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HK®22900Q7 fabricated story that, since no biological changes were noted in the ex- posed --bbits and rodents, we sacrificed and ate half of the control rabbits because of the existing meat shortage. To accommodate the expanding medical and laboratory examina- tions, we acquited, in late 1942. a three-story building called then the Maude Slye Building, which was adjacent,to Billings Hospital but has since been torn down. Later Dr. J. Garrott Allen took over the supervi- sion of the Metallurgical Laboratory Health Clinic and became active as well in the study of the effects of pehetrating radiations on blood coagu- lation. Temporary buildings were constructed on the north campus for plutonium chemistry, inc(uding separation of Rhis~ element from the fission mixture, and for other chemical studies related to the original objectives. The Jones Chemistry Building was used initially and has be- come a national monumedtt because a great dea.W of the early work on plutonium was done there by Glen Seaborg and others. The Ajte>rna!h, of December 2, 1942 When the great historical event occurrhd in Stagg Field on December 2. 1942. all systems 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 opera- tion, including the medical division Faere in Chicago as well as Oak Ridge, remained a civilian operation under the Univetsity of Chicago. but we were all reporting to the Army Manhattan Engineers. Colonel Stafford 1S'arren, then of the University of Rochester, and Captain Hyman Friedell were the Army medical representatives, with whom we were in frequ,ent 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 sou;res or from ingested, inhaled, or injected fissiun products. Dr. J. Nickson supervised the administration of mintite quan- tities nf plutonium to two patients who had terminal cancer in order to study its behavior in man and to make analyses for Pu bvdy burden possible (5). Mrs. Marks atfd I personally trained most of the medical technical personnel and helped, set up the medical labs at Oak Ridge and Han- 204 I L~rn U. farnF+rr. • From Atom to Etv

HK@2290048 I , ford. With Dr. Egon Lorenz, I was deeply involved in large-scale ex- periments at the National (ancer Institute (NCI) in Bethesda. Maryland. The NCI eaperinpents had a single objective.-the lifetime exposure of groups of inbred mice and guinea pigs to daily doses of 0.1-8.8 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. Orher general clinical and pathologic effects that might obtain were monitored and involved the collaboration ot Walter Heston. Thelma Dunne, M. Shimkin, Margaret Deringer. Allen Eschenbrenner, and J.tne Doniger. among others. The lowest dose, 0.1 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 [6j. All the other doses. which tvere higher than 0.1 roentgen per day, produced significant ef- fects on the blood counts and greatly increased the induction of ttpnors. 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 massivee plutonium re- actor plant went into operation at Hanfor-4. 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 pltttonium was separated from the other by- products of fission. These hundreds of radioactive isotopes were a nui- sance in one sense, since the only objective of the project was to recover plutonium. But everitually some of these by-products became a boon to biology and medicine. In early 1943, wheh 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 stafl: 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 NCI, of which Compton was a director. He talked to m,- 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. I-le had not only studied their blood counts and found that they developed leukopenia and anemia, but he had also I PrrsP-lmrs in Btolo~ ernd Sfedvinv • Winrrr 1981 1 205

HK12290049 > uncovered some unusual new findings relating to porphyrin metabolism. We agreed that it would be a plus if we could get him full or part time. Since Watson was a VIP type, University of Chicago President Robert Hutchins invited him to dinner. 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 noxioios aubstances on porphyrin metabolism. In discussing this and trying to persuade Wats~on to come, Hutchins told him at dinner what the Met Lab uas 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 Stone) "and a damned young intern from Billings" (that was L. O. Jacobson). Since I wasn't at that dinner, h had no chance 'for rebuttal. Watson thought that statement by Hutchins was so funny that he told me the story. 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 our progress. One evening. I was at a private dinner with Hutchins and others. At the proper tifne, whecn he and I were chatting and drinking 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 frorqt Billings." His reply came without hesitation: "Yes, Jake. that sounds like something I might well have said " Progress reports front all pans of the project were required. Some were prepared every day, others were expected at less frequent inten•als. Robert Mulliken was in charge of the information service-all docu- ments went through his office. He had the able assistance of Hoylande Young. Herman Fus"sler. and others. Eventually these thousands of documents were the basis for a permanent record called the National Nuclear Energy Series [3]. 1 mention this part of our activity as a re- minder 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 206 1 Lrop O. farobnn - From Alom to Evr

