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N14®22900S7 ! v /A Z7,7- i ~ FROM ATOM TO EVE J ) by LEON O. JACOBSON Reprioted From: Perspectlvo In Biobgy aod Mcdkine Vdnme 2A Namber 2 Wioter 1981

NK12290038 FROM ATOM TO EYE* LEON 0 fACOBSONt In the Beginning In January of 10421 was an assistant in the Department of Medicine at the University of Chicago. One afternoon I was helping an intern catheterize 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 otdrselves as well as the patient. During this medical protedure. I heard my name being called re- peatedly over the t.elepage, indicating an emergency. Since we had now completed our catheterization. I hurriedly removed my gown, scrubbed my hands, and went to the nursing station. The message from telepage' had been taken-it was simply, "Repon to the dean immediately." As a medical student and later as a house officer, I had never had any contact with the dean g office, but I knew that William Taliaferro was the dean, for his face graced the center of every medical class picture on the walls of Billings Hospital corridors. At that moment in my mind's eye I saw him with a stern and sinister look. , As I hurried to the dean's office, I wondered if I had done something wr7ng. Was I behind in summarizing the patients' charts at discharge or death? Was there a complaint from a patient or patients I might some- how 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 could not 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 rbsed door and ushered me in. There sat Itean *Read in part to a private interdisciplinary social club (Stochastics) at the University of Chicago. February 1979., tEmeritus profesmr, Ilepartment of Medikine, Joseph Regenstein pmfessor, Biological and Medical Sciences. University of Chicago. ® 1981 by The Univetsity of Chicago. OOs 1-598281/2402-04Y9S01.00 Pmpertivrs in Biology snd Medkine ' Wint.r 1981 I 195 i

NK12290039 Taliaferro, Dr. George Dick (Chairman of Medicine), Dr. Arthur Bachmeyer (Director of Hospitals and Clinics), Dr. Paul Hodges (Chief of Radi'olugy). 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 rninute: and my mind was muddled up with vague fears and conjectures. "Hcllo, Leon. You know Dr. Dick, Dr. Bachmeyer, and Dr. Hodges, of course; meet Professor Wollah 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 ~ou are the one they need to help them with a special problem they are having in their research." How could I help C:ompton 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 aphysician aud 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 anarnow, the clinical use of radiophos- phorus' for treatment of the leukcmias, research on pernicioas anemia, and the like. Perhaps, I thought, they can't find anyone else, so they have decided I'm it--sounds like routine stuff to me. George Dick looked at me through his penetrating eyes and said, "Your suiroeillance of these scientists will be an exciting adventure in prevenu4e medicine and closely related to your snecial interests in blood and blood-form:ng 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 yourgartieipation in their program is essential to its progreas." What could I say?. I'm sure I had been signed, sealed, and delivered before I even got to the dean's ofl'ice. So I came up with -the dich "e-- "Thank you, I71 be glad to hear more details and will try to do my best." The cotiversation' 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=and 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 $illings, where I shared an office with four cages of mice on which I was conducting an 'I did this r!esearch in collaboration with Louis Slopn, who provided the radiophos• phwus'sp produced m the cyclotron. Dr. Slotin. who lefl the htetallurgical laboratory to join the t.os Alamos staff, was the second individual to succumb to a nuclear accident: this accident occurired 'ni late 1945 atter the Nagasaki and Hiroshima detonations. 196 1 Lron t). faroDn.on Frrom .imom to E:w

