ASH Oral History: Leon Jacobson

Q: This interview is with Dr. Leon Jacobson, February 28, 1989 at the University of Chicago. I am Madeline Marget.How are you Dr. Jacobson?

Jacobson: I am fine.

Q: Good. I'll see that we know that it's recording for a fact. [machine off] Dr. Jacobson, would you like to tell us about your early life at all? What some influences were?

Jacobson: Yes, I can because I'm rather proud of it. I grew up in North Dakota. My parents owned a large ranch. I went to a country school. I passed the state examination when I was eleven but my parents and my teacher decided I was too young to go to high school, which would have meant I'd have to "batch" it in my own space during the frigid winter months. So when I was twelve I went to a high school, but I had to have an apartment because it was too far from home. It was actually seven miles, but in the winter time you can't get there in a Model T. You ride a horse or bicycle or walk, but it's too cold to continue as winter sets in. So, I would stay there for most of the year in an apartment with another student who had the same problem. I or we cooked our own meals. When I went to college at age 16, I had decided I wanted to get a degree in agriculture. I knew a lot of the people in the ranching and farming business, and I knew the county and regional officials who were interested in agriculture, I hoped if I studied Agriculture I might be able to help to modernize that business (kind of naive at that age). So, I went to college at North Dakota State University in Fargo North Dakota and took my first two years in agriculture, which I loved dearly. Then I went broke, because this was in the middle of the twenties and dustbowl and everyone was broke at that time, including me. So, I decided maybe the best thing to do was to try to see if I could teach school. So, I contacted the state superintendent of Public Instruction in North Dakota and gave her my whole background and so on. And she said, yes, I could teach but I should take a couple of courses such as educational psychology. And I wrote then to various places asking for a country school teaching position and finally ended up as a school teacher in Sims, North Dakota.

Now, Sims, North Dakota, by that time, had lost hundreds of people as the result of the closing of the coal mine because of its low BTU per ton, for the Northern Pacific Railroad engines. The brick factory also closed. These industries plus the free land had brought my mother and her family, and my father and his family in the late 1880's to the now extinct village. When I went there to teach, only a depot and a general store remained of a once populated and industrial town. Our ranch was contiguous to the little village. I taught there for three years. I had twenty-seven children in all eight grades. I taught them all in the same room, although we had another room for play, because they used to have first through fourth in one room and fifth through eighth because the population was greater, previously. My pupils used the spare room as a play room. I taught them manual training. The mothers of the children came in to teach sewing, etc., about once every two weeks; and we'd ski and sleigh ride during the noon hour. At any rate, I changed my mind about what I wanted to do during this wonderful experience, partly because if you have children in one room, and they're age five to whatever, you're going to have epidemics. And we did. We had whooping cough. We had measles. You name it. And I got interested--I helped one boy in particular who had petit mal (epilepsy), and it was a very interesting problem. He would be reading--I had the children read to all the other students after lunch hour if they were able to read well-- and I think he was reading Tom Sawyer, I don't remember which one. But he would be reading and then all of a sudden he would stop, but remain standing. Five or less seconds later, he would come back to consciousness again and continue reading where he had left off, and would not have missed a word. He would start exactly where he left off. But if he had these outside, he might run into a post or something, and he did. I communicated with the doctors in Bismarck and had him taken care of. That's how, I guess, I got thinking about medicine.

The other reason for changing my college training objectives was that, during the summers, I worked in Bismarck, North Dakota as a chemist in the state regulatory department. So then, when I went back to college, I took all the requirements I needed for entering medical school. I applied to only one institution and that was this one, here on campus, the University of Chicago and got in. I was still broke, so someone suggested I write to a man by the name of Shreve Archer who was head of Archer Daniels Midland Company of Minneapolis, Minnesota. Well then, he wrote me a letter and asked for information. I think I gave him reams of information. And finally, I got a letter from him and he said that he would give me a loan of $750 a year for the four years, assuming I did well. He would charge five percent interest, payable after graduation, as I was able. And I also did work all the time I was in medical school such as doing lab work in the evenings and with my then relatively minimal training in clinical medicine I would examine patients, call the patient's doctor and he would come in or not depending on his judgment of the situation.

Q: What did you tell Mr. Archer that persuaded him to support you?

Jacobson: That, I don't know. I wasn't begging him. But he asked me really important questions, I guess. He'd done it before for other people. Maybe he just decided he liked me. By the way, I never saw the man. He was on the board of Continental Bank here in Chicago, so he'd fly in from Minneapolis. He would send me a note and say, "Well, I'm coming in to Chicago and let's have lunch." I would, of course, write back and say, ''I would be delighted.'' But he was always too busy, so I never did see him. When I graduated, I told him I had graduated. And he sent me a lovely letter canceling the debt. So what was I to do to repay him? I actually then started a student loan fund in his name with the permission of his family and put all that money back. It was a lot of money then. But four-times-$750 is not a fortune. At any rate, I put it into loan funds for students.

While I was in medical school and I had to work as I noted previously, one of the heads of department, Clarence Hodges-- a very famous man in radiology-- taught me how to take x-ray pictures, develop the films, and how to give x-ray exposure to a given object, it might be mouse, rat or what have you, but not human. This is how I really got started in the radiation area. I took some special courses in diseases of the blood-forming tissue from Dr. William Bloom and his associates. That was for at least six months. He'd give me special assignments. And then I graduated from medical school in 1939. I continued some of this work with him and began to do research in diseases of the blood, studying other cases that were recorded and the current hospital cases available.

Q: Why blood?

Jacobson: Well, I was interested in diseases of the blood because I saw a lot of it as a student.

Q: There was no hematology then?

Jacobson: Yes, but it was a section of the department of medicine as a specialty, and I had a very good teacher there. And of course as an intern and even as a resident, you rotate through these things. One day, the man who was head of hematology asked me if I would stay with him as a second-year resident, because I had finished my first year of residency. Then I saw a lot of cases. But what happened was that he left because of the army, although he was never called to duty.

Q: This was not Dr. Bloom?

Jacobson: No, it was Gurth Carpender. Carpender was the man who was the head of hematology at that time, before the war. He was English, born and educated. He was not put in the army, for whatever reason. He went to the University of Southern California and took over hematology there.

Q: What was his first name?

Jacobson: Gurth. G-U-R-T-H. He didn't have a large girth, however.

Then they put me in charge of hematology, even though I was only just out of residency, and were working on radiation exposure experiments. I also had a couple of other research programs going at the time. Then, one morning I was called up to a hospital floor to show house officers how to take care of a patient with a case of "watering pot" perineum; tuberculosis, that is. Do you know what that is?

Q: I know what tuberculosis is, but I don't know what--

Jacobson: Well, "watering pot" perineum is a terrible disease process, because the bladder is infected with the tuberculosis bacteria. The process erodes through the wall of the bladder and then erodes through to the perineum and lower buttocks, creating a fistula. So they pass urine that way. They have to be catheterized and irrigated every now and again in order to stop drainage through the skin in these areas referred to. So I was up there helping them, showing them how to do it, all dressed up with gown and gloves on and all the rest of the stuff. And there was an emergency call for me. Since I had finished the show and tell I got out of my gown, mask, and gloves, and washed up; answered the phone from the nursing station, and they said, "Go down to the dean's office immediately." When that happens, you think, "My goodness, what have I done?" You go through that in your mind. I couldn't think of anything I had done that was bad. So I walked down there immediately, after I had taken my gown and gloves off. The secretary took me to the door, opened it, and I walked in, and there was the head of medicine, George Dick, the dean, William Taleferro, the head of radiology, Paul Hodges, the head of the hospital, Arthur C. Bachmeyer, and two people that I had never seen before. The whole conversation-- I got over my fright because I didn't see any sign of anger or sternness-- no one was-- they were smiling. I sat down after I'd met them all. And I might say that, the only one of that group who didn't look very cheerful was the dean. But actually that day he finally smiled. So, I was introduced to the two strangers by the dean. He said, "We've called you down here because there is some activity on campus that requires someone who is interested in blood and who has had good training in medicine. We have decided that you're it." It wasn't said quite that way, and I have to admit that the dean wasn't really an ogre. Over the years that followed he helped me set up experiments on the effect of shielding various lymphatic organs and irradiating the balance of the body. It took very little shielding to preserve an immunity, for example shielding the appendix of the rabbit would prevent suppression of the immune response.

Q: What year was this?

Jacobson: It was February of '42. They said that some of the material they're working with was hazardous to health. And since I had been doing working with Dr. Carpender and had taken special training with Dr. Bloom and I knew blood forming tissue and I saw a lot of such patients as a house officer, finally as an instructor, even as attending [physician]. Everyone talked a little about why they needed me, so I had a general opinion. At first it seemed to me that all they wanted was someone to examine the people at regular intervals. But they didn't tell me what was going on. They told me that they would give me the whole set-up for hundreds of people to be seen and [their] health monitored. Blood, physicals, etc. They'd give me all the space I needed, all the help I needed; I could recruit people to help me do physicals and all that. What could I do but acquiesce; we were at war.

Q: Who were the other two men present at the dean's office?

Jacobson: One was [William H.] Taleferro; he was the dean, George Dick, chief of department of Medicine. Another one was Paul Hodges; he was head of radiology. The two men were Norman Hilberry and the other man, also a physician, was Creutz.¹

Well, when they said what they wanted me to do, I didn't see how I could get out of it. So I said, "OK. I'll do the best I can." We all shook hands. They said, "Now, these two men" - Hilberry and Creutz-"will take you off and talk to you some more right now." I took them up to my laboratory. I had mice in cages in my office and I've said many times that that interview didn't last very long because I don't think they could stand the very strong odor of mice. At any rate, they told me at that time that we were dealing with radioactivity and I had had experience with that too, especially with the diseases mentioned (Rx of polycythemia, leukemia, etc.). It was in late '39 that I started it with the help of the physicist Louis Slotin; a couple of years into atom bomb geometry Louis Slotin were killed in an experiment on how to detonate a plutonium bomb.

That meeting didn't last long but then they arranged with me to meet again and we met over in the physical science area, in one of the buildings, the physics building-- Ryerson-- that's the name of it. That's where the whole headquarters of the Metallurgical Laboratory was located.

Q: Ryerson?

Jacobson: Ryerson. That's where Arthur Compton had his office, Compton was Director of the Met Lab, as did the others involved; [Enrico] Fermi, [Leo] Szilard, [Eugene] Wigner, Anderson, [James] Franck, Creutz. Then one day I said, "Look. I know I'm working with radiation, and I have general security clearance. I can't talk about the project, not even to my wife, my friends, or my patients. In fact I can't talk to anyone except within the security area, and even there one was not supposed to speak of the real objective, it had a super secret classification." I was somewhat uncomfortable under these circumstances, so one day I called up Dr. Eilberry and I said, "Look, I want to see you." "Come on over." So I went over to Ryerson, sat down in his office, and I told him I didn't think I could be effective in my position unless I knew something about what was cooking. He said, "I can't tell you." One was not supposed to talk to anyone about what was going on in the Metallurgy Labs. But he said, "I'll tell you what I'll do. I'll administer the oath of secrecy and then I'm going to hand you a book and I want you to look on page 473 and read the second paragraph." I took the book and I found the paragraph and it said, "If you were to wake up one morning and half the world was blown away, then you'd know we'd harnessed the atom." That's all he said, but I was under oath. That was it. I found out at that time, and if anyone thinks I wasn't shaking and at the point of tears he or she is nuts.

As things went along-- this was early '42-- we had a lot of discussions because there was so much work to do if you were to be prepared to study the localization effects of thousands of isotopes or the penetrating radiations that would be produced in an atomic reaction. So, it was decided we'd have a biological program as well a medical one. And they asked Dr. Robert Stone, who was head of Radiology at the University of California, San Francisco. He had been involved with Ernest Lawrence, working with him with the isotopes that were artificially produced in the first cyclotron. And he had also used the cyclotron to try to see whether fast neutrons would be any better than X rays for the treatment of malignancy. So, he was made chief of the whole program here. Then they called in Kenneth Cole from Columbia. He was a physiologist with a great deal of background-- not in radiation necessarily, but in biology and physiology of the nervous system, the heart in particular. Then he recruited people. I was a part of that division.

Then after the first pile became active in, I think it was December 2, 1942 of the same year, Stone had to move to run the Oak Ridge center. I was then asked to handle the Chicago part of it, and I essentially became associate director of health because I really had to check everything for him. But I had a large program under Cole in radiobiology as well. I also had a program in Bethesda with Egon Lorenz. He was a German physicist who had learned biology as well over the years. Then they also had all the other kinds of people you'd like to see around, like the geneticists and so on. I then was asked to join in a very large study at the National Cancer Institute in Bethesda trying to determine whether the so-called tolerance whole-body dose was correct. In fact, at that time 0.1 roentgens per day was considered a safe dose. We started out with doses of 0.1 to 8.8 roentgens per day. We used special inbred mice and guinea pigs, and so on-- pure genetic strains. I'll tell you what the end of that was, although it went on and on and on for several years. Didn't finish, some of it, until after the war was over. But I had to fly back and forth. I also set up the hematology laboratories in Oak Ridge and in Hanford. In fact, we had trained most of the technicians here in Chicago; then they went down there or up there-- any of these places where they were needed. I was not the boss of these places. I was a consultant, in a sense. But they needed the help of someone who could check on the technical medical laboratory work as well, as well as gather these people and train them for their medical technology work.

Well then, coming back to early 1942, people were just coming in to Chicago by droves because it was growing and growing and growing. No one was allowed in the pile unless they were part of the pile operation. But I was and so was Ray Zirkle who was a radiobiologist, and two technicians of mine: Miss Evelyn Gaston and Mrs. Edna K. Marks. Both of these extraordinarily talented women are coauthors on many of my publications. It was these talented ladies who really kept my whole research program under control. But there many others who were important, but we had to train some of them and send many of them to Hanford where the plutonium production and separation was done, and others were sent to Oak Ridge or Los Alamos. We had an enormous number of experiments going on various things-- artificially produced radioactive isotopes had a high priority. As all of them were, before the pile went into operation. We even did work on plutonium that had been discovered and isolated. But we just had trace amounts of plutonium for biological studies whereas we had unlimited amounts of various radio isotopes for biological experiments that were produced in cyclotrons and later from pile operations.

Q: How much was known about plutonium then?

Jacobson: Well, the man who discovered it was here on campus during the war and we got trace amounts quite early for physiological studies, etc. __________________
 ¹Creutz, who was one of the men who met with the Dean and I, was the man who in late '41 or early '42 dashed into Arthur Compton's office all excited. He exclaimed to Compton. "Do you realize that when and if we get the piles in controlled states and begin producing plutonium in large quantities, we'll have thousands of radioactive molecules as well as penetrating radiation doses, thus a large potential risk to all our personnel? We'd better get a medical and biological study going to see we get maximum monitoring of dose, and medical studies to detect any radiation injury." Compton obviously went to work on this matter almost immediately. --LOJ

Q: What's his name?

