely small amounts with terrific accuracy made this field worth investigating. This radiophosphate had an extraordinary tendency to concentrate in brain tumors as compared with normal brain. It remains the highest differential concentration between an abnormal tissue and a normal

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tissue that's ever been discovered. Here was the very first thing that we stumbled onto. We found that the most malignant intrinsic tumor of the brain, called glioblastomas, concentrated [phosphorus 32lto a minimum of around 400 percent on up MR. WHITTEMORE : This would have been variations with the type of tumor or just the patient? DR. SWEET: No. This is all the most malignant tumors we are talking about now. But in our first paper a half a dozen other tumors of varying degrees of malignancy, had a tremendous tendency to concentrate the substance. MR. WHITTEMORE: Now did this stay as a permanent concentration? I know in some of your papers you mentioned that the differential might vary with DR. SWEET: No. It varies with time. In this one, however, instead of rapidly disappearing, when one stops the intravenous injections, it would gradually decrease over the course of about 4 8 hours. So it was right away a substance that we

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1 could detect with a so-called Geiger-Muller counter and a rod that had the sensitive components f o r detection of2 beta particles at the tip. A sudden burst of radioactive3 4 counts would indicate the site of the tumor. MR. WHITTEMORE: Right. Now this would have been during an operation?6 DR. SWEET: Yes, that's the idea. Often we had, at that time, the only way we had of determining 9 any possible space-taking mass inside the head, was to put air into a fluid containing cavity normally present10 inside of the head, and trying to judge the11 distortion of those cavities where a mass was located,12 if we could. This was an indirect demonstration of the13 14 mass. Here was a direct demonstration, this is where the tumor is for sure. So for oh,'maybe 20 years, this1s 16 was an adjunct to neurosurgical operations, especially fora tumor below the surface. 18 MR. WHITTEMORE: Now during these operations, the P-32 would have been administered19 intravenously during the operation? DR. SWEET: That's right. In fact, we could 22 give it before the operation to allow a little time to

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1 build up the concentration. We would actually give the 2 phosphate a little before the operations began. 3 MR. WHITTEMORE : Were you measuring a 4 differential? That is, would you have been measuring 5 the P-32 elsewhere in the body as well? 6 DR. SWEET: No, no. In the brain. We were interested in the difference between normal brain and the Brain tumor. Especially when the difference was substantial we could get an idea of where the boundary of the tumors was, how deep it would have been down. Then we could, shifting the position of the counter, get a rough idea of the actual configuration of the MR. WHITTEMORE: Maybe you could say a little bit about the positive nature of diagnosis of these tumors at that time, and also, what the prognosis was in those days for these kinds of tumors. DR. SWEET: Well this very malignant tumor had an absolutely frightful prognosis, which is the situation today. Tremendous effort has been brought in to developing better treatment. We still are in a sad state on that score although at the present time, for

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about two or three years, we hope that we're on the right track finally. But this is one of the most lethal tumors anybody has found. Tremendous efforts have gone in to trying to treat it effectively with chemotherapy. The tactic that I will shortly describe to you is extremely complicated. For that reason, the National Cancer Institute has found it unwarranted to support this kind M R . WHITTEMORE: So at the time, these would have been patients who already knew that this -- They had been informed that this was a terminal tumor that they had? If we can go back to the '40s. DR. SWEET: Yes. Well, unfortunately, we still say the same today. We do 'not have a treatment that we can assure you will really be useful treatment as far as a cure is concerned and our efforts are However, through this entire time, ever since the OS, a wide variety of efforts has been carried on. The direction of my efforts was guided by this first experience. I should amplify that a little

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bit, why we thought that the phosphate was concentrated in this way. Which was basically because there is a phenomenon called the blood-brain barrier. The brain apparently is such an important organ that it possesses a mechanism to meter the rate at which atoms and molecules enter the substance of the brain from the bloodstream which no other organ possesses. There is no What the barrier consists of is a cleft between the two endothelial cells, the cells that line the inside of the blood vessel wall. Instead of being absolutely tight against each other, all other organs but the brain will have a little tiny gap. That little cleft permits the ready exchanges. But the blood brain barrier in the brain consists of this phenomena which is referred to as tight junctions, instead of gap junctions. So we thought, well, this barrier would be a terrific aid to us in finding something that can't get into the normal hrain, but will get into the brain tumor.