HK12290040 experiment. There the briefing began, but it lasted only 15 minutes. I had many questions, and they gave evasive answers to some of them. Finally, they said ihey had to leave because of experiments in p'rogrrss, but I'm quite sure that it was the essence of mice in the room that shortened the briefirdg time. S'oon thereafter, I met them for further information in Eckhart Hall in Wollan's office. The office had a musty smell and I added another ingredient, the smell of mice. 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 appendbx. 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 rne up a wall. I just didn't get the pitch. After the final ex~m, my professor called me in. He wore a long face, and the mofirtent I saw him, my physiognomy resembled 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 frien*lly he became. I soon found out why-=-he would give me a passing grade in physics if I agreed to become a niedical missionary. I never went to Africa, as I'm sure he had in mii{d, but I've kept the promise and preached medicine and meflical sciench every day of my life since that interview. By the way. I had no probiem with the next semester course in physics. While I.+as in med~al school, Dr. Paul Hodges selected me to do the radiography for variotts scientists who were using experimental animals to study diseases like pneumonia and tuberculosis. I developed the films and reported the results as well. In the same room under the supervision of Dr. Jane Hamilkon from the Department of Physics was an X-ray therapy machine for dudies on the biological effects of radiation; with Dr. Hamilton's tutoring, much additional reading, and patient iristruc- tion fr9m Do•. Hodges, I learned a great deal about penetrating radia-/ tions. Perhaos it was this background that had led Hodges, Dick, and Rrbertson 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. Fanally, 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 seerecy, and after I had taken ia, he said, "Suppose you read this paragraph in this physics text:": He handed me the book, arid there, in esseti.ce, 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 a devastating instrument of war-an atomic bomb--was the objective of this project was an over- PersJrwrn-es rn Beolagi and .Nrdutn. • WinUr 1981 I 197 I

Hlc12290041 whelming experience. 1 know I blanched; I know I had a bump in my throat, and for a frtoment at least I was speechless and at the point of tears. To find mysi'lf involved in the effort to split the atom in an atomic pile, and in the awesome codsequences were it to succeed, hit me with my hands down. I realized that by now I was inextricably involved, and I already felt 5 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-dedth and morbidity, sickness, destruction, and a lasting question of morality. Health C,onsideratiores for th,e ScientiJu Personnel More briefing .4as forthcoming from Hilberry, Wollan, Edward Creutz, and others, and at each briefing the magnitude and the serious- ness 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. I It was clear that 2s 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, including Fermi, Teller, Franck, Hogness, Zachariasen, Szilard, Zinn, and Seaborg. 1 found out which of them had a wooden leg by simple inspection, not by failing to feel an anterior or posterior tibial pulse. I found that there was only one woman physicist among all these intellectual giants. She was Leona Woods, a young, brilliant. and beautiful person who has recently written an account of her experience on ihe Manhattan Engineer Project. [See book review in this issue. Eotrott.) Local professional help was mobilized for exami- nations because scientists, technicians, guards, and secretaries came to Chicago by the hundreds. We had to set up individual schedules for inieial and repeat exams for each individual, depending on his or her work area, and on the potential exposure to penetrating radiations, radioisotopes, and toxic chemicals each might receive. 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 ha:ing Enrico Fetmi, and especially Ixo Szilard [1), wait for an hour in the clinic? The same procedure was used for the laboratory exams. Mrs. Edna K. Afarks, a nurse and superb lab technician whom I hireda was in charge, and we gathered many more experienced technicians. ' Why did we doo so many repeat histories, physical exams, and lab 198 1' Lron O. farnAcon • From Atom to Eve

w KM2290042 exams? Simply because, at that time, there was no way of mass- monitoring radiation exposure, except by observing changes in the skin 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. However, this problem 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. With the availabifity of monitoring equipment it became possible to recruit radiological physicists, such as Rose, Mor- gan, and Parker. under whose leadership an effective health physics monitoring system was established. Feasibility Studies At this point you tqight well ask, "Why did the decision to involve medicine and. biology not come long before 1942? Why weren't in- formed 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 in- numerable experiments to determine whether a sustained controlled atomic reaction could, in fact, be achieved. Could natbral 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 [2J. There was the uraniurn-235 gaseous diffusion separation work being done at the Uni- versity of Californi.a~ Berkeley. And there was the plutonium production work at the Univetsity of Chicago. 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 Persqrciaes in Biotogy and Medinru • Wintrr 1981 1 199