Jacobson: His name was Glenn Seaborg. By the way, he borrowed one of my microscopes and used it for 2 1/2 years to study plutonium crystallization, as well as other rare elements. I still have the microscope as a memento of its history and use. He won the Nobel Prize for discovering it. I'll never forget one incident: He and his wife used to go out to the beach here in Chicago on Sundays. One Sunday night he called me up and said, "You know, I didn't get much sun, but I'm burned." I said, "Well, I'll come on over, but sometimes you don't really realize that you're being burned." He was worried that the radiation he got in the laboratory plus the sun had made it come to a head. Reassured him, nothing happened.

I got involved then with, besides administrative; I was doing experiments, as I already told you. But we had to check anything that they would imagine that would come out of the fission reaction that produced plutonium. So we picked the ones that are the most abundant and those that are apt to be the most trouble, among which was strontium 89-90 [90Sr, 89Sr]. But we studied many others. It was almost routine that if you found something interesting, of course you could pursue it if you wanted to or it required extensive study. I became fascinated with strontium; it's a bone-seeker. I gave it intravenously via the tail vein to mice, and it completely destroyed the marrow-- 0.2 of a microcurie per gram. But the mice didn't get anemic and didn't die. I found out why, they had transferred blood formation from the devastated marrow to the spleen. Now they did have a premature death in a sense; they didn't live to be three years old. That was because they had other effects, such as development of sarcoma of the bones, and they frequently developed cataracts and were blind. I thought about these experiments a great deal and decided I would just reverse the process. That's how I did the spleen-shielding experiment. By the way, have you ever tried to put a needle into a mouse's tail vein? It takes practice.

So, what I did was-- You can operate on a mouse with light anesthesia-- just make a little slit and bring out the spleen which is about 3/4 of an inch long and a quarter inch wide. Of course it has vessels going into it and nerves, an artery, and a vein coming out. With a little maneuvering you can get it out with its pedicle intact. I had a lead box made that wouldn't compress the pedicle, and we had that checked. I had the experts-- including Ray Zirkle-- irradiate irradiating the mice with the lead box shielding only the spleen at first and of course we put radiation monitors inside the box-- to be sure the spleen was truly protected-- Then I did the experiment. You start out with the LD50. LD50 means that if you give a total body dose of 550 roentgens to mice, half of them will die. They all lived if the spleen was shielded. We kept on raising the dose, even getting as high as 1000 to 1100 roentgens, which is always lethal without shielding. They would still live at LD100, which was in the range of 750 roentgens. At 850 or 900 to 1050 R more than 50% would live unless they had a surgical accident, such as a non-functioning compressed spleen pedicle. And then within a week I knew that not only had the shielded spleen taken over as a major producer of all the different blood cells as we shielded but it destroyed the marrow. However, the bone marrow began to recover in a day or two and was essentially normal within eight days. Then came a question of international interest; why is the bone marrow corning back so rapidly? My first thought was that it probably was a humoral problem; there was something humoral from the spleen going out the spleen pedicle via the blood, but I had to admit that there was the possibility of the transfer of cells from the shielded spleen. In fact, I had histological evidence that the cells were leaving the spleen via the renal vein in the pedicle. That was later proven by someone else-- that is was at least in part a cellular transplantation, but I believed that humoral factors were involved as well. Of course I had already transplanted splenic tissue into the peritoneal cavity intravenously and it had worked, so I knew that; but that wouldn't have proven that it wasn't humoral, at least in part. That was a very interesting period because other investigators were working on these questions all over the world, and among them were [D.W.H.] Barnes and [J.R.] Loutit from Harwell, England. Harwell was the British atomic energy center located north of Oxford. Other groups involved in pinning down the notion that transplantation of spleen hemaloporetic cells was the main reason for bone marrow recovery and survival of the animal included Egon Lorenz, from the National Cancer Institute at Bethesda, with whom I was involved in the attempt to determine the whole-body tolerance dose of x-rays or gamma rays. I had to go to Washington D.C. and to Oak Ridge and to Hanford and so on down the line just to be sure about experiments in progress or check out how things were going in the laboratories. So I traveled quite a bit. One time I was on a train going to Oak Ridge and I went via New York. That was not an uncommon thing to do, in those days, for security reasons. One could get a lower bed or an upper, but the chances of getting a compartment was practically reserved for officers of high rank. I had no rank; I was a civilian. At any rate, on one trip by train to Oak Ridge via New York, a fellow, a nice looking business man type, was sitting in the men's room. I don't know if you know what they looked like, but there was a place to sit for five or six people. I came in and there were a couple of other fellows there, and the business-type fellow said to us, "How would you guys like to go drink a whiskey?" Well, maybe I didn't, but I think I was the first to answer yes, but I'm not sure. Well, so we had a drink or two, and this fellow started talking about what he knew. I'll just give you one thing he said: he said, "You know, there's a place called Oak Ridge and it's just growing-- trucks going in there-- it's all top security. It's said they're working with uranium." Well, when we got to Philadelphia, I got out of there, I got out of that room. I told the conductor, I said, "Now, for security reasons, when we stop in Philadelphia, I've got to contact somebody, and I don't want to be left here." Because they usually stopped for a while in places like Philadelphia. So I turned the guy in. I knew his name, I knew where he lived, and so I told it all to the central security office. I often wondered what happened to this guy. I mean, after a while I started wondering, so I finally tried to check it out-- security told me that, yes, they had contacted the man, and they just told him to keep his damn mouth shut.

Q: Do you know how he knew?

Jacobson: Well, you see, some people are just very observant. There were such people on this campus, not very many-- There was one by the name of C.P. Miller, and he was a professor of medicine and a great scientist. He knew many of these people who came in to Chicago and were urged to join in atomic research. His wife was from the Pullman family and they had a beautiful a house on campus here. My wife and I were very close friends of theirs. We used to go over there every once in a while for dinner. It became obvious to me that he knew a great deal that he gleaned from these people coming in from New York, Princeton, etc., who had not been sworn in or joined the project as yet. But they were the kind of physicists who were working with fission and stuff at their home base, and they'd let something out in general conversation, and Dr. Miller caught on. So I turned him in. Well, turning them in doesn't mean anything because they haven't done anything wrong. But they're just told to be careful and not say anything.

Q: What was your status then? You were a civilian doctor, but really you sewed the government, obviously?

Jacobson: That is correct. The project was under the Manhattan Army engineers. My guess is the reason they didn't make us go entirely under army control was probably a decision of the scientists for the very reason that non-military control reduced the amount of red tape and the effort would proceed faster. You could move fast. The Army Corps of Engineers appointed the head of radiology from the University of Rochester as the medical director. He became the leader for the army. I don't remember what his rank was, he was up high. Then he had chosen another radiologist to work with [Frodell?]. They were both in uniform. They came in about once every month or so. Usually I had to speak to them and show them around. Robert Stone would either be away or he had a little difficulty with one of these people because they were both radiologists. So in a sense, you know the people that were involved here, I don't have to get all the names and stuff. There were hundreds people, but the top ones were only about fifteen or twenty. [Harold] Urey, for example, was here, as well as the other ones I told you about.

We would monitor these animals in the atomic pile room, which was located in Stagg Field, the football field, and nothing happened to them. And I'll tell you something anecdotal-- So you'd have to take them out and examine them and sacrifice some to look for any evidence of histological damage. We would check everything. You'd check the blood and all that stuff. We didn't do that very often because nothing was happening to the animals that suggested radiation injury.

I told the story-- and it's partially true-- there was a meat shortage then. And if you had a control that had not received any exposure in terms of radiation, you could eat that rabbit. And we did eat a few. We did experiments on chickens, and we ate a few chickens. But they were also in the control group. I didn't particularly like it, for some reason it wasn't as though you'd bought them at the market. But one time the man who ran the animal farm for me came down to me and said, "Wouldn't you really love to have a beautiful rabbit that's been a control? I'll fix it all for you." I said, "Fine." So he did. He brought it down. I brought it home and my wife Elizabeth cooked it-- baked it. We sat down at the table and my son Eric was then about six years old. He just dove into that rabbit and ate it like it was starving. Betty and I took one bite and stopped. The boss of the animal farm had put-- he had sterilized the places where he cleaned and dressed the animal. He was using something-- a disinfectant. I want to tell you it wasn't very good but I guess Eric thought it was part of the flavor of the rabbit.

Well, the day came that the atomic bomb blew in Japan, of course we already knew the test results in Nevada before that. The day that the Chicago group [Enrico Fermi, et al.] got the reaction going, I wasn't in the room. No one was in the room at that time except my animals and the staff-Fermi's staff, or his special colleagues. So I didn't see that. To my knowledge, no one else outside of that very small group was involved. But I knew about the Japan bombing right away, so I called my wife. Said, "Listen to the radio. Go out and buy the paper if it isn't delivered yet, and you'll find out what the hell I've been doing these past few years."

Q: You had not told her?

Jacobson: No, no. She had never even pushed me for it. She knew I was doing biological work. She knew I was doing radiation work. I'd done that before all this started. She knew I was busy and I had to travel and this and that. But she didn't really know what was cooking. Enrico Fermi's wife, like my wife, believe it or not, also did not know what was cooking. She found out the same way as my wife did.

Now I'll come back to the things we were doing. After the strontium experiment and blood-forming tissue in the bone marrow was destroyed and it was transferred to the spleen, I mean the manufacturing system, then I did spleen shielding, of course, and the animals lived after receiving doses in the lethal range. The reason I did that was because I thought if you're knocking out the marrow and the spleen starts, there's got to be a message. Something's got to go through to tell that spleen to go to work. I started checking all this. Meantime, my program in Washington was going well and Dr. Lorenz asked me one day to come to dinner --he was a great cook, as well as a number one biophysicist. He had been married in Germany but she'd died, or something. So he cooked dinner and we'd sit around and chat about science. One day he said, "You know, Jake, you've done this spleen stuff and you've transferred the spleen cell material to the abdominal cavity and it worked, would you mind if I just use bone marrow?" I said, "Heck, I don't care, because I've got so many things cooking, I don't need any more work. Go ahead." Because we already had the same program going anyway. So he did that and it worked just as spleen shielding worked, and essentially proved that a repopulative marrow phenomenon occurred, spleen cells or was it bone marrow, and both were. That essentially proved that it was at least in part a transplantation phenomenon. But someone else did it, interestingly enough, with rat marrow. So you had a mouse with rat marrow living, although mice given rat marrow eventually died of a rejection phenomena.

Q: Who did that?

Jacobson: A fellow named Leonard Cole out at the Naval Research Center in California.

Q: But you did not pursue bone marrow transplantation yourself, Dr. Jacobson?

Jacobson: I had transplanted the shielded spleen cells and that worked just as marrow did. Well, I did for a time in the beginning. But once I got into an area of science that I couldn't handle for various reasons because you can't do everything. Genetics, for example, is a very complicated thing; but then it became apparent that if you irradiate, you suppress the immune system and therefore a transplant establishes itself; and if you use a genetically pure strain and use that material, of course you never have any problem; but if you go into a different strain, then if you transplant one strain into a different strain, then they will have immune disease and maybe die.

This last week there was an article with one of my pictures on the cover of Cancer. They had a write up in there by someone in which they said-- and I'm not quoting myself, I'm quoting them-- that it was the bone marrow business and the spleen business that led to a great deal of work on transplantation, and therefore they gave me some credit for that. Well, I don't really claim any credit because it was obvious. There are all kinds of things that I could have told you about that particular year because it went pretty fast. But I'll go on a little bit now about what happened in the next step.

Q: You made a reference to ongoing, long range research on the cumulative effects of radiation?

Jacobson: Well, up to right now, what we found was that this relates to the work Lorenz, I, and others were doing at the National Cancer Institute-- the then accepted one-tenth of a roentgen per day was too high and they'd taken it down. As I recall, I couldn't find any evidence in the blood that it was harmed with a daily dose of 0.1 roentgen, but upon pathological examination they found that after exposure over a long period they developed ovarian tumors even at that dose. Then there were other things going on in various parts of the country on tolerance work, and of course that's why the so-called acceptable dose was reduced considerably. Of course, some people think there is no acceptable dose.

END OF SIDE 1, TAPE 1; BEGINNING OF SIDE 2, TAPE 1

Jacobson: The fact that I was so interested in what it is that controls blood formation, I began to work on erythropoiesis. I was aware of the fact that around 1900 a Frenchman had found that there was probably something in the blood stream in anemic animal's et cetera-- I don't think he used any humans. He called it erythropoietin. This hormone controls red cell formation. But no one really paid much attention to that because they had no reliable assay methods back in 1900. The only assay method you had was to inject the material (blood plasma) and you didn't really know how to concentrate the material. But gradually over the years, they never forgot that and a lot of people worked on it. One group out at Cal Tech under Borsak, et al, found out if they boiled the plasma, they could reduce the volume without destroying the molecule-- whatever it was. Here I was working with my colleagues-- my technical group-- on assay methods. The California group at Berkeley had decided in their mind it was probably made in the pituitary, but I found that in trying to develop things in terms of the assay of this very interesting growth factor-- I won't go into all the experiments I did-- we tried hypophysectomized animals, they were excellent in this sense: that if you take the pituitary out of a rat, the red cell count and red cell mass falls in 2 to 3 weeks, as do the reticulocytes. The blood count falls to about 50 percent of what it was normally. If you then do the reticulocyte count, you'll find it goes down ahead of the fall of the red cell mass, and the reticulocyte count within 2 to 3 weeks of hypophysectomy falls nearly to zero. That turned out to be a very good assay method for erythropoietin rich plasma, but was time consuming and complicated. The next step was to simply bleed the animal, and it would produce more erythropoietin, so it made the development of assay procedures easier. If you're using the hypophysectomized animal, of course you're interfering with a great many other things once you take that out. The next thing we used to measure erythropoietin was animals in a low oxygen chamber. They produce more red cells than normal and are in a polycythemic state when you bring them to a normal room oxygen level. They have practically no reticulocytes in the peripheral blood and therefore are sensitive to the injection of erythropoietin or erythropoietin-rich plasma, and are therefore ideal for assay of erythropoietin. This method of assay was really excellent. I do not take credit for discovering that because that was known for a long time. Whether they knew that the reticulocyte count went down immediately, I can't remember. But it falls very quickly when animals are put in low oxygen atmosphere-- or you could transfuse them and produce the same thing. Then I had other people working with me, not for me, on the chemistry in our lab, and [Eugene] Goldwasser, an excellent biochemist, ran that show but was always in touch. I talked him into working with me and he took over the problem, consuming less time than my methods. He also was in charge of the chemical structure and other functions of the hormone. He and his colleagues had already determined a large part of the molecule.

Q: Was it Eugene Goldwasser?

Jacobson: Yes. So he developed assay methods-- cultured cells and so on-- with another young man, Sanford Krantz, and others. I wrote a book on erythropoiesis, Krantz was actually the author; I was the co-author. He's in the southeast, now. His name is Sanford Krantz, an associate or full professor interested mainly in hematology.