HK82290050 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 cdllected from universiiies the country over as well as from Canada and England% Some years after the war, Law- rence Kimpton became chancellor of the University of Chicago. While Enrico Fermi. Szilard. Wigner, Allison, and other 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. 1..•as the head of the Section of Hematology at the U'niversity, 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 beautv 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 obvi- ously enormous size in terms of space and manpower. Meetings were often held during the day in the Eckhart Hall con- ference room near Compton's office, attended by the leaders of vatious aspects of the project's efforts. These meetings Hrre held for discussion of progress and exchange of ideas. Attendance was largely confined to individuals such as Fermi, Szilard, Hilberry. Franck, Spedding, Sea- burg. Wigner. Allison, Doan, and others who had crucial responsibilities. Latimer or one of his staff at the University of California and Chipman or one of his staff at MIT would come in and report quite frequently. Either 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 class- room at Eckhart or in Rosenwald at which a larger number of the scien- tists from various sectioris of the project were p.resent. At these meetings, Compton or General Groves would stress the urgency of the mission and give some general information on the cutrent status of achievin;'their goals. General Groves actually teased the Met Lab personnel on occasion by suggesting that other niethods of obtaining pure fissionable material, such as the electromagnetic separation of U-2S5 being carried out at Oak Ridge, might succeed before the Chicago group working with DuPont would achieve large-scale plutonium production and separation. Prr*prtisvs fp Brofop ond .Nediriru • tt'intar 1981 1 207

N R12290051 Some people who attended these meetings in Eckhart and in Rosen- wald 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 to visit me in Eckhart, he asked me more thau 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 oper- ati,on under the auspices of the Army Chemical Warfare Service. Dr. John Hutchens, who later beuhme 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 conta..t was important to our work on atomic energy, since the biological effects of some of the war gases mimicked those of radiation. RESEARCH ON NITROGEN MVSTARDS E. S. Guzman Batrnn, a biochemist in the Department of Medicine, wds interested in the effect of penetrating radiations and chemical war- fare 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 chemi- cal compounds, when given to laboratory animals (mice and rats) before thky were irradiated, markedly reduced the mortality of recipient ro- dents, even after exposure to doses of X-radiation that were in the lethal ra nge. My interest in war gases was stimulated by Barron, but especially by the work of Dr. Clarence Lushbaugh and his colleagues in the Toxicity La~,b. Lushbaugh was concerned with morbidity, mortality, and general pathological effects of HNz [methyl-bis (P-chlorethyl) amine hy- drochloridel. The effect on the blood and blood-forming tissue was an important pan of his observations. At a secret seminar one afternoon in January 1942. Lushbaugh suggested to me that he and I should try this nitrogen mustard on patients with cancer of the blood (leukemia, Hqdgkip'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 208 I l.ran O. Joro6ion • F'rom Atnm tu Etr J