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forgetting to mention this feature of the phosphorus, the 32 phosphate. Rapidly metabolizing organs in their normal activity are letting all manner of substances get in and get out, sometimes at a great rate, to do the job of the liver, for example, and many different chemical manifestations of the body's functions. The bone marrow that makes all the red and white blood cells, working day and night, constantly. So we probably don't have a very good chance of finding just any substance that will concentrate in rapidly metabolizing brain tumors, because rapidly metabolizing normal tissue would be the same. What we need, obviously, is something that is innocuous, that goes into rapidly metabolizing tissue and then add something that makes it dangerous, and point that something at the brain. Within a year of having this idea, here was a paper, published by two gentlemen, called Conger and Giles, entitled "The destruction of lily bulbs by interaction between slow neutrons and boron." There are two different stable normal

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1 isotopes, boron. One, 82 percent of the naturally 2 occurring substance, is 11-boron, and 18 percent is io3 boron. Ten-boron is the atom that makes nuclear power 4 possible. It has this tremendous tendency to capture 5 slow neutrons that are given off as fast neutrons in 6 uranium disintegration. Upon capture of a slow neutron, t 7 the boron atom then disintegrate instantly into two other atoms. Either beta particles or gamma rays are the commonest products of atomic disintegration and being far smaller than atoms travel significant distances in tissue. But the atoms can't go anywhere, because they're so enormous, relatively speaking. So they go only the distance of about the diameter of a red blood cell, a little bit more, around 10 mu. One atom, the alpha particle, the helium atom, goes off in one direction, . The other one, the lithium atom, goes 180 degrees in the other direction, giving up 2.4 million electron volts in this minute area. we just get the right boron compound, we may end up with boron-10, which itself is quite a trick, to separate boron-10 from boron-11, neither of them charged. You

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have to do it by their masses. Well, never mind, the rest of the story there. It turned out that we did not have any rapid method to measure precisely the concentration of boron in anything, tissues living or dead. So the way we had to do this when we were treating a patient was at ,the operation, in which we removed the main tumor mass in order then to give the boron so that the radiation would destroy the tiny bits of tumor cells in the otherwise normal brain. So we would give a modest amount of the boron compound at the operation when we removed the main tumor mass and could in a circa four hour procedure measure its boron content. Then we'd give about four times that amount just before radiation on the assumption that we'd have four times as much boron in the blood stream at the time of the irradiation. MR. WHITTEMORE: So you would give them boron before the operation as well? So that you could measure what was in the tumor when you took it out. DR. SWEET: Yes. Right. The reason for this inaccuracy was that it took about four hours to do

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a single determination on a specimen. So we had to do our determination on the specimen taken at the first operation; it would take a day or two before we looked at the specimens. That worked out reasonably well. We took blood, of course, from the patient at the time of the irradiation, several samples serially during the course of the irradiation. Eventually, the boron concentration in the samples was measured and the dose was determined. But to our horror, on patient number 21, she got a very much larger dose of radiation, and died in three weeks of a radiation injury. MR. WHITTEMORE: Just to clarify, this would have been a combination of not being able to tell right at that moment what the Boron was. DR. SWEET: At that hour, yes. MR. WHITTEMORE: And also, the focusing problems of the neutron beam, because of limits on how well it can be focused. DR. SWEET: Well, yes. A number of other features that needed to be improved. We knew that the particles, the neutrons

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given off at the uranium disintegration of a nuclear reactor, were so-called fast neutrons, coming off with massive energy. They would penetrate tissue to a comparatively modest degrees, about six or seven centimeters at the most. The original neutrons coming off, so-called fast neutrons, ionized matter by knocking the electrons out of their orbits, destroying matter in that fashion. We had to get the fast neutrons slowed down into what's called the epithermal range, which meant not enough energy to knock the electrons present in all atoms out of their orbits, but not so slow that the atoms could capture them. Once the neutrons are in the c slow neutron range of velocity they are susceptible to capture by atoms. Then that's where this 10-boron comes in. It captures the slow neutrons with tremendous avidity. The number that indicates that capture crosssection, the unit called llbarnsll,is 3800 for boron-10. All but chlorine, of the normal atoms in the body, are 12 or less, chlorine is [inaudible]. So that's why the 10-boron put into control rods that drop into the mass of fuel elements in a

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reactor, keep the evolution of power under the strictest control. If there's any intimation that things are getting out of control, the whole lot of boron control rods drop and in a minute fraction of a second, the whole reaction stops. Well, that wasn't the feature of boron that we were interested in, of course, but just to mention So, what we decided was that we've got to have means of determining boron, that will be done in a few minutes, preferably seconds. It was about 20 years, before an astute physicist at Brookhaven, Ralph Fairchild, solved the problem. He unfortunately died of a heart attack. He knew what even many physicists didn't realize, that in addition to the alpha particle and the lithium atom appearing upon the disintegration of the boron atom, there's also a 468,000 electron volt gamma ray emitted, which penetrates the skull. Determination …