At any rate, Krantz and Goldwasser developed other forms of assay of erythropoietin and as time went on, it became better and better. Then we got involved with the government because we thought that we could probably produce and monitor or determine what the dose-- in a sense, how accurate was that material. We went to Swift and Company-- Armour, I mean. There was a man-- a biochemist-- there that Goldwasser knew. Then we went on to Washington and they finally gave us enough money, actually through Armour and Company. Armour and Company had a large sheep ranch out here. I never went there, but what they did was they injected phenylhydrazine into the sheep which hemolyzes the red cells, and when they got down to a hematocrit of about 6 percent they bled them and processed the blood.

Q: Phenylhydrazine?

Jacobson: Phenylhydrazine, it's a chemical compound that hemolyzes the red blood cells. So when they get down to about 6 percent hematocrit and they were too weak to breed, they were bled. Then they processed the blood chemically and developed methods for concentrating the hormone present in the anemic sheep, a process which actually was developed by this chemist from Armour and Gene Goldwasser, from our labs. Then finally it was gone to England to Mill Hill for standardization. So we had a standardized material for testing for erythropoietin for anyone who needed it in their experimental work.

Then coming back to the things that I was concerned about. The reason I got into that erythropoietin business was simply that I just wasn't satisfied that it was all that simple; it needed thorough study.

Q: Was there a connection from your radiation study?

Jacobson: Well, of course if you radiate with high enough dose, you're going to get anemia because you would destroy marrow. One thing suggested another, and it was all involved with the strontium-effect, the transplantation-effect, and so on and so forth. That's how I got into the erythropoietin area. I had a wonderful time there, too. Gene Goldwasser would get discouraged once in a while. Well, he never finished that molecule, but had part of it correct. But he was on the board of or a consultant to the California company that developed a method to produce the erythropoietin molecule from cell cultures, not really from scratch. People did it with cultured cells and using modern techniques of isolation of molecules. He had about half of the molecule done which I guess was helpful even in the end. But it was interesting that I had worked part of the experiment out trying to figure out what organ it came from. I think I alluded to the fact that the Berkeley group thought it was the pituitary. But there was an article that I had not seen, but someone reminded me of, by Rudi Schmid, who was here at the University of Chicago-- he became dean of the medical school at the University of California at San Francisco-- and some of his colleagues. This was after he left the University of Chicago. I think he was in Boston at the time, at Harvard. They had studied a case with a peculiar abnormality in the circulation of the heart. They tested the blood for the erythropoietic levels, and they decided that erythropoietics were made below the diaphragm. That didn't mean anything to me when I started looking for the site of production because I decided I had to look everyplace. But then I did the definitive experiment on the kidney and proved that it was made there. But of course the proof was not truly established until they had shown in tissue culture that it was made in a particular part of the kidney that had a rich blood supply. But it was widely accepted by many people, but on the other hand there were others who were trying to look at the liver or tried to think of complicated ways that it was made-- whether it was the kidney or kidney in part or what have you. Well, I just sat down and listened and watched. So I've had a wonderful time.

At the same time I've had a very large practice in hematology.

Q: I wanted to ask you about that too -- I was interested in how much clinical medicine did you practice through all this research.

Jacobson: I figure you can do almost anything as long as you get some sleep. But I was head of medicine and had a large and active outpatient clinic. I was director of the Argonne Cancer Research Hospital. I was chairman of the department of medicine. Then I became the dean. All those things take time, but I wasn't doing them all at once--usually two at a time. They built the  Argonne Cancer Research Hospital because I suggested--well, not because, but I suggested to the dean, who was Lowell Coggeshall--a very famous man-- that we ought to have an institute or whatever you want to call it that was designated to work with isotopes as opposed to the bomb: it would be atoms for peace.

Q: When did you suggest this?

Jacobson: This was early '46, right after the war.

Q: His name was Coggeshall?

Jacobson: Lowell Thelwell Coggeshall. He was a malariologist. Well, he said, "I think that's a splendid idea. I'll look into it immediately."So, he went over to see the provost and the president, and they thought it was a good idea. Of course, I don't know what went on over there, but they must have agreed with the idea, because it was taken to the board of trustees within a week. They okayed it. Then the next part was: where are you going to get the money? Dr. Coggeshall called [Leonard] Scheele who was then the head of NIH [National Institutes of Health], and he said, "I think it's a great idea. But we can only give money at this moment to cancer and heart disease. But please apply anyway." This went on for a few days and finally in conversation, by phone, etc., he told Coggeshall, "Two Senators have just died from cancer. Now, the Congress has appropriated 25 million in their honor to study cancer. But the Congress said, 'This shall be under'-"I don't remember what the law said exactly-- but they wanted the Atomic Energy Commission to handle it. So we ended up back at the Atomic Energy Commission. This was in the early fifties.

The first thing that happened was very interesting because the answer was yes; they thought it was a splendid idea. They would go ahead and build it and pay for the scientists and all that. The university agreed to put it on campus. That's where we ran into some problems because the law said it must be in a national nuclear laboratory. So, they worked that out by calling this the Argonne Cancer Research Hospital, managed by the university just as the university was managing Argonne National Laboratory. So, in essence it filled the requirement and they built it. And I ran it for them. I actually got involved in the inside architectural aspects. We had a very nice program there. When I retired-- became emeritus-- I was still director. But I had turned it over sometime before. But it was marvelous because you had the proper space, and facilities, and equipment and a liberal budget; you didn't have to apply to seventeen-hundred places to get money to do your work. I had freedom to pick people and I was fortunate to pick some very good ones like Dr. [Janet D.] Rowley.

Q: Is this Janet Rowley? I had a chat with her.

Jacobson: Yes, she's marvelous. And a matter of fact, she had been doing other things, but I had a lot of patients available. I had a big clinic, leukemias, and lymphomas and so on. And the reason I had so many patients with problems like that was because I introduced HN₂. It was a Yale group that introduced HN3. You know what that is?

Q: No.

Jacobson: That's war gas. As it turned out, HN2 was effective in the Rx of lymphones and leukemia whereas HN3, used by the Yale group, was very toxic and therefore discontinued.

Q: Is this nitrogen mustard?

Jacobson: Yes. Because you do something like that, then patients come from all over. I don't want to exaggerate that, but I had lots of patients. And when Dr. Rowley came over here, she asked if she could work with me-- well, not me-- work here. I talked to her a long time. I had known her as a medical student.

Q: She was a student here?

Jacobson: No, she had already finished medical school. So, she moved in to the space I provided for her in the Argonne Cancer Research Hospital; I was its director. Then she wanted to work with the material we had because if you want cells and you want to look at the chromosomes and determine if there were chromosome abnormalities in any of our cases, one being detached or something, then it's wonderful if they are the ones that are involved. And that's how she discovered things-- by just examining these things. She's a lovely, wonderful, hard-working person. I published one paper with her. I think in that case it was negative in the sense that we found no abnormality-I didn't study the chromosomes; she did. But that's the only paper I ever had with her because I wasn't looking at chromosomes. She was. I never wanted to be on papers I wasn't really deeply involved with, but I did supply the clinical material and discussed her progress from time to time.

Q: That's unusual to publish negative results.

Jacobson: Well, I'm not sure they were negative results, but sometimes negative findings are as important as new findings. I am only saying that she had found no chromosome abnormalities, I think, in those first cases she got. I can't remember even what kind of a leukemia these patients had. It might have been Hodgkin's for all I know-- which is not leukemia.

That's about all I think you need to know. I could go on for days and days because there are so many anecdotal things that happened in some things that I had gone into in terms of what I've been up to. I am very appreciative of what other people do. I don't feel puffed-up about anything. Never have. One can't help but appreciate when people recognize you for whatever. When I got into the [National] Academy [of Science] it was interesting because I didn't know I was nominated for membership, of course. Coggeshall called me from Washington. I had never published in the Proceedings [of the National Academy of Science]. I never had any problem getting my papers published, but it never occurred to me-- because that journal is so highfalutin in terms of the status right then of whatever-- molecular biology and so on. I guess I just didn't think of that because the kind of papers I published seemed to fit in the physiological journals. I got a few prizes. My portrait hangs in the capital in Bismarck [North Dakota]. The governor called me, and I thanked him, and all that sort of thing, and from then on the secretary always called me-- a male secretary. One day he said, "You know you're going to be hung in the capital." I said, "I don't want to be hung in the capital. I want to be hung in effigy cause it's closer to the ranch out in Sims, North Dakota." He didn't think it was funny, though. So, I'm hung there-- with Lawrence Welk, in the capital. And whomever it was who discovered the South Pole. I think it was the South Pole. Anyway, he's from North Dakota. I can tell you one joke about Lawrence Welk and I. It's no joke. I went out there to get an honorary degree at North Dakota State University. My wife was with me. And she and I had both been there to school. So we knew everyone. It wasn't a small college, but it was not so large that-- you could almost know everyone. We came into Fargo. Fargo has about 40 thousand or 50 thousand people, but the airport is no bigger than a filling station. The plane comes right up to the door. There was an orchestra out there playing. I recognized the leader of the band and I said to Betty, "I wonder if they're here to welcome us back because I'm going to get an honorary degree?" She said, "Maybe." We got up to go out and we were near the front. There were two or three other people standing outside and the band kept going as they went by. As I got to the bottom, the band didn't stop, so obviously it wasn't for me and my wife. But somehow I glanced back and I saw Lawrence Welk coming down the ramp. So, I learned a great lesson from this episode. If you think you're a big shot, you're going to be set down. At any rate, after this was all over, I told this story on a number of occasions. The man behind me was not Lawrence Welk. It was a man who led an orchestra during the war. Eisenhower called that band some name which became famous all over the world because of the fact he was doing it at that time. And that's who was behind me. But I figured if I ever said that, trying to tell this joke on myself, they would never know who this man was anyway. So, then I wrote to Lawrence Welk, because I knew him in my youth. He used to play out in North Dakota. And I told him exactly what I had done. And he wrote a little note back-- about two paragraphs long-- and he said, "Look, if you won't tell anybody, I won't. But I may use the story."

Q: I have a few questions for you Dr. Jacobson. Just tell me if you get tired. I'd like to know more about your colleagues actually, they sound very interesting, and similarly about your students, the people whom you trained?

Jacobson: At the time I came here to medical school, George Dick was a very famous researcher in the hemolytic streptococci. Infectious Diseases. Dallas Phemister was head of surgery. And Anton Carlson, the great old Swede, was head of physiology. There were all kind of people who were very famous, and I don't mean just half and half. I mean really famous.

Q: Is that the reason you chose Chicago to come to?

Jacobson: Yes. But there were other people in the Medical School that I knew. I had interviewed the head of German at North Dakota State by pure coincidence about school way back before I came to Chicago. I had gone to Fargo because I wanted to know more about what I should do in the world. At that time he said-- He graduated from the University of Chicago in the language department. And when the time came up I had made my decision to go into medicine, I'm sure he had a lot to do with my getting right through without a single problem. I was interested in German, although I'm Scandinavian and I speak the Scandinavian languages. I got very interested in German in high school and I kept on going. I knew so much German when I got to college, that they just gave me advanced work. And the zoology teacher, for whatever reason, asked me to help out in botany and zoology. Of course I grew up with plants, and animals and stuff, so I made some money that way too-- teaching botany, etc. They had a little high school there and I would help or even run the class occasionally. Another person-- this is college I'm talking about now-- the head of history was named Professor Hunter. I loved history, so one day he said, "Do you want a job?" And I said, "Sure. What is it?" He said, "Well, every week I want you to take The New York Times Book Section and to further reduce that." And I did that for a number of years. I'll tell you another story. It's funny. I had never had any physics. I had all the math I needed-- and more. But I had not been exposed to physics and since I changed from agriculture to get courses I needed to go to medical school, I had to go into the second semester without the first with the engineers-- not with the agriculture group, the engineers. I was lost from the first day. I learned a little, I'll have to admit. After the examination, my teacher called me. Professor so-and-so, and he said, "You didn't do very well on your exam." I said, "I know I didn't." And I told him why. He had some sympathy for that. Then we just talked some more. Finally he said, "What are you going to do?'' I said, "I'm going into medical school." He said, "I'll tell you what: I can easily give you a 70 instead of a 69." He didn't tell me actually. "I'll tell you: if you'll just kind of dedicate your life to whatever you're going to do, I'd just rather you just go over and be a missionary in Africa." I said, "I can't promise that at this point, but I certainly will do everything I can to be a decent citizen and help others." So, he passed me. That's the only problem I ever had in school. Because they skipped me in the grades. They skipped me here and there. But I guess we all go through these hurdles once in a while.

I loved medical school and the teachers were marvelous. I loved my training because I had time to do research all the way along even as a student. I was able, with the help of this wonderful guy in Minneapolis, Mr. Archer, plus the fact that I worked at anything I could do that within my ability in science. That all helped me. I can't tell you whether I was a good chairman or a good dean or anything like that--

Q: I was going to ask you about the deanship, though. You were a dean for exactly ten years. Was that statutory?

Jacobson: No, but you see, at that time, deans throughout the country had short tenures then went back to their research work, and I had the longest stint. Not the oldest in the sense of age, but at that time they were turning over so fast. Since I quit being dean then, the man from the University of California at Los Angeles and one other one some place, bypassed me in terms of length of time as dean. They were deans longer. But right now it's very difficult to keep deans because of the problems that are involved with patient care, cost of operating hospitals and all that. My guess is that there will be a turnover again back to short terms, although I think that's a mistake.

Q: You think longer is better?

Jacobson: Oh, yes. Some problems, you can't get a hold of for a while. Now, I'm retired-- not retired, I'm emeritus, I'm working as hard as I ever was.

Q: What are you working on?

Jacobson: I'm on boards. I'm on bank boards-- the trust type. I'm on some of the boards that here at the university have to do with children or have a research orientation-- such as the Sprague Foundation Fund, the Brain Research Foundation, etc. Then I'm on boards that give away money; I'm chairman of one in New York that gives grants to basic and medical science, for which I have to thoroughly study. You do it, just as you expect other people on the board to do it. These things are very consuming. Then I have hobbies. I work with wood up in my country home which is my real residence. I have all kinds of tools that you can imagine to work on wood. I carve. I'll show you some carvings. I don't have much here. I've had the best of eight worlds or ten worlds. Normally they say two worlds. Why do they say "best of two worlds."

Q: I don't know. One of them is spiritual, I suppose.