HK12290052 was safe (in terms of mortalitj•), but large enough to damage blood- forming tissue, was in the range of 0.1-0.2 milligrams of HN2 per kilo- gram 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 effc~t. Accordingly• one dissolved the material in water or saline and injected it immediately IV. 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 HNz from 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 0.1 milligrams per kilo- gram. 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 ad- vantage, in a deliberately planned human experiment such as this, that the dose is controlleJ 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, re- spond to a drug or to a toxic substance in a way similar to animais. ' Therefore the first trial is inevitably a time of great concern. Obviously, to proceed with this cli,;i:.al trial, we had to obtain the permission of Dr. George Dick, Chief of Medicine, as well as of Franklin McLean, the director of the Toxicity Laboraiory. Dick was experienced as a clinical investigator, and his cautious supportive role in the venture cannot be overemphasized. The participation of Dr. Charles Spurr and Dr. Tavlor Smith as part of the clinical research team was essential. LushbaugFi, with hic vast biological and pathological experienre with the nitrogen mus- tard 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 p-cxeed 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 24 hours. Within 15 minutes the patient became extremely nauseated and for several hours had severe vomiting: but about 8 hours after the itijection, he was able to drink water, although he had no appetite. All vital signs were normal and remained so. -fwo and 4 days after the first injection, the same dose was repc ated. 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 defi- nitely had a remission. The first dramatic therapetltic effect came when we treated a patient who had a classical case of Hodgkin's disease (a cance, affecting the Prrsprrtrt•es m BtologY mul.ltrdinur • n'intrr 1781 I 209 r

HK®2290053 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 whefever they could be found by palpa- tion or X-ray examination. (Up until 7943. X-ray tYeatment 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 ofter6 had daily spiking fever up to 104°, drenching sweats, no appetite, and other symptoms related to more general tumor invasion of organs and tissues. We decided to give this patient an injekon each day for 4 days. Again the dose was 0. l milligram per kilogram of body weight. The patient had the usual nausea and vomiting after each dose, but within 6 hours after the first dose his temperature returned to normal. The lymph nodes grew smaller and eventually disappeared. The patient achieved remis- sion. 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 HNs, but the combination of X-ray therapy and ni¢rogen mustard was a tremendous step forward. What I have just described involving HNs (methyl-bis (P-chlorethyl) ami,rde hydrochloride] represents abrief summary of the first therapeutic ttialof a particular mustard gas in the therapy of the leukernia-lymphoma group of disease, an experience rerv helpful to our extensive work with radiatimns and radioactive fission products. The cure rate for these diseases has been greatly increased sinre 1913 because, over the years, 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 percent. As pointed out by Gilman [7], numerous laboratories were set up at universities throughout the United States in the early 1940s to study chemical warfare agents under the auspices of the U.S. Office of Sci- entific Research and Development (OSRD). In late 1942 and early 1943, Thomas Dougherty, working with the Yale group, administered one of the nitrogen mustards (tris [P-chlorethyl) amine) to mice of the Gardner strain that had lymphosarcoma He found profound regression of the tuo'tor. Dr. Gustav Lindskog joined Drs. Gilman, Goodman, and Dougherty in conducting a clinical trial using the tris compound on pa- tients 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. Howevcr, as Gilman noted [7], this group of basic and clinical imestigators abandoned further clinical studies because of other pressing problems related to the war effort. Id July of 1943, Dr. Milton N'interqitz 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. , 210 1 Lrun o. JarnM,m • from Atom to ftw

1 NK12290054 Thus, the independent clinical investigations of the Yale group and the Chicago group, each working with nitrogen mustards, but of differ- ent chemical strvcture; became known to other investigators who were engaged with chemical warfare agents under the wartime secrecy re- strictions imposed on s,uch endeavors. After this meeting, clinical scientists, including Uoyd Craver frottl the Memorial Hospital in New York, referred patients with Hodgkin's dis- ' ease to me for treatment. Craver later came to spend some time with our group in Chicago to familiarize himself with our results and our' pro- tocols. He and others then began to use the bis compound in their own chemotherapy prartice. Use of the tris compound was essentially aban- doned, 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 bf choice for years to follow. Since the research work (biological and medical) was classified as secret, the charts of our patients simply recorded that substancex had been injected at x time inx quantity. I reported otir findings at the annual meeting of the Associa- tion of American Physicians in May of 1946, and soon thereafter a number of publications on the subject appeared [i;-10]. I:RYTHROPOIETIN RESEARCH 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 produc- tion in the spleen, though significant, was not spectacular. We now had available one of the most dreaded of the fission products. eaSr, a beta-ray emitter. This radioisotope is physiologically interchange- able with calcium. Thus, after being injected in mice, it is localized almost exclusively in the bones. Hhere all of the formed cellular elementsof 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 88Sr per gram of body weight, given intravenously to the mouse, completely destroys the bone marrow. Unexpectedly, howevek; a dramatic finding came out of the experiment. The mice whose bone marrow was destroyed did not become anemict 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. Prrs/wrtkws fn Biologt and.tfrdinne • N'inter 1987 1 211