HKS2290043 Football Field to a pilot plant operation at Oak Ridge and the final productain 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, these 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 tneire likely, and the decision was made in Washington to locate the first experimental pile in Chicago under the direction of Arthur Compton [2]. By early February 1942. Fermi, Szilard, Wigner, ~llison, Wheeler, Breit, Mialliken, 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 cheniists-McCoy, Spedding. Franck, Seaborg, Johnson, Boyd, Coryell, and Burton and co-workers--and by thf key engineers, Tom Moore and Miles Leverett. The Metallurgical laborAtory was rapidly assuming at least a semblante of effective organization under such leadership, and its professional and operational staffs wcre growing almost explosively in the early months of 1942. The Metallurg'ual Z.aboradory 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 sec urity measure to cloak its real nature. There !tad been casual talk for years that, since metropolitan Chicago was a center for the metallurgical industry, the University should recognize some sort ofohligation to it establishing a Metals Institute. Here was the chance to fulfill that obligation an effectively hide what was actually going on. No one would have bVlieved in January 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 faoed in the design of production piles. MEDICAL ASPECTS While my initial assignment to the project came as a result of COmp- ton'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 stan. I was the lone physiciam scientist on the project staff in February 1942, and II believe I was the 200 1 l.nm O. Jamb.+on ' From A+om to E-

HN92290044 first to be officially a part of any of the related nuclear weapons projects [3J. (The only possible exception was Joe Hamilton in Berkeley, and I don't think he was in then.) In April of 1942, this situation changed suddenly and dramatically. Norman Hilberry told me that, at that time, pile design had pro- gressL-d to a point where the shielding design group became deeply con- cerned with, the magnitude of the radiatiotrt 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; bnt 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 priorexperience, a 10-gram radium source was about the most intense radiation emitter for which there were 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 said that Creuu came into his ofTice one morning in a highly agitated state. He first broke the news about the magnitude of the radia- tion 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 interac- aon of radiation with living systems and of• the behavior of radioactive isotopes introduced into Gving systems than existed at the time. Hilberry passed the word on.to Contpton. Both 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 biomedical program under way. It was clear that such a program would have to go far beyond supervi- sion 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 many fission product radioisotopes that are the by-products of the fission chain reac- tion which produces plutonium, the element that the whole Metallurgi- cal Project was about. (It had been estimated 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.) INCREASING THE STAFF As the outlines of the necessary biomedical program became dear. Compton approached the selection of personnel in a rather unusual PPrVlAVPS tn BIDIOgy QMlI AJP1tf7RP ' WMtPI 1981 1 201

NK®2290045 > I i i . way. He already had me in place, and my show was in operation. It was rumored that Cotnpton had invited, or, shall we say, !rers'uaded, 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 simulta- neously 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. Ken• neth Cole's name came up. He was one class behind me at Oberlin, where his father was dean of men. I knew him tiery 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. Cole had properly stressed that he could not be responsible for the medical aspects. Gompton 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 prograni. So he called Stone. Stone came and Compton persuaded him to join up. After Stone left, Compton opened the door from his office to mirle and said. "Norman. I seem to have hired two men for the same job. Will you please straighten it out?" In wartime it worked. Stone, Head of Radiology at the University of California, San Fran- cisco, had collaborated with F.. O. Lawrence in using fast neutrons gen- erated in the Berkeley cyclotroc tp 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 examine carefully the effects of the fast- neutron therapy on the blood and blood-forming tissue of the necipients. 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 centems in this country, including the University of Chicago, are again conducting trials with fast-neutron therapy. 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 nta,hittes and related equipment. Here, briefly. is part of Cole s account of his Chicago experience (taken from (4) and a personal communication). I got a call to come to C'.hicago for consultation. Compton and Hilberrjr 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 arld would not take the medical responsibility. It was an exciting 4 years; we grew exponen- tially to a biology~ staff of nearly 400 before splitting in part to Site X. Oak Ridg,e. It took 6 months to get our lab in operation in a lysoli7led stable of an extinct tce 202 1 Lro>r 0. fQroGion • from Atom to F.re