Jacobson: I've had a marvelous life, so far. From rags to riches. Because during the Depression-- the Dust Bowl-- we didn't starve on the ranch. We were never starving; you just didn't have any money. You had stock and you had chickens and you had turkeys and you had what-have-you. I borrowed money when I went to college. I borrowed 375 dollars. Then, when I got back and teaching school, I paid it off. I paid half of it off, and I had money in the bank as well. Then the bank closed, like all of them did. I had to pay the debt, but I never got any money back from my deposit. So, essentially all the money I'd saved was gone, because I was making 80 dollars a month. That was quite a lot, in those days. One thing I didn't tell you about the school teaching experience was that the state chose my school as a demonstration. So the state superintendent of instruction came with her whole entourage and spent three full days with me. I almost had a stroke when that letter arrived because I'd never been under that kind of situation. Of course you have teachers and all the rest of the stuff in school or college, but to be teaching in eight grades-- Until they walked in the door, I was nervous. But once they got in there, I wasn't nervous anymore. I can't tell you why. I think it was simply because I decided that I would do just exactly what I'd been doing every day, every day. That's what I did. They enjoyed it, I guess. They seemed to enjoy it. They took cuttings from all my plants. I had letters from them.

Q: What can you tell me about the American Society of Hematology?

Jacobson: In what sense?

Q: How much you've been involved with it?

Jacobson: I was very early, but I'm not now. Of course they have international things. I don't always go to them now. I go to local things. I go to some of them. I travel a lot. I go to Europe about every other year to look at projects we're financing. I go to the Karolinska in Stockholm. I go to Oslo, England, Paris or anyplace else where we may have given grants or the Board wants me to talk to somebody because we like the kind of work they're doing. I have a tremendous amount of contact with science and scientists, so I don't have to go to all of these scientific conferences. They've changed to a degree; they have simultaneous speeches at all these meetings. That is a pain in the neck because instead of having a reasonable number of presentations where you have time to talk with your colleagues who are in other fields or in your same fields-- like a boardwalk. We used to do that in the Association of American Physicians and young Turks. It's all so specialized now. Of course I'm specialized in that sense; I'm not opposed to specialization, providing you have a good general knowledge of medicine. If you're going to do research, you almost have to specialize because otherwise you have no system to work on.

Q: What do you remember about the organization at the beginning?

Jacobson: I was not involved in that. I'm not even sure I was ever an officer. I was a local officer here at the central society which is a very good society. Partly, I'm not a politician. I don't work with those things. Since I was here in the city, I was involved with most of the organizations in a positive way.

Q: I guess my final question is what do you hope for?

Jacobson: Hope for in what sense?

Q: Well, that's a good question because I asked another doctor that and I got a very personal reply, but I really mean scientifically and professionally and personally as well.

Jacobson: One has aspirations of course, but my aspirations had to do with my education, the pursuit of my science, and of course I've had plenty of things that have happened. I've got prizes, I've got medals. I don't see that I have any special aspirations beyond that. I belong to the National Academy of Sciences, and the American Academy of the Arts and Sciences in Boston, and of course I belong to the Medical Sciences. I have no aspirations for anything else. People say you have to aspire to something you probably can't reach, but that is not true if we're talking about accolades. Accolades should never be one's objective, other scientists should decide whether an honor should be given to a researcher.

Q: What else would you like people to know?

Jacobson: I have a wonderful family, but my first wife died six years ago and I married again in January of 1990, to a lovely lady who is a surgeon (her first name is Elise). I had two children by my first wife, a boy and a girl; both are married and both have children. I have a home on the shores of a lovely lake up in Michigan which I keep open all winter, if you want to skate or ice-boat to ice fish, you can up there anytime you are in this neck of the woods. My son and his ten-year old son are sailors and I'm a woodworker, so I keep doing that sort of thing. I even have to work during the summer to keep up with all these things we were talking about. I'm not hung up on anything. I don't expect anymore accolades in my life. I've had plenty-- maybe more than my share. Every time this sort of thing happens, I always think about the guy that I think should have gotten it instead of me.

I'll tell you an example: I'm a so-called Master in Internal Medicine in the Hierarchy of Medicine. There are 113 now 112 or something-- in the United States who are so classified. But I was put in there when there were only 25 or 30. That was one of the greatest honors in one sense you could get because it had nothing to do with money, didn't have anything to do with medals; you just got up there, had to stand up there, and you were the thirteenth. Well, even with a hundred now, that's still not very many. But by then, you have nothing to do with that. I know I've been a good physician. I've loved it so. I'm a generalist in the sense of the kinds of people I take care of, but what naturally happens is that if you're in a specialty in which you have done something then you attract patients in that area, but that doesn't mean you don't see a wide spectrum.

Q: Is there more to talk about nitrogen mustard, for example, or victims of radiation accidents?

Jacobson: I'll just talk about radiation for just a second. The man that produced radioactive isotopes for my early use was Louis Slotin-- we had a cyclotron on campus that produced the radiophosphorus. Do you know how you do that?

Q: No.

Jacobson: The cyclotron irradiates sulfur, which changes under these conditions into Phosphorous 32 [P32] Then I would give it to patients.

He was one of the people killed in Los Alamos. He was demonstrating how to put a bomb together, and the story is-- I wasn't there, fortunately-- that he had the elements which if you put together you'd have a reaction. You could separate them just a fraction and nothing would happen. He had put a screwdriver in temporarily and the screwdriver fell out. And they had instantaneous fission. He died within 24 hours---48 hours. There were four or five others in the room and I saw them later-- checking their blood. They became sterile. Some of them lost their hair. But they all recovered and had babies, fine, normal babies. I'm talking about the people. The reason they probably survived is that Dr. Slotin, who made that original mistake, pushed them apart again. He got something like 25,000 roentgens. I don't know what the number was. It's in those books probably.

END OF SIDE 2, TAPE 1; BEGINNING OF SIDE 1, TAPE 2

Jacobson: During the war, we not only had the metallurgical laboratory on campus-- that was a fake name because after all metallurgy could be involved with war work. On campus as well was a large group who were interested in war gases not because we wanted to use it but because we had to be prepared if others did. They were working here and I knew all of them. I was cleared for it. In a sense the effect of gas mimics to some extent of penetrating radiation and HN2 (war gas). One of the people working there, a colleague of mine, both of us were on the faculty, was Clarence Lushbaugh. We talked about the fact that he had found that the blood-forming tissue was very sensitive and it had other effects too. And we went into great detail on this. I went over all his work. We finally figured a dose on the basis of milligrams per kilogram that would be related somewhat to less than a lethal dose. Not an LD10 or LD50. And it was a tenth of a milligram per kilogram. Thats what we settled on. I had to get permission to use it and I went to the chief of medicine who was George Dick. I went to the dean. We didn't have these committees like we have today. George Dick had been in the First World War. He knew about these things. He also had a broad knowledge about many things. Same was true of the dean. I got permission. After all, we also knew it affected blood forming tissue, lymphatic as well as general hematopoietic tissue. We gave the first dose. The way we did it, we started intravenous saline solution going in the arm vein, and I would inject the material which had been weighed on a microbalance and then dissolved, then immediately inject it, because otherwise it deteriorates. It doesn't last very long before it changes. Very soon after it goes in the body, they get sick to their stomach and they're very sick and vomit. I had to work on how many times you've got to do it, how many times could you do it. Finally, it ended up I'd do it on four successive days. I never had any fatalities or anything like that with doses that low. But most of them were sick and you'd watch the counts. The blood count was about the best thing to monitor the status of blood production. The drug not only made the patients sick to their stomachs but the white blood count also fell; the platelets would come down. We monitored these things (besides tender loving care) to be sure the patient was OK. The lymph nodes would start disappearing almost immediately in Hodgkin's. I tried it on leukemia patients, too, and patients with polycythemia, but I concentrated on the lymphomas. It was spectacular in some cases of Hodgkin's disease.

I'll give you one example: The man who was head of radiology and x-ray therapy and whatever at Sloan-Kettering in New York was a friend of mine. His name was Lloyd Craver. Very well known in radiation circles especially. He had heard through his chief, who was Rhodes, that I was doing something with some kind of a chemical, so he called me up and asked if he could send his patient up to me because of the fact that he had given her everything he could in the way of radiation and she was still spiking a very high fever like crazy. He sent her in here. I didn't do anything for a day or two, just watched her. Then I went ahead and gave her four injections, one per day. After the first injection her temperature came down to normal and never went back up again and she never had a recurrence. She died several years ago; I don't know how old she was. Never a recurrence of the disease. Now that was unusual. One probably cured a few, but even at that time period, in a general way you got a sense that this is going to control all patients but the mustard and radiation and maybe cure 15+ percent, or something like that. I don't know how many we cured because when I wrote that first definitive report on HN2 I had patients still living, in fact. But the only area where it worked the best was in the lymphomas. That's where I concentrated. In July of '43, there were many people involved in the chemical warfare business and one of them was the dean at Yale who was a pathologist. I loved the guy-- a real snappy guy.

Q: What was his--

Jacobson: His name was Milton Winternitz. He was a pathologist but was dean during the war and one of the leaders in studying gases for military purposes. I loved that guy. He pulled my leg all the time. I flew in there. I'd never been to Yale before. My taxi driver let me out; I said I want to go to the medical school. I didnt know where I was on campus and he let me out here ten blocks away. I finally found the Med school by running into strays here and there, and found out how to get to where I wanted to go. It was just myself and the Yale group because we were the only ones who had done the work. I reported on the cases I had to them and they went over the two they had. They had stopped it because HM3 was too toxic. That hasn't come out in everything, but that is what happened. But since there had been success of whatever sort-- There really was some success and as an adjunct to x-ray therapy would probably be even better. The chemical warfare group in Washington released it to a number of people throughout the country, [Maxwell] Wintrobe and x,y and z so trials could proceed. In 1946 we published a paper and at the same time the Yale group published a paper, but up to that paper was added the work that everyone else had been doing with HM2after July 1943. I was a little angry about that because the AMA [American Medical Association] said they would publish both these papers in the same issue. They published the Yale one first, one week apart. Mine was the second one. Normally then you would refer to the other. It didn't make any difference in one sense but it kind of griped me at the time because it would have been the fairest thing to do. At any rate, I had the one that worked, but everybody else who was cleared in terms of security began using the one that I reported on at Yale. So there were a lot of cases in that first report in 1946, because other investigators were alerted and it was given to patients by Wintrobe, Dameshek, etc. After 1946 I believe the molecule was changed a bit and it received a different name. But they used it in combination with other things up until the present. They do occasionally use it now. But that's all we had besides radiation, for a long time.

Since I had a lot of these people with various kinds of hemopoietic diseases; I was interested in all of them. Polycythemia also helped get me into the spleen problem and bone marrow because in polycythemia rubravera, not infrequently, the bone marrow space scleroses as time goes on and all the blood formation, or a large part of it, goes to the spleen for all practical purposes and the spleen is huge. On the other hand, you could maintain them pretty well. You had to watch things like gout if you gave them anything to hemolyze cells. First they were using phenylhydrazine. I used it once and quit because of the release of things that precipitate gout. In the leukemias, what you'd have to do was decide at any point in time whether or not it was a benign form or not. Benign means only that at this point in time you really don't have to do anything. You'd be surprised how many of those there are. In general however, from my experience as I've looked at the reports or listened to a report some people just treat it without knowing whether it will run a benign course for a long time or a rapid one. I just had a patient die about a month ago whom I had taken care of for around forty years. She didn't need treatment until a year ago. Im sure if I'd have given her treatment from the beginning, she'd have been dead now from a worn out system. That means you have to watch the patient. That's just one example. People who have these kinds of problems also have other kinds of problems. We're really almost dealing with all patient diseases anyway all the time, but I saw patients with heart disease and ulcers and everything else. I have a very large service. I was terribly interested in people. I probably gave them more time than almost anyone. I'd sit down and talk to them and sometimes thats better than medicine. Sometime their complaints are so obviously messed up with their problems or their personality or their way of thinking, that you need time to talk to them. I love my patients and they love me. That's really true. That's a very nice relationship.

Q: Did you treat patients who were victims of radiation accidents?

Jacobson: I did see all the people who were irradiated with Slotin at Los Alamos, but that was done in Chicago when they were sent to me for a check up on their blood status, etc.

Q: I noticed particularly that you wrote a paper on Yugoslavia. Did you actually treat patients from Yugoslavia?

Jacobson: No, but when they had that reactor accident, they sent them to the closest center and that was Paris. I knew the man in Paris and he knew about my work and then he did transfusions. If you look at the articles, if you know what to read about them and how to interpret them, there's a real question about whether he helped them of not. I don't know.

Q: Who was this? [Georges] Mathe?

Jacobson: Yes. He's the guy whos been doing it. He has been very much interested in transfusions. I see him every once in a while. I don't ask him questions about whether he's gotten any good results or not. Of course its been proven since that it will take care of marrow after its been destroyed or reduced to hardly anything. But if the dose is big enough, you cant save people anymore than you can save an animal. At least I can save them up to 1,000 R but I don't know how much farther. I think I probably could have gone up to 1300 or what ever, but that would still have shortened their life and probably over 500 R which is LD50, would probably have shorted their life as well as producing blindness and tumors when you give whole body. Mustard, as toxic as it is, as far as I know, is not carcinogenic whereas X rays are.

I think that you can combine the practice of medicine and research. I think it's better if you can combine your medical experience with work in the laboratory that's related to whatever your main interest might be, because I think it makes you think more. Flashes don't come like that; its something you kind of work out, so if you want to call that a flash out of nowhere, I suppose that's what thoughts are, but it's a progressive thing. You find out one thing, and you find out another, and maybe that tells you what combination to put together. Certainly that was true of almost of all the things I did in the radiation field in terms of research. I'm not talking about the routine thing where you're exposing hundreds of animals to a given small dose. In one sense that's research, and someone has to do it, but it isn't something that you dream about because it's so wonderful. Whereas if you're dealing with something like origins of hormones, reversing radiation effects, existence of a hormone or where it's made or trying to develop ways of testing for it, or you put two or three together in terms of thinking about the next step-- whether it's with radiation or with hormones. You can't really explain these things. It doesn't come to you in dreams. You may dream about it, but you won't get answers that way. Be nice if it would. But generally it just kind of evolves, your thinking, your dreaming, your shuffling things around for a point of view, but you are actually, honestly trying to get to the point where you see a way of doing something and you can try it out. You don't know if its going to work. Sometimes it does. But I can only tell you this, that it is tough to do both and especially if you're involved in administration at the same time. My wife wondered how could anyone do all those things, but I didn't come home arguing or be mean. I think when I left the office, very rarely was I preoccupied, although after she and the children probably went to bed, I would probably be writing, or diagramming or something. So I did put in quite a few hours and sometimes I'd have to go back to be with the technical staff because sometimes they would work all night, depending on what experiment we were doing-- if you'd want to catch it at given points, you had to be there. It's been a very busy life. I'm 77 now. I might pass out next week, but I'm feeling pretty good, and I'm still having a wonderfully busy life. And now with a lovely wife of the past seven months, I still love life and all it offers.

Q: Thank you very much Dr. Jacobson.

