Grand Elixirs
Lawrence had brought the idea of clinical use of Na24 to Poillon (who marked it "basic, with important commercial applications") in his report for 1934. He had in mind, apparently, that the gamma rays of radiosodium might replace radium's in the general treatment of cancer. In the spring of 1935, about the time that he began to worry about excessive exposure of cyclotroneers to neutrons, he also began to plan provisionally for clinical tests of Na24 and P32 . He was confirmed in this intention by a visit in April of Charles Sheard, head of biophysical research at the Mayo Foundation; and also by the Board of Regents, who responded to Sproul's report about the discovery of Na24 by declaring their interest in "the far reaching biological aspects of the discoveries and the new possibilities of radio therapy."[111] In May, Lawrence lectured the board of the Research Corporation on the power of the rays from radiosodiuim; in July, he could make 50 mg of the stuff, enough, he thought, for clinical tests; in August, treatment began, or would have, had the cyclotron not broken down.[112]
Radiosodium did not answer expectations. As advertised in the Research Corporation's patent, it did not cause harmful side effects, to dogs at least, even when given in large doses; but then neither did it do outstanding damage to tumorous tissue. Two leukemia patients received doses of radiosodium in the spring of 1936; one had 147 mCi in all, the largest quantity of active
material administered that year. Neither benefitted or suffered. Hamilton inferred that he might practice safely on normal people. He fed his subjects from 80 µCi to 200 µCi of patent-pending Na24 while they sat with one hand (and its arm) in a lead cylinder grasping a Geiger counter (fig. 8.6). The counter indicated that active material reached the hand within a few minutes of ingestion. In subsequent, more careful experiments with the same setup, radioisotopes of sodium, chlorine, bromine, and iodine made it from mouth to hand in from three to six minutes.[113] Injected in one arm, the tell-tale tracers arrived in the other in about twenty seconds. Radiosodium accordingly had some employment in studies of circulation and water balance in the body. It became a diagnostic tool for vascular disorders; for a time it stood literally at the cutting edge of research, as an indicator of the best site for amputation of impaired parts.[114]
The most useful of the harmless tracers of Hamilton's experiment was radioiodine because it concentrates very strongly in a particular organ, the thyroid, which has at least as much iodine as all the rest of the body. The first in the field were a group in Cambridge, led by Saul Hertz of the Massachusetts General Hospital and including Robley Evans of MIT. They gave I128 made with neutrons from a Rn-Be source to rabbits, which, when "finely minced," disclosed that they had deposited radioiodine in their thyroids very soon after eating it—which was fortunate, since I128 has the inconveniently short half-life of 25 minutes. Hamilton wanted something with a week's demi-duration, and so informed Seaborg. "I then told him that I would try." A month later, Livingood and Seaborg presented their 8-day iodine, I131 , untangled from the results of irradiating tellurium with deuterons.[115] With this I131 , Hamilton and Myron Soley of the Medical School
Fig. 8.6
Hamilton's arrangement for detecting the circulation of
radioactive salts. The hand in the lead cylinder grasps a
Geiger counter. Hamilton, Jl appl. phys., 12 (1941), 449.
showed that uptake of iodine by patients suffering from toxic goiter or overactive thyroid exceeded tenfold the uptake by normal persons, and that parts of thyroids invaded or destroyed by cancer cells could not fix iodine at all. (This last information came from autoradiography: sufferers about to have their defective thyroids cut out ingested radioiodine; sections of the removed thyroids were laid against x ray film; and the portions of the sections containing the active material photographed themselves.) It appeared that the rate of manufacture of the hormone issuing from the thyroid, thyroxin, depended upon the organ's ability to take up iodine and that radioiodine would not be a good weapon against thyroid cancer.[116]
Research and development then split. L.I. Chaikoff of the University's Department of Physiology and several collaborators used cyclotron-produced I131 to study the general biochemistry of iodine; by 1942 they had made important progress in elucidating the process of its fixation in the thyroid.[117] Hamilton and Lawrence, and also Hertz and Roberts, moved on to therapy. The treatment of noncancerous hyperthyroidism began at Berkeley in 1940 and about the same time at the Massachusetts General Hospital, which received I131 from the Laboratory for the purpose. Both groups had much the same experience. In four of five cases treated, the cyclotron-produced I131 (or, rather, combination of I131 with the 12.7-hour I130 , also discovered by Livingood and Seaborg), diminished the goiters, relieved symptoms (some of many years' standing), and increased emotional stability within a week or two of administration. Does ranged from 5 to 28 mCi. No deleterious side effects occurred within six years of commencement of treatment. Still, a cautious physician could not rule out development of thyroid cancer or damage to kidneys or bone marrow. Chemical and surgical treatment improved; and the best judgment when the first clinical experiences were evaluated limited radioiodine to patients intolerant of the new drugs or unable to undergo therapy. Effective treatment of thyroid cancer by I131 dates from after the war.[118]
The work with radioactive species of alkalis and halogens, however promising and stimulating, was but side play in the Laboratory's great drama of radiomedicine. The protagonist there was radiophosphorus—easy to make, of convenient half-life (about 14 days), with a good strong beta ray (maximum of 1.7 MeV), and known to concentrate in bones. In 1935, Hevesy and a colleague