HK®229004b f I 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•2J8 from Spedding just before the Stagg Field pile went critical. Then the Corps of Engineers took over and the battle for survival of a truly biological pn,gram began with General Groves on the one hand and tuPont on the other. I'U never forget the time when fission products became available and George Svikla and I decided to try a radioautograph for fission product dose. An exposed guinea pig was frozen, sawed into thick sections, and reassembled with X-ray him 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 counterpifn at Site X, Qitk Ridge. Everything was all tightly programmed, but after Hiroshima and tiagasaki, the Chicago radiobiology program all blew up as the Argonne, National Laboratory came intu 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 Stone from Swedish Hospital in Seattle. He recruited Dr. Nickson and Dr. Margaret 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 at 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 areas of the body. Dr. Albert Tannenbaum was asked to and did initiate a com- prehensive program on uranium toxicity in rodents at Michael Reese Hospital. I have made reference to the rumor that Stone and Cole each came to Chicago thinking he would be the director of biology and medicine; but it all turned out well without any obvious friction. Cole became head of all biological investigations: Cantril, after working for a time in Chicago, went to become Head of Industrial Miedicine at the Oak Ridge Labora- tory, and I became Associate Director of Biology and Medicihte under Stone, He and I shared a small suite of offices in Eckhart Hadl, 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. Edna 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. Zirkle and I had rabbits and mice in the uranium pile room before. ,;uring, bnd after the atomic reactor in Stagg Field went ctitical. These animals were mon- itored at ftrquent intervals for blood count changes, just in case physical monitoring failed. Both Zirkle and I have often told this story, partly to indicate that there was biological monitoring, but always adding the Prrsprrtim in Biotogy and Medirme • Winter 1981 1 203

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

H K1229-0057 were "assembled" for studies of the rapidity and efficiency of the calcu- lated geometry and other factors involved in an instantaneous (mi- crosecond) buildup 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. Feupeople 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, Can- tril, and I, and some health physicists were aware that, on,July 16, 1945, the first test was to occur at davbreak 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 }hat brought this test to fruition. No one could escape thinking about the potential political, economic, moral, and ethical issues that would emerge once the first self-sustaining atomic reactor became, a reality in 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 that a communication was prepared by laboratory personnel. signed by many of the leading scien- tists, 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.l assume Ihat President Truman made such an effort, but if he did, the effort fai:ed. 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 Dis- trict, irhich begins with a statement by the president`of the United States: "Sixteer. hours ago an American airplane dropped one bomb on Hiroshima. Japan. and destroyed its usefulnrcc 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 largcst bomb ever yet used in the history of warfare." The Manhattan Engineers report then goes on: "These fateful words of the Presidet,t on August 6, 1943r, marked the first public announcement of the greatest scientific achievement it) 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-ti's square miles of the city, killing 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:" , 214 I 1,., 0. farnG+on • FromAlomloF.w P I J