Jacobson: You're welcome. END OF SESSION

Addendum

A list of some of my colleagues who worked actively with me or are listed as senior author on some of the publications:
Clifford Gurney, M.D., Professor of Medicine, University of Chicago. Now retired from medicine and research but active in other areas of public interest. Lives in Florida. He was a hematologist and one of the best clinicians I have ever known. He also did work on erythropoietin because he was interested in such diseases as polythemia, renal disease anemia, etc. We published a few papers together. When Goldwasser, Krantz, and others had purified erythropoietin as best they could, Dr. Gurney without my knowledge tried our highest titre erythropoietin (made from sheep plasma) on himself. He had a near fatal reaction but a complete recovery in a few days. That stopped any attempt in my group from trying the drug on humans until the California group developed the pure stuff.

William Bethard, M.D. Did residency training and then joined our research group. Was an expert in iron intake by red cells and developed much improved techniques. He left University of Chicago to become head of health at General Dynamics in California.

Ernest Buetler, of G6PD fame. He and I published a couple of papers, not on G6PD but on growth factors-- not very significant papers. He is now Director of Research or something like that at Scripps Institute in La Jolla, California-- absolutely brilliant scientist, as is his son.

Louis Plazak and Walter Fried-- these two men were college students at the University when they came to work with me. They then took their medical training at the University of Chicago School of Medicine. Both are near geniuses and terrific investigators. They worked until far into the night all through med school and still were tops in their class. Plazak is at Harvard in surgery and Fried has been Chairman of Medicine at Rush here in Chicago, and is still there. Most of their work with me involved the study of hypophysectomized rats-- what caused their red cell mass to fall to about 50% of normal. How useful were these rats for assay of erythropoiesis? This was a great challenge for them. I have to give you a little information so you can understand what the project was all about. When on hypophysectomized a rat, their red cell mass slowly falls and stabilizes at circa 50% of the original level. The Berkeley group (John Lawrence's group) thought that this was due to a reduction of erythropoietin and that the fall of erythropoietin meant that the pituitary gland made the erythropoietin; many others thought so as well. However, I sat down with Plazak and Fried and they too guessed that the Berkeley people were right. But I did not, however, and I told Plazak and Fried to go ahead and study the matter, to think it over, and I would put my ideas in an envelope, sealed and in my secretary's hiding place (for her private things). I said that in one month we would get together and if they hadn't figured it all out I'd tell them what I thought. My thought was that of course the pituitary affected almost everything but in doing so reduced the oxygen requirement and thus produced the slow fall (almost three weeks) to a steady state about 40% lower than normal. In fact, the rat's reticulocyte count (which tells us whether the red cell mass is at a steady state or above normal from transfusing with red cells or below normal), produced by blood loss or reduction in oxygen need which can be produced by hypophysectomy. Incidentally, we used the hypophysectomized rat for assay of erythropoietin beginning about 2 to 3 weeks after hypophysectomy, at which time the retic count had fallen to minimum levels during the period it adjusted to its reduced O2 requirement. It eventually reached a steady state roughly 50% of its normal mass and the reticulocyte count went up as needed to maintain the new steady state.

At any rate, I then called Plazak and Fried into my office and said, "Well, why are the retics reduced to almost zero after hypophysectomy?" They still thought it was because the hypophysis was the erythropoietin producer. At that moment I called my secretary in and asked her for my note. She brought it in and had them read it. It simply said: When the hypophysectomy is done the metabolic requirement for O2 is reduced because of the innumerable things that the pituitary "controls" in the body. With the reduction of the O2 requirement, the production of erythropoietin in reduced wherever that is and so the red cell mass falls to the steady state required. Plazak and Fried were converted, and the source of production of erythropoietin was not revealed. Charles Higgins, who received the Nobel Prize in 1965, and I are great friends and had tea about once per week, and we'd just talk. He asked me one day where erythropoietin was made (he'd read the Berkeley paper) and I said, "Not in the pituitary, as John Lawrence and his colleagues think. I have preliminary findings that are rather conclusive that this hormone is made in the kidney." He said, "Jake, you're crazy." He continued with his arguments and I with mine, but as time went on in my lab, I had conclusive evidence that the kidney was it.

However, he and I remained friends and we still have tea and shoot the bull. He's a wonderful showman and can electrify his lay audiences with his positive approach and dramatic illustrations of molecular structure, using different colored small balls, etc.

Mrs. Edna K. Marks, B.A. as well as nursing degree and huge lab experience, and Evelyn 0. Gaston, B.S., a professional nurse and brilliant technically. These two began and ended with me when I closed my lab in 1984. I had many other technical staff members but these two were talented, innovative, and contributed as much or more than I to experimental technique, etc.

Eugene Goldwasser. I talked him into joining me, he had had wonderful training but the challenge of working on isolation and structure of the erythropoietin molecule fascinated him. He had a number of biochem students and post-docs who worked with him and they did get at least part of the structure before the California group finished it off.

Raymond Zirkle. At the beginning of the biology program at the Metallurgical Lab in 1942, Dr. Zirkle, a world renowned radiobiologist from the University of Indiana, joined the program at Chicago. He and I did considerable work on the comparative effects of fast neutrons, gamma rays, and x-rays on biological processes. He remained at Chicago after the war, establishing an Institute of Radiobiology. He passed away two or three years ago.

Eric Simmons. He was brought to Chicago by Dr. Zirkle and worked with us in the above mentioned, and also later worked exclusively with me on various studies such as effects of various radioactive isotopes, pile or cyclotron produced, on blood and blood forming tissue, etc. He has retired.

Sanford Krantz. Already mentioned in text. A very able clinician, hematologist, chemist, etc. Also worked with Dr. Goldwasser on molecular structure of erythropoietin.

Alvin Feinstein, now at Yale and head of Medical Statistics there. He didn't really work with me, but was my advisor on statistics-- taught all of my colleagues statistics-- held a class on statistics once a week, which was very popular, adjoining my labs in the main University of Chicago Medical School. This non-credit course was open to anyone. He was attached to my group to do whatever he wished. He is recognized now all over the country and I think the world because of his knowledge and understanding and teaching, as well as his publications.

Mathew Black, now deceased. He was a Dr. William Bloom/Maximov type morphologist of the blood and blood forming tissue but not as rigid as his above mentioned brothers in the identification of the stem cell. Speaking of Dr. Bloom and Alexander Maximov (who for years published the most popular book on blood and blood forming tissue), I must tell you two vignettes:

Dr. Gurney took a special course on "Blood and Blood Forming Tissue" from Dr. Bloom. One day in Bloom's lab Dr. Bloom called Gurney over to where he was sitting and looking at slides. He said, "Dr. Gurney, what is the cell in focus?" Gurney looked at it a while and said, "As far as I am concerned, it's a lymphocyte." Dr. Bloom responded, "No, that's a stem cell." They argued about identification processes and finally Dr. Gurney said to Dr. Bloom, "What's the cell," and Bloom said, "It's a stem cell." So Gurney asked, "How do you know it's a stem cell?" Bloom answered, "Because Maximov said so. End discussion."

Dr. Bloom was indeed a great anatomist and morphologist. His book had the best illustrations in history. He and his wife did a great deal to help us out in studying radiation effect on blood and blood forming tissue. I loved both of them.

Egon Lorenz. He knew practically nothing about histology, his interest was devoted almost entirely to all types of radiation and survival, tumor formation, blood effects, etc. He was one of my closest friends. He came from Germany (as a refugee or what I don't know). His son was in the German Army during World War II. He had divorced his wife before he came to America. He and Ray Zirkle were the most knowledgeable scientists that I have known in radiobiology. He was also a great cook. After spending all day in his labs in Bethesda talking to him and his colleagues involved in the NCI program on checking the tolerance dose, we would go to his apartment for a few drinks and a dinner he would prepare. He was a gourmet cook. Other times we'd go various places where the best fish or snails or shrimp or clams were to be found in the Bethesda area. He knew the best places to eat in the whole Washington D.C. and Bethesda area.

He died of a coronary a few years ago. About two years or so before he died he married a lovely girl much younger than he. They were very happy. After his death she made it quite clear to everyone she could "button-hole" that he had never been properly recognized for his accomplishments. She kind of made an ass of herself for a while, but that's all in the past now.

The other NCI people involved in the study of low-dose radiation and tolerances, etc., were Heston (statistics and genetics), Thelma Dunn (pathology), and several others who came and went after the total experiment was ending.

William Taleferro, Dean of the Division of Biological Sciences and the Medical School during the Met Lab days. He helped me by discussing my experiments that involved the immune system, but we never collaborated.

One more story about "how you can be brought down to earth." I once gave the so-called Insulin Lectures. The year I did this I lectured in Norway, Sweden, and Helsinki, and then went to Copenhagen for a dinner given by the King and Queen of Denmark at his country estate. After all this I went back to Norway for a few days to visit with surviving relatives and other professional friends. My closest friend was head of the Department of Medicine at the medical school in Oslo. He was also the King's physician (who I met at that time). On the day before my wife and I left Norway for a return to Sweden, my friend and two other physician investigators from the medical school came to the station to see us off on the train to Sweden where I was to speak at the Karolinska. After my host had contacted the station master to be sure all was in order for our departure, he had to go see the King for the second time that day because the King had fallen during his morning skiing. So they departed and the station master said to just sit down and relax with a cup of coffee and he'd call us when it was time to go. So Mrs. J. and I were sitting and sipping coffee, however I became fascinated by a young man who seemed to be talking to himself, gesturing, etc. Finally this long-haired but good looking young man came over to our table. He didn't say hello but asked, "Are you from the U.S.A.?" I said yes. Then he said, "Are you a professor and a scientist?" I said yes. Then he said, "By any chance are you from Houston?" and I said no. He then asked in his perfect Oxfordian accent, "Where are you from?" and I said from the University of Chicago, and he said without a second's hesitation, "How boring!" Then he left abruptly. Being a former North Dakota ranch boy I had some experience in boxing, and I felt like punching him in the nose but didn't for the only reason that I didn't want to arrive in Stockholm all beaten up. So again, I realized that whenever you are a big shot, you'll be taken down to size.

By the way my wife Elise and I just got back from a visit to Norway where I was decorated in the palace of His Majesty King Olav V. He was and is very sick so he couldn't make the presentation. It's called the Medal of Merit, it's beautiful, and also has a scroll which appoints me as a Knight (with no known duties). It is the highest honor available to a civilian, but you don't have to address me as "Sir"-- just plain Jake is what I'm used to. Elise and I spent one week on a 23 passenger schooner and toured the fjords and many of the tributaries in the northwest part of Norway. In late June the University of Chicago Alumni Association presented me with the highest honor given by the university-- again a gold medal and a sore right hand.

From Atom to Eve

[Read in part to a private interdisciplinary club (Stochastics) at The University of Chicago February 1979]

In January of 1942 I was an assistant in the Department of Medicine at The University of Chicago. One afternoon I was helping an intern catherize a patient with a "watering pot perineum." This descriptive phrase applies to an individual who has active tuberculosis of the bladder with multiple fistulae that lead from the bladder through to the skin in the perineum and lower buttocks. No antibiotics were available for the treatment of tuberculosis, and since such patients were highly infectious, the nurse, the intern, and I were all properly gowned, masked, and rubber-gloved to protect us as well as the patient.

During this medical procedure, I heard my name being called repeatedly over telepage, indicating an emergency. Since we had now completed our cauterization, I hurriedly removed my gown, scrubbed my hands, and went to the nursing station. The message from telepage had been taken -- it was simply, "Report to the Dean immediately." As a medical student and later as a house officer, I had never had any contact with the Dean's office, but I knew that William Taliaferro was the Dean. His face was in the center of the picture of each medical student graduating class hung in one of the Billings Hospital Corridors. At that moment I saw him in my mind's eye with a stern and sinister look.

As I hurried to the Dean's office, I wondered if I had done something wrong. Was I behind in summarizing the patients' charts at discharge or death? Was there a complaint from a patient or patients I may somehow have failed to please? Was my chief of medicine dissatisfied with my performance? There were other thoughts darting in and out of my mind since, for the life of me, I couldn't imagine why Dean Taliaferro would want to see me.

I arrived at the Dean's office and told the secretary who I was. She knocked on the Dean's closed door and ushered me in. There sat Dean Taliaferro, Dr. George Dick (Chairman of Medicine), Dr. Arthur Bachmeyer (Director of Hospitals and Clinics), Dr. Paul Hodges (Chief of Radiology), and two men I had never laid eyes on before. By now my respiratory rate had doubled, my heart was racing at least 125 beats per minute, and my mind was muddled up with vague fears and conjectures.

"Hello, Leon. You know Dr. Dick, Dr. Bachmeyer, and Dr. Hodges, of course; meet Professor Wollan and Professor Hilberry. Please have a chair. Leon," he said after we were all seated, "Mr. Hilberry and Mr. Wollan are from the Physics Department. Dean Arthur Compton has talked with Dr. Dick, Dr. Robertson, Dr. Hodges, Dr. Bachmeyer, and me, and we have decided that you are the one they need to help them with a special problem they are having in their research." How could I help Compton and his physics group, I thought. Taliaferro continued. "They are doing research with penetrating radiations produced by the cyclotron, as well as with radioactive substances. They need someone who is a physician and who knows the blood-forming tissue as you do, to keep careful tabs on those who are or may be exposed to these hazards." George Dick and O.H. Robertson were aware of my research on estrogen effects on the bone marrow, the clinical use of radiophosphorus* [Footnote: In collaboration with Louis Slotin who provided the radiophosphorus32p, produced in the cyclotron. Dr. Slotin, who left the Metallurgical Laboratory to join the Los Alamos staff, was the second individual to succumb to a nuclear accident and this accident occurred in late 1945 after the Nagaski and Hiroshima detonations.] for treatment of the leukemia, research on pernicious anemia, and the like. Perhaps, I thought, they can't find anyone else available, so they have decided I'm it -- sounds like routine stuff to me.

George Dick looked at me with his penetrating eyes and said, "Your surveillance of these scientists will be an exciting adventure in preventive medicine and closely related to your special interests in blood and blood-forming tissue. Professors Wollan and Hilberry will give you the background, but I assure you that the work they are doing is essential to the war effort and your participation in their program is essential to its progress."

What could I say? I'm sure I had been signed, sealed, and delivered before I even got to the Dean's office. So I came up with the cliché "Thank you, I'll be glad to hear more details and will try to do my best." The conversation continued with Wollan and Hilberry saying a few words about the human hazards involved in their work, Bachmeyer stating that a laboratory and clinic space would be made available, and Taliaferro mentioning the relationship of radiation injury to immune suppression, as everyone stood up. I mumbled something like, "Thanks, it all sounds interesting." Wollan and Hilberry and I left the Dean's office together and walked up to the third floor of Billings, where I shared an office with four cages of mice on which I was conducting an experiment. There the briefing began, but lasted only fifteen minutes. I had many questions, and they gave evasive answers to some of them. Finally, they said they had to leave because of experiments in progress, but I'm quite sure that it was the essence of mice in the room that shortened the briefing time. Soon there after, I met them for further information in Eckhart hall in Wollan's office. It had, a musty smell, but I added a different dimension with the mouse smell I brought with me.

