Preview and Overview
Beginning in 1934 and 1935 the Laboratory pioneered two sorts of interdisciplinary work centered on products of the cyclotron. The earlier, radiochemistry, enlarged its domain as the energy of the deuterons it chiefly employed increased. Up to the summer of 1935, when the cyclotron first bombarded at 4 MeV, direct activation by deuterons did not penetrate much beyond potassium, although for a time Lawrence thought he had transmuted platinum. In late 1935, with the energy at 5 MeV, the activation extended to antimony; in late 1937, when the 37-inch operated at 8 MeV, and recovered for Berkeley the lead in energy usurped by Michigan a year earlier, it reached uranium. Here the Laboratory had a monopoly.
Neutron activation could be practiced anywhere, with modest means, and throughout the periodic table. Here the cyclotron conferred the advantage of intense neutron beams obtained from deuterons incident on targets of lithium or beryllium. The range and complexity of neutron activation were much increased in October 1934, when Fermi inserted a block of wax for one of lead in a measurement of absorption. (He had in mind, perhaps, the finding of his collaborators that the intensity of activation by
neutrons depended in some cases on the material on which the irradiated substances stood, and the observation by Joliot and Curie that neutrons directed at a layer of paraffin made a particularly strong impression on an ionization chamber.) The silver thimble whose induced activity served Fermi as a measure of neutron flux responded more enthusiastically to neutrons passed through wax than to neutrons striking it directly. He explained that nuclei susceptible to (n,g ) reactions capture slow neutrons more easily than fast ones. Between 1934 and 1936 Fermi's group identified more than 80 radioelements—about half the radioelements known in 1937—made by neutrons fast and slow. The Rome work created both an opportunity and a complication at Berkeley. It indicated that everything could be activated by neutrons; and it required that experimenters learn to discriminate between the effects of fast and slow ones.
The study of the reactions induced by deuterons or neutrons at Berkeley produced more than new entries, some of great importance, in the lengthening list of activities. The Laboratory had to its credit the first artificial (d,p) and (d,n) reactions, which, however, it had to share with Caltech; the first experimental demonstrations of K-electron capture, whereby a nucleus decays by swallowing one of its nearest satellite electrons; a full demonstration of the Oppenheimer-Phillips mechanism of (d,p) transformations; and early examples of isomeric nuclei.
Usually teams of two or three worked at the experiments, but even those who labored alone had important help from other members of the Laboratory. Everyone depended upon the crew on duty to keep the cyclotron going. Many turned to Kurie and his collaborators and successors, for example, J.G. Richardson and Ernest Lyman, to determine in their cloud chamber the sign of the beta particles given off in decays under study. Since each staff member became an expert on a few elements—Kamen recalled
that when he started work in 1937 only bismuth and tellurium were unassigned—an explorer had to consult experts on neighboring elements, or McMillan, who became the authority on them all, when hacking through the tangle of reactions in the middle reaches of the periodic table. And also in the middle reaches, particularly among the transition metals of the fourth and fifth period and the platinum metals of the sixth, the chemistry easily acquired by physicists no longer sufficed for clean separation of the elements of an activated target. Chemists became essential collaborators.
The first chemist to have an ongoing connection with the Laboratory, Glenn Seaborg, began in the spring of 1936, when Livingood, perplexed by the mess of activities in a tin target irradiated with deuterons, sought his help. Their ongoing collaboration—Seaborg at the sink, Livingood at the electroscope—produced the largest quantity of information about nuclear reactions obtained by any group in the Laboratory. In the fall of 1938, when Livingood went to Harvard, Seaborg continued the collaboration by mail, struck up a new one with Segrè, and brought his students from Chemistry to help in the increasingly difficult chemical separations.
The collaboration of Livingood and Seaborg instanced not only the assimilation of chemists into the Laboratory, but also a fundamental change in the character of its nuclear chemistry. Their first try with tin was made in the old hit-and-run manner: Livingood bombarded with deuterons for three hours; Seaborg separated for a few more; Livingood observed the decaying fragments; and the two enriched the Physical Review with rough indications of three activities in indium (if they were not owing to tin contamination), two in tin, and two in antimony. There were perhaps twenty-four hours of experiment in all and three months from irradiation to manuscript. The business had, of course, to be repeated. Gradu-
ally Livingood and Seaborg's experiments became more elaborate and reliable. Between February and June 1937, for example, they bombarded seven elements from chromium to antimony, some many times, with deuterons or neutrons; Seaborg split the activities into a great many samples, which Livingood filed and observed for as long as they showed life, sometimes for two years and more. Among the products disclosed that busy spring was Fe59 , which became the standard, if rare, tracer for iron in studies of the blood.