at Bohr's institute (for theoretical physics!) fed rats P32 made from Rn-Be neutrons on S32 , measured the hot phosphorus in the feces, destroyed the animals, and found, among other things, that bone is a dynamic tissue. Further inquiry disclosed that young rats concentrated phosphorus very quickly and substantially in their growing bones.[119] The inquiry continued in San Francisco at the University's Medical School with samples of P32 having activities 100 or 1,000 times Hevesy's and with chicks in place of rats. The researchers, S.F. Cook, K.G. Scott, and Philip Abelson, confirmed that new phosphorus goes primarily to the bones, and also to the musculature; and they found that between 4 and 60 days after ingestion, the labelled phosphorus migrated from muscle and small intestine to bone and bone marrow. The spleen enjoyed high deposits throughout.[120]
These results encouraged the speculation that P32 might help control blood diseases such as polycythemia vera (a multiplication of red blood cells causing nosebleeds and an enlarged spleen) and leukemia. John Lawrence treated a lady suffering from polycythemia vera in 1936; her symptoms remitted (permanently, as it happened), and plans for proceeding to leukemia were made. Early in 1938 John Lawrence took the entire output of P32 from the 37-inch cyclotron. Part he fed to cancerous mice, part, in therapeutic doses, to a leukemic human. The mice confirmed the supposition grounding the therapy: they concentrated the active phosphorus in their fast-growing tumors, especially in tissue invaded by leukemic cells, and did so at the expense of deposition in their bones. Hence the indication: P32 as a weapon against cancers of the bone and bone marrow.[121] The human suffered from chronic leukemia of the bone marrow (myelogenous leukemia). He got 70 mCi of P32 over two months, which made his blood picture normal; a great triumph, which, as Lawrence
rightly cautioned in telling Chadwick, "should not be mentioned in public." But in private, he advised, it might be just the thing to mention to people considering building a medical cyclotron. That was certainly the message that Karl Compton took home from his visit to the Laboratory during April 1938, when the patient's blood appeared so nearly normal that it did not allow firm diagnosis of his condition. As MIT's Robley Evans reported Compton's reaction: "Immediately on arriving home from his visit to your laboratory, Compton called me over to describe with unbounded enthusiasm your leukemia work. . . . I am sure Compton's visit to 'cyclotron headquarters' did much to kindle his already enthusiastic support [for a cyclotron for MIT]."[122]
This was to compound Lawrence's optimism with physicists' ignorance of medical matters. John Lawrence was much more circumspect than his brother. He wrote Evans that the remission accorded his patient might have been accomplished by x rays, a point that Ernest Lawrence then kept in mind. In a report on the treatment of two cases of myelogenous leukemia published in a biomedical journal, John Lawrence and his collegues limited themselves to facts about uptake of P32 in the blood and retention in the body, and made no clinical inferences.[123] By June 1939, John Lawrence was treating a dozen patients, who took a total of 20 or 25 mCi a year, and had in consequence a life expectancy that he judged to be similar to that procured with x rays, some two or three years. In July he left for Europe, to bring tidings of the Laboratory's progress in radiobiology and radiomedicine to the British Association for the Advancement of Science. He mentioned Hamilton's work with radioactive alkalis and radioiodine, the indications for leukemic therapy, and the occurrence of remissions under treatment.[124]
The meeting of the British Association ended as Germany invaded Poland. Two days later, on September 3, 1939, Britain declared war. John Lawrence then set sail in the Athenia , which the Germans promptly torpedoed. The physician saved himself, bravely, after tending the wounded. Ernest Lawrence pulled what strings he could to obtain a berth for John on the first American ship sailing from Britain to the United States. The most useful of these strings involved leukemic politics. Early in August the Laboratory had received a visit from F.C. Walcott, an influential Republican senator from Connecticut until the Democratic landslide in 1936, who had come West as a guest of Herbert Hoover. He had a son, Alex, suffering from leukemia. The senator placed his hopes in the cyclotron and P32 and asked that John Lawrence stop to see Alex in New York on his return from Europe. When John seemed stuck after the sinking of the Athenia , Walcott pulled his strings, attached to the American ambassador to Britain and the president of the merchant marine. Within a week John had a berth on the Nieuwamsterdam .[125] He was restored to his leukemia patients, who now included Alex Walcott, in October. Results were mixed. P32 did nothing for Alex. Evaluating the situation in February 1940, a few months before Alex died, John Lawrence could not rate P32 more effective than other therapeutic agents in the control of leukemia. His best hope was that "possibly it will turn out to be slightly better."[126]
The continuing study of the metabolism of phosphorus in mice supported the hope. The physiologists at Berkeley showed that the generation of phospholipids in tumor cells took place as vigorously as in the most active organs, the liver, kidney, and small intestine, and that, in contrast to the normal active organs, tumors retain their P32 for long periods of time.[127] Lawrence and his associates