I had taken physics and advanced math in college. The former I shall never forget; I missed the first semester of the physics sequence because of a ruptured appendix. I enrolled with the engineering students for the second sequence in physics, green as green. As far as I can remember, it is the only course that ever drove me up a wall. I just didn't get the pitch. After the final exam, my professor called me in. He wore a long face, and the moment I saw him, my physiognomy joined his. He told me I had done poorly on the exam.

But as we talked, his face softened. In fact, the more we talked the more enthusiastic and friendly he became. I soon found out why -- he would give me a passing grade in physics if I agreed to become a medical missionary. I never went to Africa as I'm sure he had in mind, but I've kept the promise and preached medicine and medical science every day of my life since that interview. By the way, I had no problem with the next semester course in physics.

While I was in medical school, Dr. Paul Hodges selected me to do the radiography for various scientists who were using experimental animals to study diseases like pneumonia and tuberculosis. I also developed the films and reported the results as well. A higher energy x-ray machine for studies on the biological effects of radiation was in the same room, under the supervision of Dr. Jane Hamilton from the Physics Department. With Dr. Hamilton's tutoring, much additional reading, and patient instruction from Dr. Hodges, I learned a great deal about penetrating radiations.

Perhaps it was this background that had led Hodges, Dick, and Robertson to suggest that I handle the health hazard problems in The Office of Scientific Research and Development Project in the Physics Department.

Conferences with Wollan and Hilberry and others continued. Finally, since it was not clear to me just what their research project was all about and I felt I needed to know more if I were to be effective, I asked for more specific information. Hilberry administered the oath of secrecy, and after I had taken it, he said, "Suppose you read this paragraph in this physics text." He handed me the book, and there, in essence, it stated: "If some morning you should awaken and find half the world blown away, you will know that a nuclear fission chain reaction has been accomplished." Realizing the possibility that devastating instrument of war -- an atomic bomb -- was the objective of this project was an overwhelming experience. I know I blanched; I know I had a lump in my throat, and for a moment at least I was speechless and at the point of tears. To find myself involved in the effort to split the atom in an atomic pile, and in the awesome consequences, were it to succeed, hit me with my hands down. I realized that by now, I was inextricably involved, and I already felt five or ten years older.

The secret remained with me until one day in August, 1945, when, early in the morning, I called my wife and said, "You've been wondering what I've been up to these several years. Turn on the radio -- get a newspaper." That was the day of Hiroshima with its dreadful consequences -- death, and morbidity, sickness, destruction, and a lasting question of morality.

Fine china had been made there in Hiroshima, and I facetiously asked one of my colleagues, Austin Brues, who was in the Biology Division of the Metallurgical Laboratory and who was going to Hiroshima after the blast, to bring me the few pieces we needed to restock our set for our table. He did -- a cup and saucer that now was a single misshapen mass and a sugar bowl with the lid cockeyed and welded half open. More briefing was forthcoming from Hilberry, Wollan, Edward Creutz , and others, and at each briefing the magnitude and the seriousness of the health hazards to all scientific personnel from penetrating radiations and from the many radioactive atoms produced in fission became more obvious and more alarming.

It was clear that, as a physician, I first had the duty of arranging space to examine all employees of the Met Lab. No one escaped a thorough physical examination, a urine test , and complete blood counts. I recall personally examining many of the great experimental and theoretical physicists and chemists among whom where Fermi, Teller, Franck, Hogness, Zachariason, Szilard, Zinn, Leone Marshall, and Seaborg. I found out which of them had a wooden leg by simple inspection, not by --failing to feel an anterior or posterior tibial pulse. Local professorial help was mobilized for examinations because scientists, technicians, guards, secretaries came to Chicago by the hundreds. We had to set up individual schedules for intital and repeat exams for each individual, depending on his or her work area, and on the potential exposure each might receive to penetrating radiations, radioisotopes, and toxic chemicals. To facilitate all this, we had a special area set aside for physical exams, with specific appointment times that we adhered to rigidly. Could you imagine having Enrico Fermi, and especially Leo Szilard [1] wait for an hour in the clinic? The same procedure was used for the laboratory exams. Mrs. Edna K. Marks, a nurse and superb lab technician whom I hired, was in charge, and we gathered many more experienced among which was Evelyn Gaston.

Why did we do so many repeat histories, physical exams, and lab exams? Simply because, at that time, there was no way of mass monitoring radiation exposure, except by observing changes in the skin, especially on the fingers, and in the blood count. A fall in the white counts, and especially a reduction in lymphocytes, was the most sensitive and reliable biologic evidence of exposure at that time.

However, the problem of monitoring the extent of individual exposure was tackled promptly by a group of the old cosmic ray physicists, including Drs. Volney Wilson, Wollan, Jesse, and Shonka, all of whom were experts at radiation detection work with the machine shop's production efforts, badges with sensitive photographic film, pocket electrometer dosimeters, and a variety of radiation detection meters became available. And with the availability of monitoring equipment it became possible to recruit radiological physicists, such as Rose, Morgan, and Parker, under whose leadership an effective health physics monitoring system was established.

At this point you might well ask, "Why did the decision to involve medicine and biology not come long before 1942? Why weren't informed physicians and biologists consulted during the period when feasibility studies and the many committee meetings of physicists, chemists, and engineers were going on?"

Perhaps I can best answer this question by stating that it took innumerable experiments to determine whether a sustained controlled atomic reaction could, in fact, be achieved. Could natural uranium be produced in a pure form and in a sufficient quantity so that a pile could be built? What material would be used to slow down the fast neutrons and to enhance their capture by uranium-235? As we now know, graphite was found to have acceptable characteristics for this purpose.

By the end of 1941, small amounts of money (in the tens of thousands of dollars) had been authorized and used for various studies related to the ultimate goal of an atomic bomb. It was not until December of 1941 and January and February of 1942 that decisions emerged, one after another, involving the President of the United States and his advisors. These advisors included many individuals, some of whom were on The University of Chicago faculty: Fermi, Compton, Szilard, Allison, Bush, Conant, Sachs, Einstein, and many others. The decision was made to proceed with all haste, with not just one approach, but several, to the production and separation of fissionable material. [2] There was the uranium-235 gaseous diffusion separation work being done at the University of California at Berkeley. And there was the plutonium production work at The University of Chicago under Glen Seaborg. The isotope separation projects ended up with production plants at Oak Ridge. The plutonium work moved from the natural uranium graphite pile under the stands at Stagg Football Field to a pilot plant operation at Oak Ridge and the final production facilities at Hanford, Washington. The decision to proceed with an all-out approach was related to the fact that there was reason to believe that Germany was involved in a similar program and might be well ahead of us.

During the last half of 1941, those working on the project became reasonably confident, but still were not sure, that a chain-reacting pile could be achieved. The same was true with the other projects involving different approaches that; were being tried elsewhere. Experiments done in the late fall of 1941 and early January of 1942 made success appear much more likely, and the decision was the made in Washington to locate the first experimental pile in Chicago under the direction of Arthur Compton.

By early February 1942, Fermi, Szilard, Wigner, Allison, Wheeler, Breit, Mulliken, Manley, and their co-workers were either in Chicago or on the way. Shortly, this core of physicists was joined by a similar cadre of chemists, McCoy, Spedding, Franck, Seaborg, Johnson, Boyd, Coryell, and Burton and co-workers and by the key engineers, Tom Moore and Miles Leverett. The Metallurgical Laboratory was rapidly assuming at least a semblance of effective organization under such leadership, and its professional and operational staffs were growing almost explosively in the early months of 1942.

When I asked Norman Hilberry how and why the Chicago operation got its name, he responded "The decision to name the project the Metallurgical Project and the laboratory operation at The University of Chicago the Metallurgical Laboratory was made as a security measure to cloak its real nature." There had been casual talk for years that, since Metropolitan Chicago was a center for the metallurgical industry, the University should recognize some sort of obligation to it by establishing a Metals Institute. Here was the chance to fulfill that obligation and effectively hide what was actually going on. No one would have believed in January 4, 1942 that this obvious project in physics and chemistry would, within six months, be hiring metallurgists like mad in order to solve the really crucial problems being faced in the design of production piles.

While my initial assignment to the project came as a result of Compton's long research experience in the field of x-rays and consequent realization of the health hazards involved, the true immensity of the problems was not recognized at the start. I was the lone-physician-scientist on the project staff in February 1942, and I believe I was the first to be officially a part of any of the related nuclear weapons projects. [3] In April of 1942, this situation changed suddenly and dramatically.

Norman Hilberry told me that, at that time, pile design had progressed to a point where the shielding design group became deeply concerned with the magnitude of the radiation control problems posed by the core of an operating nuclear chain reaction pile. Not only was the radiation generated enormously greater than anything ever experienced before, but hundreds of new radioactive isotopes would be formed which would have to be dealt with in the chemical processes required to recover plutonium from the irradiated uranium. In prior experience, a ten-gram radium source was about the most intense radiation emitter for which there was valid biological and medical data. The intensities being computed for the core of an operating production reactor were the equivalent of thousands of tons of radium, some hundred million times greater.

Hilberry that Creutz came into his office one morning in a highly agitated state. He first broke the news about the magnitude of the radiation health problem and then pointed out the imperative need not only to monitor present staff and future operations personnel, but also to gain a far more profound knowledge and understanding of the interaction of radiation with living systems and of the behavior of radioactive isotopes introduced into living systems than existed at the time. Hilberry passed the word on to me and to Compton. Both Hilberry and Compton had realized that there would be radiation problems, but both were startled at their magnitude. Compton immediately assigned Hilberry the task of getting an active bio-medical program under way.

It was clear that such a program would have to go far beyond supervision of health surveillance. It would have to undertake the study of the biological effects of fission products -- fast and slow neutrons, gamma rays, x-rays, beta rays -- and the even larger problem of the many fission product radioisotopes that are the byproducts of the fission chain reaction which produces plutonium, the element that the whole Metallurgical Project was about. (It had been even in 1941 that, if but a very few kilograms of plutonium were produced and purified and if fission by fast neutrons could be induced, an explosion with a destructive power equivalent to that of some tens of thousands of tons of TNT was possible.)

As the outlines of the necessary biomedical program became clear, Compton approached the selection of personnel in a rather unusual way. He already had me in place invited or, and my show was in operation. It was rumored that Compton had shall we say, persuaded two individuals to join the Met Lab in 1942, each of whom thought he was to be head of the Health and Biology program. He more or less simultaneously invited both Dr. Kenneth Cole and Dr. Robert Stone. Hilberry recalls, "Creutz and others, as you might well guess, were demanding that a biophysicist head the project to ensure adequate appreciation of the radiation effects. Kenneth Cole's name came up. He was one class behind me at Oberlin, where his father was dean of men. I knew him very well. Compton ok'd the choice; I got Cole on the phone and he came out. He and Compton had a long session, and Compton hired him. Cale had properly stressed that he could not be responsible for the medical aspects. Compton got to thinking about this and realized that medical credibility was not only going to be essential for the health surveillance activities, but would also have to be part and parcel of the whole radiobiological program. So he called Stone. Stone came and Compton persuaded him to join up. After Stone left, Compton opened the door from his office to mine and said, "Norman, I seem to have hired two men for the same job. Will you please straighten it out. In wartime it worked."

Dr. Stone, Head of Radiology at The University of California (San Francisco), had collaborated with E.O. Lawrence in using fast neutrons generated in the Berkeley cyclotron to treat a variety of diseases, such as cancer and severe arthritis of the spine. Blood counts and other tests had been done on these patients. Later in 1943 and 1944, as these exposures continued, Stone asked me to review the case histories and to see some of the patients, but primarily to explain carefully the effects of the fast-neutron therapy on the blood and blood-forming tissue of the recipients. The damage to some of these patients was severe, and the trial with fast neutrons was discontinued. Only in the past few years has interest in the use of fast neutrons been revived, and several medical centers in this country, including The University of Chicago, are again conducting trials with fast-neutron therapy.

Dr. Cole, a physicist, had spent years working on nerve conduction and other problems in biology that required a physicist-biologist type. At Columbia, he had collaborated with Ross Golden on calibration of x-ray therapy machines and related equipment.

Here, briefly, is part of Cole's account of his Chicago experience. "I got a call to come to Chicago for consultation. Compton and Hilberry told me the story of nuclear fission and demanded that I take charge of the biomedical problems. I knew at least how to start after convincing them I could and would not take the medical responsibility. It was an exciting four years; we grew exponentially to a biology staff of nearly 400 before splitting in part to Site X, Oak Ridge."

"It took six months to get our lab in operation in a lionized stable of an extinct ice plant south of the Midway, called site B, and it was expanded twice. We had cyclotron-produced radioisotopes and the availability of 250 kV x-ray machines for radiobiologic studies; but that was it until I got one of the first practical hunks of uranium-238 from Spedding just before the Stagg Field pile critical. When the Corps of Engineers took over and the battle for survival of a truly biological program began with General Groves on the one hand and DuPont on the other. I'll never forget the time when fission products became available and George Svikla and I decided to try a radio autograph for fission product dose. An exposed guinea pig was frozen, sawed into thick sections, and reassembled with x-ray film between sections. Svikla watched as the machinist cut the guinea pig in slices using leaded gloves etc. and then carefully replaced the band-saw blade. I stole H.J. Curtis from a Hopkins Aviation project, and he later became my counter-part at site X, Oak Ridge. I Everything was a tightly programmed, but after Hiroshima and Nagasaki, the Chicago radiobiology program all blew up as the Argonne National Laboratory came I into being. Everyone had his pet hate that he kept to himself until the war was won. War is so disgusting, so futile."

Simeon Cantril, a radiotherapist, was brought here by Dr. R.S. Stone from Swedish Hospital in Seattle. Cantril recruited Dr. and Mrs. Nickson to collaborate with him not only on health effects monitoring, but also on programs he initiated at Sloan-Kettering in New York, at Michael Reese Hospital and The University of Chicago on the effects on man of various doses of whole-body x-irradiation. At that time, x-ray therapy was used almost exclusively for treatment of localized in areas of the body. Dr. Albert Tannenbaum was asked and did initiate a comprehensive program on uranium toxicity in rodents at Michael Reese Hospital. I have made reference to the rumor that Dr. Stone and Dr. Cole both came to Chicago thinking they were to be the director of biology and medicine; but it all turned out well without any obvious friction. Dr. Cole became head of all biological investigations; Dr. Cantril, after working for a time in Chicago, went to become head of medicine at the Oak Ridge Laboratory, and I became Stone's right or left hand man who was involved in both biology and medicine under Dr. Stone. He and I shared a small suite of offices in Eckhart Hall, where Compton's office was located.

Also invited to join the Met Lab was Ray Zirkle, a radiobiologist from - Indiana University in Bloomington, who brought with him several of his colleagues and graduate students, including Eric Simmons and Charles Hagen. Drs. Zirkle and Simmons, Mrs. Marks, and I teamed up on many studies, but our principal collaborative study was a project on the comparative biologic effects of these penetrating radiations. Dr. Zirkle and I had rabbits and mice in the uranium pile room before, during, and after the atomic reactor in Stagg Field went critical. These animals were monitored at frequent intervals for blood count changes, just in case physical monitoring failed. Both Dr. Zirkle and I have often told this story partly to indicate that there was biological monitoring, but always adding the fabricated story that, since no biological changes were noted in the exposed rabbits and rodents, we sacrificed and ate half of the control rabbits because of the existing meat shortage.