NK12290058 In theEnd Thus the war ended. The Met Lab on campus rapidly became a part of the Argonne Laboratory. Stone and dnost of the borrowed professionals returned to the universities or corporations from whence they had come. Iwas 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 rest•arch on what is often referred to as "Atoms for Peace." REFERENCES 1. LlBnv. L. M. The uranium people. Nex York: Scribner's. 1979. 2. S.yI-rH• H. D. Atomic energy for military purposes. Princeton• N•J.: Prince- ton Univ. Press, 1946. 3. STO>,E. R. S. Introduction. In Industrial Medreine on the Plutonitim Project, edited by R. S. STONE. NatL Nucl. Energy Ser. 4, vol. 20. Washington, D.C.: Atomic Energy Commissuon, 1951. 4. CoLL, K. S. Mostly membranes. Annu. Rev Physiol. 41:1-24, 1979. 5. 1/cKso,%. J. Blood changes in human beings following total body irradiation. In Indusnial ,bledicine on {he Plutonium Project, edited by R. S. S•roxr.. Natl. Nucl. Energy Ser. 4, vol. 20. Washington, D.C.: Atomic Energy Commission, 1951. 6. LoaL%z• E. Effect of longcmntinued total body gamma irradiation on mice, guinea pigs. and rabbits. V I, Conclusions and applicability to the problem of human protection. In Btologu EfJeds fj External X and Gamma Radiation, edited by R. ZtRKLe. Natl.'.Vud. Energy Ser. 4, vol. 22B, Washington. D.C.: Atomir Energy C:ommission, 1951. 7. GILSt,ue. A. The initial trial of nitrogen mustard. Am. f. Surg. 105:574-578. 1963. 8. Gtu.tAK• A.. and PHIUPs, F. S. The biological amines and therapeutic appli- cation of the jB (beta)-chloroethyl amine and sulfide. Srien<•e 103:409415, 1946. 9. GoODS1A\• L. S.; WtNTROBE. M. M.: DAMESHEK. W.; GOODMAN. M. J.: GIL- sfAn, A•: and McLENNAN, M. T. Clinical experiences with the use of methyl-bis (P-chloroethvl) amine hydrochloride and tris (PKhloroethyl) amine hydrochloride (nitvogen mustards) in the therapy of Hodgkin's dis- ease, l}•mphosarcoma• leukemia and certain allied and miscellaneous dis- orders. fAbfA 182:126-132, 1946. 10. JACOBSON. L. 0.; SPL'RN, C. L.: BARRON. E. S.; SMITH, T.; Ll`SHBAItGH, C.: and DicK. G. F. Nitrogen mustard therapy: studies on the effect of inethyl- bis (beta chloroethyl) anJne hydrochloride on neoplastic and allied dis- orders of the hematopoie,iic system. fA,tfA 132:263-271, 1946. 11. JACXIBSON. L. 0.: SIMMpNS, E. L.: and BLOCx. M. Effect of splenectomy on toxicity of Sr•89 to hematopoietic system of mice. J. Lab. Clin. Med. 34:1640-1655. 1949. Prrslxetnrs tn BroloRs and.Sledinne • N'intn 1981 1 215

HK92290059 12. JACOasoy. L.0.: MARtts. E. K.; GASTON, E. 0.: RossoN, M. a.: and 2t¢ttt.E. R. E. The role pf the spleen in radiation injury. Pror. Sor. Exp. BioL Med. 70:740-742. 1949. 13. JACOBSON. L. O.; StMNoNs. E. L; MAtkRs. E. K.; RossoR. M. J.; BETHARD. W. F.; and GASroN. E. O. The role of the spleen in radiation injury and recovery. J. Lab. Clin. Med. 35:746-770, 1950. 14. LtNDat.EV, D. L.; ODELL, T. T.; and TavscHE. F. G. Implantation of func- tional etythropaietic elements following total-body irradiation. Pror. Soc. Exp. Biol. Med. 9Q:512-515, 1953. 15. Ne.wEtr., P. C.; CouE. L. J.' HABERMEYER, J G.; and ROAN, P. L. Growth and continued function of rat houte•marrow cells on X-radiated mice. CancerRes. 16:258-261, 1956. 16. FoRD. C. E.; HvstERTON. H. L.; BARNEs, D. W.; and Lotrrn. J. R. Cytological identification of qadiation-chimaeres. Nnltcre 177:452-454, 1956. 17. WEIDEN, P. L.; SCHUCTER. S. J.: and BANAp, M. Marrow transplantation for aplastic anemia and leukemia: reviaw of results and blood product support required. Prog. Clin. Biol. Res. 28;295-312, 9978. 18. CAnstrrA, B. M.: 'FHOMAS. E. D.; NATHAN, D. G., et al. A prospecove study of androgens and bone marrow transplantation for treatment of severe aplas- tic anemia. Blood 53:504-514, 1979. 19. JACOHSON, L. 0.: ~Got.DwA3sER, E.: GutttaEV, C. W.: FtttED. W.; and PtzAx, L. Studies on erythropoietin: the hormone regulating red cell production. Ann. N.Y. Acad. Sci. 77:551-03, 1959. 20. JACOBSSON. L. 0.;, GoctnvassER, E; FRtt:D, W.; and 1Pt~AS, L., Role of the kidney in erythropoiesis. Nature 179:638-634,1957. 216 1 Leon o. Jorobwn • Flom Aronr'w Ebe