at the Crocker Laboratory confirmed the phosphorophyllic tastes of leukemic tissue.[128] In this respect humans behaved like mice. Lawrence and Lowell Erf, a physician expert in hematology and supported on fellowships, gave tracer doses of P32 to seven patients about to die of various cancers. In their last moments, as autopsy disclosed, they had put as much phosphorus per gram wet weight in their malignant tissues, or in tissues infiltrated by malignant cells, as in their most active organs. These results, according to John Lawrence, had constituted the rationale for the therapeutic use of radiophosphorus. The argument, however, was indirect. The first direct trials against cancerous growth in mice were, in Erf's words, "very disappointing."[129]
On May 18, 1940, Arthur Compton and James Murphy of the National Advisory Cancer Council looked in to see what the council supported at Berkeley. Ernest Lawrence, on John's advice, had gone to Sonoma to recover from a sore throat; but he came down to the Laboratory to meet men so important for his future work. The day did not go well. Murphy, an expert on animal experimentation, graded the Laboratory's procedures and facilities poor or worse. Cooksey later visited Murphy's institute. "[I] was tremendously impressed with the facilities. . . . It was obvious that our set up was terrible in his eyes." The conversation on May 18 switched to politics. Compton complained that an article he had written for a newspaper outlining the duties of scientists toward science and the nation had been misinterpreted. He planned to reply. Lawrence and Cooksey told him, politely no doubt, that he should have kept his mouth shut in the first place. Berkeley reserved its radicalness for technology and medicine. The report of the site visitors helped the NACC decide not to underwrite the expansion that John Lawrence suggested to it: investigation of differential effects of n rays and x rays on animals; metabolic studies of iron, sodium, potassium, sulphur, and iodine on hundreds of animals; methods to improve uptake of potassium and boron in
tumor tissue. On first consideration, NACC declined support for animal experimentation and cut back that for Stone's clinical application of neutron rays.[130]
Ernest Lawrence was not accustomed to such rebuffs. He accepted that the council might not care to support experiments with animals to refine neutron therapy or clinical use of radioiosotopes. "But it is totally incomprehensible to me that there should be any suggestion of curtailing the clinical program with neutron rays. . . . It seems to me a primary obligation on the part of all of us to see that the program of exploring these possibilities be carried forward full steam ahead. . . . The cancer program simply must go forward as Dr Stone and my brother have planned it." Compton, the recipient of this appeal and demand, allowed that Stone's program would most probably be funded in full.[131] It was. But the council stood its ground on animal experimentation.
The clinical program with radioelements rested on a financial and technical base quite different from that of neutron therapy. Treatment did not require immediate access to a cyclotron or special facilities at the Laboratory. The chief therapeutic agent, P32 , came so plentifully that, in John Lawrence's estimate, he could treat all the chronic leukemia in California without interfering with other obligations of the cyclotron.[132] The cost of machine time for making P32 could be passed on to the patient. The positive signs of phosphorus therapy outweighed the negative and opened the brief flurry of interest in commercial production of radioisotopes by cyclotrons arrested by the war. The psychology of support appears plainly from the initiative of Hans Zimmer, professor at the Harvard Medical School, dying of leukemia, who believed that he had obtained some benefit from P32 . It bothered him that the amount of radiophosphorus available fell far short of the nation's, if not of California's needs. He appealed to the Carnegie Foundation for $12,000 for a cyclotron for his Medical School.[133] Although John Lawrence advised against rushing
commercial production, Poillon pushed it, confident in and counting on the Research Corporation's patents on the cyclotron and the Van de Graaff.[134] Despite the attitude of the NACC, the Laboratory had no trouble expanding the basis of support of its biomedicine in 1940/41. The clinical program in radioisotopes had the support of the Jane Coffin Childs Fund for Medical Research, the Darian Foundation, Merck and Company, the Columbia Foundation, and the Donner Foundation.[135]
In 1948 Byron Hall of the Mayo Clinic evaluated the results of the clinical use of P32 in Berkeley, the Medical School of the University of Rochester, and his own institution. "It is too early [he wrote] to make a final evaluation of this form of therapy." But he allowed that it had brought relief to sufferers from polycythemia vera and the chronic forms of leukemia. The clinic had by then treated 154 cases of the one and 33 of the other. Symptoms in almost all of the 124 cases of polycythemia vera for which adequate follow-up data existed improved or disappeared. In 85 percent of the cases, the blood picture remitted satisfactorily and risk of hemorrhage and thrombosis decreased. Remissions of up to five years were achieved, but most lasted under two years. Complications—drop of white-blood-cell count, severe anemia, acute leukemia—occurred in a total of 30 percent of the cases. In general, P32 raised the life expectancy of sufferers from polycythemia vera as much as vitamin B12 did that of victims of pernicious anemia. Twenty patients with chronic myelogenous leukemia were followed. Many obtained the same sort of remission they would have acquired from x rays. Eleven of the patients died within six years of treatment. Chronic lymphatic leukemia proved more receptive. Six of six patients continued in remission from ten to twenty-six months after treatment. Radiophosphorus conferred no benefit on patients with acute leukemia, Hodgkin's disease of the bone marrow, or multiple myeloma.[136]