To accommodate the expanding medical and laboratory examinations, we acquired, in late 1942, a three-story building called then the Maude was adjacent to Billings Hospital, but has since been torn down. Later Dr. J Garrott Allen took over the supervision of the Metallurgical Laboratory Health Clinic and became active as well in the study of the effects of penetrating radiations on blood coagulation. Temporary buildings were constructed on the North campus for plutonium chemistry, including separation of this element from the fission mixture and for other chemical studies related to the original objectives. The Jones Chemistry Building was used initially and has become a national monument because a great deal of the early work on plutonium was done there by Glen Seaborg and others.

When the great historical event occurred in Stagg Field on December 2, 1942, all things were go. Plans for pilot plutonium reactors at the Argonne Forest Laboratory and at Oak Ridge were under way, and plans for large-scale plutonium production reactors to be located in Hanford, Washington, were progressing. At about this point, the Army Corps of Engineers under General Groves took over. The whole operation, including the medical division here in Chicago as well as Oak Ridge, remained a civilian operation under The University of Chicago, but we were all reporting to the Army Manhattan Engineers. Colonel Stafford Warren, then of the University of Rochester, and Captain Hyman Friedell were the Army medical representatives, with whom we were in frequent contact.

Since the various plants were to become operational, it became a necessity for Chicago to be a training ground for almost every aspect related to the eventual goal of producing the plutonium for atomic bombs. We conducted hundreds of experiments on fission products, including lethal ranges, general metabolism in the body, localization of fission products in the body, methods of reducing the body burden of these radioactive atoms, and treatment of any overexposure, whether it be from external sources or from ingested, inhaled, or injected fission products. Dr. J. Nickson supervised the administration of minute quantities of plutonium to two patients who had terminal cancer, in order to study its behavior in man and to make analyses for Pu body burden possible.

Mrs. Marks and I personally trained the medical technical personnel and helped set up the medical labs at Oak Ridge and Hanford. With Dr. Egon Lorenz, I was deeply involved in large-scale experiments at the National Cancer Institute in Bethesda, Maryland. The NCI experiments had a single objective - the lifetime exposure of groups of inbred mice and guinea pigs to daily doses of 0.1 to 8.8 roentgens. The purpose was to determine whether the then accepted permissible dose of 0.1 roentgen per day was indeed safe. We monitored the incidence of cancer at these levels and the effect on the peripheral blood. Other general clinical and pathologic effects that might obtain were monitored and involved, among others, the collaboration of Walter Heston, Thelma Dunne, M. Shrinker, Margaret Deringer, Allan Eschenbrenner, and Jane Doniger. The lowest dose, one tenth of a roentgen per day, produced no statistically significant changes in the peripheral blood counts of the animals, but ovarian tumors developed in many of the female mice after several years of exposure. [6] All the other doses, which were higher than 0.1 roentgens per day, produced significant effects on the blood counts and greatly increased the induction of tumors.

It was an exciting time. I had to travel considerably because of my involvement with research at the Cancer Institute in Bethesda, and my supervisory and consultation responsibilities in the medical labs on the Chicago campus and at Oak Ridge and Hanford. It was an unforgettable experience to be present when the first large pilot plutonium plant went into operation in Oak Ridge, and when the first massive plutonium reactor plant went into operation at Hanford. Almost equally breathtaking was the first visit to the huge plutonium separation facility in Hanford that received the "hot" uranium rods when the fission process of the U-238 had reached a plateau. By a simple, yet ingenious remote-control method, the purified plutonium was separated from the other byproducts of fission. These hundreds of radioactive isotopes were a nuisance in one sense, since the only objective of the project was to recover plutonium. But eventually some of these byproducts became a boon to biology and medicine.

In early 1943, when plans were well under way not only for plutonium production and separation, but also for other methods for the separation of U-235 under Harold Urey and E.O. Lawrence, we at Chicago were still recruiting scientists, technicians, and other supporting personnel for our biomedical staff. One incident related to recruitment of scientific medical staff members continues to amuse me whenever I think of it. Dr. Compton knew Cecil J. Watson, head of medicine at the University of Minnesota -- probably through Watson's connections at the National Cancer Institute, of which Compton was a director. He talked to me and Stone about recruiting Watson. I had known Watson through medical circles, but also because he had done some work on the effect of pelvic x-irradiation of women with genital cancer. He had not only studied their blood counts and found that they developed leukopoenia and anemia, but also uncovered some unusual new findings relating to porphyry metabolism. We agreed that it would be a plus if we could get him full or part time. Since Dr. Watson was a V.I.P. type, University of Chicago president Robert Hutchins invited him to dinner. Dr. Watson had agreed to spend every third week in Chicago on the condition that he could bring several associates to Chicago and set up a program on the effects of radiation and other noxious substances on porphryin metabolism. In discussing this and trying to persuade Watson to come, Hutchins told him at dinner what the Met Lab was all about, and that it was absolutely essential that we have here a prestigious man of medicine known the world over for his clinical acumen and his great research accomplishments. "Dr. Watson," he said, "you've just got to join us -- we need you. All we have in medicine and clinical research is a radiologist from California" (that was Dr. Stone) "and a damned young intern from Billings (that was L.O. Jacobson)." Since I wasn't at that dinner, I had no chance for rebuttal. Dr. Watson thought that statement by Hutchins was so funny that he told me the story the next day. I had gotten to know Robert Hutchins very well because of many conferences in his office about problems involving matters of space and personnel recruitment or just to give him information on progress.

One evening, I was at a private dinner with Hutchins and others. At the proper time, when he and I were chatting in one corner of the room, I said, "I understand that the way you finally got Cecil Watson to join us was to tell him that you were extremely worried since the only physicians you had were a radiologist from California and a damned young intern from Billings." His reply came without hesitation. "Yes, Jake, that sounds like something I might well have said."

Progress reports from all parts of the project were required. Some were prepared every day, others were expected at less frequent intervals. Robert Mulliken was in charge of the information service -- all documents went through his office. He had the able assistance of Hoylande Young, Herman Fussler, and others. Eventually, these thousands of documents were the basis for a permanent record called the National Nuclear Energy Series. [3] I mention this part of our activity as a reminder that there was a time when even more progress report writing was required than today. Therefore, I am amused by the discussions I hear and the editorials I read on the awful chore imposed on researchers who must spend so much time applying for and reporting on work they are doing under government and foundation grants.

Hutchins brought Lawrence Kimpton to The University in 1943 as business administrator of the Met Lab. He had his office in Eckhart. His worries and problems involved vast Chicago enterprises on campus, and at the new Argonne Forest site, management of Oak Ridge (site X), and responsibility for many other large subcontracts. How could he help but worry, since he was not only dealing with the Army (General Groves) and private industry, but also with a very large number of prima donna academic types on campus collected from universities the country over, as well as from Canada and England? Some years after the war, Lawrence Kimpton became chancellor of The University of Chicago. While Enrico Fermi and colleagues worked on and finally achieved a  self-sustaining pile and then were occupied with the thousands of problems involved in the planning and building of pilot and production piles at Oak Ridge and Hanford what was Mrs. Fermi doing? Well, I can tell you what she was doing a good part of the time. She was a nurse's aide in my clinic. Even with my Met Lab responsibilities, I was the Head of the Section of Hematology at The University, so I had a clinic and a hospital service independent of the Met Lab Health Service. There Mrs. Fermi worked with me for a number of years. She had a natural outward beauty, as well as an inward beauty that was apparent to all of us. Our patients loved her; her face radiated peace, love, and hope.

The secrecy surrounding Met Lab activities somehow became a part of one's being. Wives and friends and non-Met Lab scientific colleagues didn't seem to be pushing for information. Almost the entire scientific community was involved in one aspect of war work or another; perhaps they were too preoccupied with their own tasks and their own adherence to secrecy to be overly concerned with the Met Lab, even with its obviously enormous size in terms of space and manpower.

Meetings were often held during the day in the Eckhart Hall conference room near Compton's office, attended by the leaders of various aspects of the project's efforts. These meetings were held for discussion of progress and exchange of ideas. Attendance was largely confined to individuals such as Fermi, Szilard, Hilberry, Franck, Spedding, Seaborg, Wigner, Allison, Doan, and others who had crucial responsibilities. Latimer or one of his staff at the University of California and Chapman or one of his staff at M.I.T. would come in and report quite frequently. Either Dr. Stone or I or both attended most of these meetings, since it was essential that we have a reasonable grasp of the real and potential health hazards that were emerging. Occasionally meetings were held in a classroom at Eckhart or in Rosenwald, at which a larger number of the scientists from various sections of the project were present. At these meetings, Compton or General Groves would stress the urgency of the mission and give some general information on the current status of achieving their goals. General Groves actually teased the Met Lab personnel on occasion by suggesting that other methods of obtaining pure fissionable material, such as the electromagnetic separation of U-235 being carried out at Oak Ridge, might succeed before the Chicago group working with DuPont would achieve large-scale plutonium production and separation.

Some people who attended these meetings in Eckhart and in Rosenwald were extremely worried lest the relatively few guards at the doors might be overcome by saboteurs who, with a few hand grenades or other methods would destroy the leadership of the whole Chicago program. For example, the late Dr. William Bloom, a distinguished member of our faculty, was extremely concerned not only about security in terms of spying and careless leakage of secrets, but also about sabotage. When he came became obvious to me in Eckhart, he asked me more than once whether I was certain that the offices weren't bugged.

Of the many war-related research projects that existed on campus, some were clothed in secrecy; others were less restricted. The toxicity laboratory, directed by Dr. Franklin McLean, was a large research operation under the auspices of the Army Chemical Warfare Service. Dr. John Hutchens, who later became Director of the Toxicity Laboratory, was deeply involved in this program. A number of Met Lab personnel had access to the Toxicity Laboratory's work on war gases. This contact was important to our work on atomic energy, since the biological effects of some of the war gases mimicked those of radiation.

E.S. Guzman Barron, a biochemist in the Department of Medicine, was interested in the effect of penetrating radiations and chemical warfare agents on enzyme systems and protein synthesis. He wrote a secret report, to which I had access, on his observation that nitrogen mustards as well as irradiation had an inhibitory effect on protein synthesis in vitro. He also observed that this effect could be reduced by the addition of glutathione to the mixture. After the war, Harvey Patt, who worked here in the Met Lab during the war and moved to the Argonne National Laboratory, reported the important observation that this class of chemical compounds, when given to laboratory animals (mice and rats) before they were irradiated, markedly reduced the mortality of recipient rodents, even after exposure to doses of x-radiation that were in the lethal range.

My interest in war gases was stimulated by Dr. Barron, but especially by the work of Dr. Clarence Lushbaugh and his colleagues in the Toxicity Lab. Dr. Lushbaugh was concerned with morbidity, mortality, and general pathological effects of HN2 [methyl-bis (beta-chlorethyl) amine hydrochloride]. The effect on the blood and blood-forming tissue was an important part of his observations. At a secret seminar one afternoon in Janury 1942, Dr. Lushbaugh suggested to me that he and I should try this nitrogen mustard on patients with cancer of the blood (leukemia, Hodgkin's disease, etc.). On the basis of his data on mice, rats, and rabbits, and his continuing counsel, we finally decided that a dose which was safe (in terms of mortality), but large enough to damage blood-forming tissue, was in the range of 0.1 mg to 0.2 mg of HN2 per kilogram of body weight. This compound is unstable when dissolved in water or body fluids. It changes rapidly to a form that has relatively little biologic effect. Accordingly, one dissolved the material in water or saline and injected it immediately I.V.

In early March 1943, the first patient was selected for trial. He was a patient with lymphatic leukemia who had failed to respond adequately to radiophosphorus and x-ray therapy. I received the HN2 from Dr. Lushbaugh, who weighed out the material on an ordinary balance. We dissolved it in sterile saline and immediately injected it in the patient's antecubital vein in the right arm. The dose was 0.1mg/kg.

It may be difficult for many to understand the deep concern one has when one is giving an extremely toxic, but potentially therapeutically effective chemical to a patient for the first time. True, one has the advantage, in a deliberately planned human experiment such as this, that the dose is controlled or calculated from experience with animals and from knowledge of all the specific organ and systemic effects of a wide variety of dose schedules. Human beings generally, but not always, respond to a drug or to a toxic substance in a way similar to animals. Therefore the first trial is inevitably a time of great concern. Obviously, to proceed with this clinical trial, we had to obtain the permission of Dr. George Dick (Chief of Medicine) as well as Franklin McLean, the Director of the Toxicity Laboratory. Dr. Dick was experienced as a clinical investigator, and his cautious supportive role in the venture cannot be overemphasized. The participation of Dr. Charles Spur and Dr. Taylor Smith, as part of the clinical research team, was essential. Dr. Lushbaugh's vast biological and pathological experience with the nitrogen mustard gases in general, and with the particular one we employed (Methyl-bis) was a constant observer and advisor and, in fact, must be credited not only with the idea to proceed, but with invaluable suggestions on dose schedules and possible toxic manifestations of the drug.

After I gave the injection, I remained with the patient for twenty-four hours. Within fifteen minutes, the patient became extremely nauseated and for several hours had severe vomiting; but about eight hours after the injection, he was able to drink water, although he had no appetite. All vital signs were normal and remained so. Two and four days after the first injection, the same dose was repeated. Each time, severe nausea and vomiting followed. But the high blood count came down, and the leukemia-infiltrated lymph nodes and spleen became smaller. The patient definitely had a remission.

The first dramatic therapeutic effect came when we treated a patient who had a classical case of Hodgkin's disease (a cancer affecting the lymph glands). The patient had been treated repeatedly with the only method available at that time, in 1943 -- x-ray therapy. The x-rays were applied to the lymphoid masses wherever they could be found by palpitation or x-ray examination. Up to 1943 x-ray treatment alone was rarely curative, but it did occasionally produce remissions for months or years. When x-ray therapy failed to produce a remission, the patient often had daily spiking fever up to 104 degrees, drenching sweats, no appetite, and other symptoms related to more general tumor invasion of organs and tissues.

We decided to give this patient an injection each day for four days. Again the dose was 0.1 mg per kg body weight. The patient had the usual nausea and vomiting after each dose, but within six hours after the first dose, his temperature returned to normal. The lymph nodes grew smaller and eventually disappeared. The patient achieved remission, and he was able to return to work and live normally and happily for many years. A spectacular therapeutic triumph like this did not occur in every patient treated with HN2, but the combination of x-ray therapy and nitrogen mustard was a tremendous step forward.