UK92290055 "The mouse spleen, a small urgaain the left upper abdomen that weighs a few milligrams. took uter biooxf formation as quickly as this function was destroyed in the bone marnow by radiostrontium (111. tis) biolugy friends iuuldti 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 polycythcmia rubra vera (a disease in which the af- fected individual makes more red cells than needed and ir. which the blood becomes as tiiirk as syrup). a small percentage of the patients- perhaps as many as 10 percent-develop calcification and fibrosis of the bone marroa•, but the spleen may take over blood formation, and this provides partial to adequate compensation. We don't know why this extramedullary production of, the blood elements doesn't occur in all human patients who develop calcification and fibrosis of the marrow. We don i 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 mammats, the spleen, liver, and even a few other tissues are impor- tant factors in fetal blood production. Shortly before or shortly after birth in maq and in rodents, blood formation except for formation of lymphucytes is taken over almost completely by the bone marrow. The bone marrow destruction by 89Sr, with rapid splenic takeover of blood fotmatiun, 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 transfor- mation? 'This question inuigued 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 exterioriaed the intact spleen and shielded it in a lead box during irradiation. These lethally irradiated animalc all lived. Not only did the shielded spleen increase blood cell formation, as occurred in the eaSr experiment, but blorxi formation in the bone marrow and tymph nodes returned to norrnal within 8 days after irradiation. So, we rea- soned that something from the shielded spleen was capable of prevent- ing 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 satine. Again the irradiated mice survived. To my knowledge, this was the first time that anyone h4 saved the life of a lethally irradiated animal (12, 13J. As other investigators studied these findings, the life-saving effect of spleen shielding or the transplantation of spleen slices or mash was ex- plained. 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 212 1 L'nn O. f oruhwn • From Atom to Ere

HK02290056 I and lymph nodes and reconstituted the entire bload-furming tissu!• quickly enough to prevent death [ 14-16]. Today these findings are applied not unly in people irradiated by accident but also in patients to whom radiation or chemotherapeutic agents, such as nitrogen mustard, are given to destrov leukemic infiltra- tion of blood-forming 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 biood- 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 fayorably to transfhsion of compatible blood- forming tissue [ 18]. . We still did not know. the answer to the question: How does the spleen of the mouse that has had its bone marrow destroyed know that it should stan to produce blood cclh? Our lah -•ories worked on this problem, and uncovered, after developing approp;iate assay methods, some of' the mechanisms that control red cell formation 119). 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 89Sr experiment by elimitiatiun of red cell production in the marrow, pro- duction of the hortnbne erythropoietin is stimulated. The increase in erythropoietin is the message that tells the spleen of the es8r mouse to begin producing red celle. Our laboratory also discovered that this essential hormone is pro- duced primarily in the kidney [20]. The large number of investigations and approaches being taken by countless scientists will eventually help us to understand how to control formation of all the formed elements of the blood. PLIlTON1UM PRODUCTION PROCEEDS TO TRIAL STAGE MeanNhile, work on the prorluction of plutonium proceeded at Han- ford and the•separation of U-235 at Oak Ridge. Long'before the amounts required for au atomic bomb were reached, the theoretical work on how to construct a bomb with these elements was urnder way at Los Alamos, New Mexico. The Los Alamos project under Oppenheimer was managed by the University of California, Berketey, but it, toD, 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 tinder stricter secrecy niles 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 botnb components /'rysprrtave tn BtoGr& mrd .1)rdrrnu • n'intvr 198) 1 21 3