Like radiochemistry, the second pioneering line, radiobiology, danced to the tempo set by the machine. In the fall of 1933, the cyclotron's beam of 3 MeV deuterons drove out so great a flux of neutrons from beryllium that, Lawrence wrote Poillon, "we are already worried about the physiological effects on us." Lawrence was then about to set off for the Solvay Congress in Brussels; en route he planned to consult Wood at Columbia about the physiological effects of neutron irradiation, which, he thought, might have a satisfactory side, "of great medical importance." Lawrence supposed that neutrons might destroy cancers more effectively than x rays, because, as Chadwick had shown, neutrons pass more readily through dense materials like lead and bone than through light hydrogenous matter like paraffin and body tissue. This differential absorption would make images taken by neutron rays the inverse of those by x rays—what appears light in the one being dark in the other—and perhaps also confer some special therapeutic benefit. "There is [therefore] some justification for the belief that the discovery of neutron rays is of an importance for the life sciences comparable to the discovery of x rays."
Losing no time, Lawrence discussed the potential of big neutron beams with Dave Morris, treasurer of the Research Corporation, vice president of the Macy Foundation, and, in 1933, Roosevelt's new ambassador to Belgium. At Morris's suggestion, between
Brussels and Berkeley Lawrence talked over his expectations with Macy's president, Ludwig Kast, who saw enough in them to grant the Laboratory $1,000 by the time Lawrence's train arrived in San Francisco. Two other grants of over twice that amount followed progress in the aggrandizement of the beam. In January 1934 Berkeley's neutron ray, "more penetrating than either x rays or radium," was intense enough to penetrate the New York Times . In February Lawrence talked about it with the University Explorer over NBC. But by then his energies were fully engaged in proving his unstable deuteron and he found it more comfortable to hint at atomic power than at cures for cancer. The collapse of the Berkeley teachings about deuterons and the discovery of artificial radioactivity then shelved development of neutron sources and concern with neutron hazards.
The steady increase in energy and current of the deuteron beam reopened the question of safety, and the "discovery" of radiosodium put a premium on pushing intensity and danger further. In April 1935 H.F. Blum, of the University's Department of Physiology, who wanted to try the effects (which he expected to be catastrophic) of neutrons on tissue containing lithium, agreed to look into safety. During the summer and early fall of 1935, John Lawrence, then very much concerned with safety, was in Berkeley recovering from an automobile accident. He followed up Blum's experiments and learned that, as his brother put it, "neutron rays are considerably more lethal biologically than x rays." "We are getting harmful doses of neutrons in a few minutes when we stand near the magnet."
Exposure of laboratory personnel to penetrating radiation had long worried directors of laboratories with high-voltage x-ray equipment, especially Tuve, who began in 1929 to press for studies of the long-term biological effects of the rays from his Tesla coil. As he wrote Aetna Life, who were doubtless pleased to read it, he took "extreme precautions," setting the tolerable dose at under 0.1 roentgen a day and the total integrated exposure to less than 1 percent of what it took to kill a rat. A roentgen, or "r unit," is the quantity of x rays that makes about a billion ion pairs (1 esu to be exact) when passing through a cubic centimeter of air. The second International Congress of Radiology, meeting in Stockholm in 1928, took the roentgen as its unit and during the 1930s most workers in the field adopted a dose of 0.1 r of x rays as the tolerable daily allotment. What should be the limit for the more deadly neutron rays? John Lawrence first suggested no more than a quarter of the x-ray limit, in accordance with his preliminary measurements on the relative lethality of the two radiations to mice. Berkeley tended to be more generous than other places. MIT's Evans recommended a limit of 0.001 n unit/day (an "n" unit being the quantity of neutron radiation registering 1 r in a certain standard detector), Aebersold ten times that, McMillan four times Aebersold's limit. No national or international level of tolerance to neutron rays was established before the war.
The discovery of the uncertain danger of the neutron background brought prudence to the Laboratory. In 1935 the dose four feet from the beryllium target was 0.2 r an hour, five times the allowable x-ray rate per day; a water barrier cut it down "quite a lot," but not enough to stop the Laboratory's neutrons from spoiling experiments in the Chemistry building. The 37-inch had a more extensive shield, a wall of water three feet thick; Fermi thought this extravagant, but the National Advisory Cancer
Council, which authorized $5,000 for it, did not. The three feet of water reduced the radiation at the control desk by a factor of three; the addition of a layer of water 1.5 feet deep above the cyclotron drove it down by a factor of ten (plate 8.1). As for the 60-inch, with four feet of water around the entire machine, the dose at the controls fell to an insignificant 0.001 r/d, or so the heads of the Laboratory claimed. Aebersold calculated that a five-foot shield would be necessary to keep the exposure at the controls, some forty feet from the target, to 0.01 n/d (n units per day). The wisdom in the field was that the background activity in Berkeley exceeded norms in other cyclotron laboratories. Further to prudence, the cyclotroneers carried ionization gauges in their pockets so as to meter what Time called the "new lethal death ray hurled by magnet[s]" and Science Service represented as a "deadly danger for young researchers." They also had their blood drawn "every so often." Documentation of the seriousness of the neutron hazard returned Lawrence to his idea of neutron therapy.