What I have just described involving HN2[(beta-chlorethyl) amine hydrochloride] represents a brief summary of the first therapeutic trial of a particular mustard gas in the therapy of the leukemia-lymphoma group of disease an experience very helpful to our extensive work with radiations and radioactive fission products. The cure rate for these diseases has been greatly in increased because over the years since 1943, because over the years since 1943, many new chemotherapeutic agents have been added to the previously available armamentarium. The cure rate for Hodgkin's disease today is in the neighborhood of 75%.

As pointed out by Gilman [7], numerous laboratories were set up at universities throughout the United States in the early 1940's to study chemical warfare agents under the auspices of the U.S. Office of Scientific Research and Development (OSRD). In late 1942 and early 1943, Thomas Dougherty, working with the Yale group, administered one of the nitrogen mustards (tris chloroethyl amine) to mice of the Gardner strain that had lymphosarcoma. He found profound regression of the tumor. Dr. Gustav Lindskog joined Drs. Gilman, Goodman, and Dougherty in conducting a clinical trial using the Tris compound on patients with a variety of malignancies who were in the terminal phase of their disease. One of these patients had a lymphosarcoma, and a marked reduction in the tumor mass was noted. However, as Gilman noted [7], this group of basic and clinical investigators abandoned further clinical studies because of other pressing problems related to the war effort.

In July of 1943, Dr. Milton Winternitz called a meeting at Yale at which I reported detailed clinical findings on the patients we had treated at The University of Chicago by using a different nitrogen mustard, namely, the "bis" form.

Thus, the independent clinical investigations of the Yale group and the Chicago group, each working with nitrogen mustards, but of different chemical structure, became known to other investigators who were engaged with chemical warfare agents under the wartime secrecy restrictions imposed on such endeavors.

After this meeting, clinical scientists, including Lloyd Craver from the Memorial Hospital in New York, referred patients with Hodgkin's disease to me for treatment. Craver later came to spend some time with our group in Chicago to familiarize himself with our results and our protocols. He and others then began to use the bis compound in their own chemotherapy practice. Use of the tris compound was essentially abandoned, since its toxicity was greater than that of the bis form. As it turned out, serendipity had played an important role in our Chicago project; we had chosen the bis compound for clinical trial, and it became the nitrogen mustard of choice for years to follow. Since the research work (biological and medical) was classified as secret, the charts of our patients simply recorded that substance x had been injected at x time in x quantity. I reported our findings at the annual meeting of the Association of American Physicians in May of 1946, and soon thereafter a number of publications on the subject appeared. [8,9,10]

Lest you think that I abandoned working on radiation and radioactive materials while doing the work on mustard gas, let me mention one experiment done in 1943 that was the basis for everything I have since done in the laboratory. It was a simple experiment. I had shown in 1940 that repeated injection of estrogens would increase ossification of the bones of mice, but that any resulting reduction in blood formation was compensated for by an increase in blood formation in the spleen; thus, no anemia occurred. However, the extra medullary blood cell production in the spleen, though significant, was not spectacular.

We now had available one of the most dreaded of the fission products, 89Sr, a beta-ray emitter. This radioisotope is physiologically interchangeable with calcium. Thus, after being injected in mice, it is localized almost exclusively in the bones, where all of the formed cellular elements of the blood except lymphocytic cells develop. The cells produced in the bone marrow are mainly red cells, polymorphonuclear leukocytes, and platelets. A single dose of 2 microcuries of 89Sr per gram of body weight, given intravenously to the mouse, completely destroys the bone marrow. Unexpectedly, however, a dramatic finding came out of the experiment. The mice whose bone marrow was destroyed did not become anemic; their platelet counts as well as their leukocyte counts went down, but remained high enough to prevent fatal hemorrhage or overwhelming infection. What was the reason? The nature of the beast was revealed. The mouse spleen, a small organ in the left upper abdomen that weighs a few milligrams, took over blood formation as quickly as this function was destroyed in the bone marrow by radiostrontium. [11]

My biology friends couldn't believe my findings, but those of us who were clinicians knew that this very thing happens spontaneously, although rarely, in the human being. As a part of the natural history of the disease called polycythemia rubra vera (a disease in which the affected individual makes more red cells than needed and in which the blood becomes as thick as syrup) a small percentage of the patients, perhaps as many as 10% develop calcification and fibrosis of the bone marrow, but the spleen may take over blood formation, and this provides partial to adequate compensation. We don't know why this extra-medullary production of the blood elements doesn't occur in all human patients who develop calcification and fibrosis of the marrow. We don't know why it invariably happens in the mouse and minimally in rats, rabbits, and dogs. We do know that, in embryonic life in practically all mammals, the spleen, liver, and even a few other tissues are important factors in fetal blood production. Shortly before or shortly after birth in man and in rodents, blood formation except for formation of lymphocytes is taken over almost completely by the bone marrow.

The bone marrow destruction by 89Sr, with rapid splenic take-over of blood formation, was an exciting experiment; but the questions it raised immediately were -- how did the spleen have enough sense to take over? What was the nature of the message that instituted this splenic transformation? This question intrigued me and my colleagues and students, and in the years that followed, we found some of the answers. We gave adult mice a lethal dose of total-body x-radiation (1,000 roentgens), but we surgically exteriorized the intact spleen and shielded it in a lead box during irradiation. These lethally irradiated animals all lived. Not only did the shielded spleen increase blood cell formation as occurred in the 89Sr experiment, but blood formation in the bone marrow and lymph nodes returned to normal within 8 days after irradiation. So, we reasoned that something from the shielded spleen was capable of preventing the death of lethally irradiated mice. Our next step was to give the mice a lethal dose of x-rays, to transplant small slices of splenic tissue into the peritoneal cavity, or to give intravenous injections of mashed spleen or embryo liver suspended in saline. Again the irradiated mice survived. To my knowledge, this was the first time that anyone had saved a life of a lethally irradiated animal. [12,13]

As other investigators studied these findings, the life-saving effect of spleen shielding or the transplantation of spleen slices or mash was explained: The cells of the spleen that were shielded or the normal spleen slices or the mashed normal spleen cells injected or transplanted into the lethally irradiated mouse started colonization in the destroyed marrow and lymph nodes and reconstituted the entire blood-forming tissue quickly enough to prevent death. [14,15,16]

Today, these findings are applied not only in people irradiated by accident, but also in patients to whom radiation or chemotherapeutic agents such as nitrogen mustard are given to destroy leukemic in filtration of blood-forging and other tissues. The irradiation-chemotherapy combination may so depress the normal blood-forming tissue that death from hemorrhage or infection or both may ensue unless normal blood-forming tissue from a compatible donor is injected into the patient and blood formation is restored to a more normal level. [17] Additionally, it has been reported that patients with ideopathic "aplastic anemia" will occasionally respond favorably to transfusion of compatible blood-forming tissue. [18]

We still did not know the answer to the question raised above: How does the spleen of the mouse that has had its bone marrow destroyed know that it should start to produce blood cells? Our laboratories worked on this problem and uncovered, after developing appropriate assay methods, some of the mechanisms that control red-cell formation. [19] This process is controlled by a hormone called erythropoietin, and its production is, in turn, controlled by a simple relationship in the body between oxygen need and oxygen supply. If oxygen supply is reduced as in the 80Sr experiment by elimination of red-cell production in the marrow, production of the hormone erythropoietin is stimulated. The increase in erythropoietin is the message that tells the spleen of the 89Sr mouse to begin producing red cells.

Our laboratory also discovered that this essential hormone is produced primarily in the kidney. [20] The large number of investigations and approaches by countless scientists that I believe will eventually help us to understand how to control formation of all the formed elements of the blood.

Meanwhile, work on the production of plutonium proceeded at Hanford, and the separation of U-235 at Oak Ridge. Long before the amounts required for an atomic bomb were reached, the theoretical work on how to construct a bomb with these elements was under way at Los Alamos, New Mexico. The Los Alamos project under Oppenheimer was managed by the University of California, Berkeley, but it too, was under military control. All of the laboratories were in close liaison at high management and scientific levels, but activities at Los Alamos were kept under stricter secrecy rules and controls than those at Chicago, Oak Ridge, or Hanford. When plutonium and U-235 became available, many experiments were done at Los Alamos in which the bomb components were "assembled" for studies of the rapidity and efficiency of the calculated geometry and other factors involved in an instantaneous (micro-second) build-up of fission in plutonium and U-235.

Finally, the amounts of plutonium from Hanford and the U-235 separation at Oak Ridge were sufficient to permit the first practical test of an atomic bomb. Few people here at Chicago or at the other sites were aware of the plans and date of the first test. In the Chicago Health Division, only a very few individuals, such as Dr. Stone, Dr. Brues, Cantril, and I, and some health physicists were aware that, on July 16, 1945, the first test was to occur at daybreak at Alamagordo in New Mexico. Many of you have read the reactions of the individuals who were present and who were responsible for the work that brought this test to fruition.

No one could escape thinking about the potential political, economic, as well as the moral and ethical issues that would emerge once the first self-sustaining atomic reactor became a reality on December 2, 1942. The leadership and supporting scientific personnel of the Met Lab became increasingly aware of the seriousness of these issues as the development of an atomic bomb became more of a certainty. It is a fact the at a communication was prepared by laboratory personnel, signed by many of the leading scientists, and sent in July of 1945 to President Truman, asking that every possible effort be made to communicate with the Japanese and try to persuade them to surrender and thus obviate the awesome consequences of atomic bombing. I assume that President Truman made such an effort, but if he did, the effort failed. The President made the decision to drop the bombs on Hiroshima and Nagasaki.

I quote from the introduction of the report on "The Atomic Bombings of Hiroshima and Nagasaki" prepared by The Manhattan Engineer District, which begins with a statement by the President of the United States: "Sixteen hours ago an American airplane dropped one bomb on Hiroshima, Japan, and destroyed its usefulness to the enemy. That bomb had more power than 20,000 tons of T.N.T. It had more than two thousand times the blast power of the British Grand Slam, which is the largest bomb ever yet used in the history of warfare." The Manhattan Engineers report then goes on: "These fateful words of the President on August 6, 1945, marked the first public announcement of the greatest scientific achievement in history. The atomic bomb, first tested in New Mexico on July 16, 1945, had just been used against a military target."

"On August 9th, three days later, at 11:02 A.M., another B-29 dropped the second bomb on the industrial section of the city of Nagasaki, totally destroying 1-1/2 square miles of the city, killinh 39,000 persons and injuring 25,000 more."

"On August 10, the day after the atomic bombing of Nagasaki, the Japanese government requested that it be permitted to surrender under the terms of the Potsdam declaration of July 26th which it had previously ignored."

Thus the war ended. The Met Lab on campus rapidly became a part of the Argonne Laboratory. Dr. Stone and most of the borrowed professionals returned to the universities or corporations from whence they had come. I was asked to become the Director of Health and Biology during the transition. I accepted, but fortunately Dr. Austin Brues took over in 1946 and remained the Director at Argonne for many years that bridged the passage of the Atomic Energy Act and the establishment of Argonne as a National Laboratory. I returned to my clinical and teaching duties and began, together with scientists the world over, to exploit the newly gained knowledge for research on what is often referred to as "Atoms for Peace."

References

1. L.M. Libby. The uranium people. New York, N.Y.: Crane Russak and Company, Inc. Charles Scribner's and Sons, 1979.
2. H.D. Smyth. Atomic Energy for Military Purposes. Princeton, N.J.: Princeton University Press, (Carey Press Corporation, N.Y.) 1946.
3. R.S. Stone. Industrial Medicine on the Plutonium Project. N.N.E.S. Vol IV, 20, 1951.
4. K.S. Cole. Personal communication.
5. K.S. Cole. Mostly membranes. Ann. Rev. Physiol. 41: 1 - 24, 1979.
6. Nickson, J. Industrial Medicine on the Plutonium Project, Dr. R.S. Stone, Editor, N.N.E.S., Vol IV-20, 1951.
7. Biologic effects of external X and gamma Radiation, Dr. Raymond Zirkle, Editor, N.N.E.S., Vol IV - 22B, 1954.
8. A. Gilman. Theinitial trial of nitrogen mustard. Am. Jr. of Surg. 105: 574-578, 1963.
9. A. Gilman and F.S. Philips. The biological amines and therapeutic application of the b (beta)-chloroethyl amine and sulfide. Science, 409: 1946.
10. L.S. Goodman, M.M. Wintrobe, W. Dameshek, M.J. Goodman, A. Gilman and McLennan. Clinical Experiences with the use of Methyl-bis(b chloroethyl)amine hydrochloride and tris(b chloroethy1)amine hydrochloride (nitrogen mustards) in the therapy of hodgkins disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J.A.M.A., 132: 126-132, 1946.
11. L.O. Jacobson, C.L. Spurr, E.S. Guzman Barron, T. Smith, C. Lushbaugh, G.F. Dick. Nitrogen mustard therapy. Studies on the effect of methyl-bis (Beta-chloroethy1)amine hydrochloride on neoplastic and allied disorders of the hematopoietic system. J.A.M.A. 132:263 -271, 1946.
12. L.O. Jacobson, E.L. Simmons, and M. Block. Effect of splenectomy on toxicity of Sr-89 to hematopoietic system of mice. Jr. of Laboratory and Clinical Medicine, 34: 1640-55, 1949.
13. L.O. Jacobson, E.K. Marsk, E.O. Gaston, M.J. Robson and R.E. Zirkle. The role of the spleen in radiation injury. Proc. Soc. Exp. Biol.. and Med. 70: 740, 1949.
14. L.O. Jacobson, E.L. Simmons, E.K. Marks, M.J. Robson, W.F. Bethard, and E.O. Gaston. The role of the spleen in radiation injury and recovery. The Journal of Lab. and Clinical Med. 35: 746 - 770, 1950.
15. D.L. Lindsley, T.T. Odell and F.G. Tausche. Implantation of functional erythropoietic elements following total-body irradiation. Proc. Soc. Exp. Biol. and Med., 90: 512, 1955.
16. P.C. Nowell, L.J. Cole, J.G. Habermeyer, and P.L. Roan. Growth and continued function of rat bone-marrow cells on x-radiated mice. Cancer Research. 16: 258, 1956 .
17. C.E. Ford, H.L. Humerton, D.W.H. Barnes and J.R. Loutit. Cytological identification of radiation-chimaeres. Nature 177: 452, 1956.
18. P.L. Weiden, S.J. Schlicter, M. Banaji. Marrow transplantation for aplastic anemia and leukemia - review of results and blood product support required. Progress in Clin. Biol. Res. 28: 295-312, 1978.
19. B.M. Camitta, E.D. Thomas, D.G. Nathan, et al. A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood 53: 504-514, 1979.
20. L.O. Jacobson, E. Goldwasser, C.W. Gurney, W. Fried and L. Plzak. Studies on erythropoietin: the hormone regulating red cell production. Ann. N.Y. Acad. Sci. 77:551, 1959.
21. L.O. Jacobson, E. Goldwasser, W. Fried, and L. Plzak. Role of the kidney in erythropoiesis, Nature, 179: 633-34, 1957.

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