In 1936 the Laboratory began to acquire biologists and physicians just as it did chemists. John Lawrence returned for the summer and came back for good in 1937. Macy money and Rockefeller riches allowed him to build up a sizable group, which, by 1940, numbered himself as director; five doctors of different sorts, including a visiting fellow, but not counting Stone, who supervised neutron therapy on behalf of the Medical School; a nurse and laboratory assistant; and four operators of the 60-inch cyclotron. The biomedical staff distributed itself into three
research groups, one for neutron therapy, another for work on leukemia, and a third for biological tracers. The enduring members, besides John Lawrence, were Paul Aebersold, who obtained his Ph.D. in 1939, after several years at the Laboratory on fellowships in radiological studies from the Medical School, for work on collimating neutron beams for radiation therapy; and Joseph Hamilton, who worked in radiology at the Medical School after receiving his M.D. there in 1936, came to the Laboratory as a Finney-Howell Fellow, graduated to research associate on NACC funds, and ended, after the war, as director of the Crocker Laboratory.
Neutron therapy began at the 37-inch cyclotron in September 1938. It seemed at first to offer some advantage over treatment by x rays. So did the ingestion of P32 in cases of chronic leukemia and polycythemia vera, and radioiodine for diseases of the thyroid. Radiosodium, in which so much was invested—cured nothing. The 60-inch cyclotron, which could treat more patients than the 37-inch, improved statistics. It appeared that the neutron ray was a cruel disappointment, but that radiophosphorus and radioiodine afforded many sufferers true benefits. The tracer research also had notable successes, particularly in elucidating steps in photosynthesis. And, as in the case of technetium in radiochemistry, discoveries of importance in radiobiology were made outside the Laboratory by people using radioactive preparations made in Berkeley.
Gluttony at the Periodic Table
The Laboratory's earliest radiochemistry, apart from radiosodium, concerned nitrogen and oxygen. These elements lent themselves to experiment: they could be obtained very pure and deployed without fear of surface contamination; they have few
naturally occurring isotopes to confuse analysis; and they are easily excited by deuterons at 2 or 3 MeV. The experimental setup, which remained standard for gases, is indicated in figure 8.1. The first to work it were Lawrence, Henderson, and McMillan. They attacked the air and detected three groups of alpha particles and two of protons, which they assigned to reactions of nitrogen, but found no radioelements and did no chemistry. The ranges they measured for the alpha particles and protons did not agree with more careful determinations by Cockcroft; once again Lawrence had to remeasure and retract. McMillan persisted, substituted nitrogen for air and Livingston for Lawrence and Henderson, and uncovered a positron activity that lasted about two minutes. A little chemistry showed that the active substance formed water; a little reasoning ascribed the activity to a new radioelement, O15 , half-life 126 seconds, and to the reactions N14 (d,n)O15 , O15® N15 + e+ . In a parallel investigation, Henry Newson, who came from and returned to the Chemistry Department at the University of Chicago, found that F17 (t = 1.16 m)
could be made by (d,n) on O16 . He thereby recovered a known activity made by (a ,n) on N14 and raised his reputation in the Laboratory. (Lawrence had judged him to lack the pushiness needed to accomplish anything there.)
Meanwhile McMillan and Lawrence worked on aluminum, which has but one natural isotope, and Henderson attacked magnesium, which has three. They used an apparatus similar to that of figure 8.1 with the target mounted in the beam. Protons, positrons, alpha particles, and neutrons came off aluminum, which could provide them all via the reactions Al27 (d,p)Al28 ® Si28 + e+ , Al27 (d,a )Mg25 , and Al27 (d,n)Si28 . The activity of Al28 (t = 156 sec), the only one studied, was scarcely fresh, having been prepared in France the natural way, by (a ,n) on phosphorus, and in Italy the Italian way, by (n,g ) on aluminum. By placing a series of foils in a line, McMillan and Lawrence measured the "excitation function," the yield of radioaluminum as a function of the energy of the incident deuterons. That brought nothing new either: the excitation function agreed with Gamow's theory.
With a little more energy—3MeV—Lawrence and McMillan, now joined by Thornton, got results that diverged from theory. Oppenheimer became interested, calculated, and concluded that disintegration via (d,p) followed the Oppenheimer-Phillips process at the higher bombarding energies. Meanwhile Henderson was getting two different radioactive products from the heaviest magnesium isotope, Mg26 , that is, Mg27 (t = 10 m) via (d,p) and Lawrence's Na24 via (d,a ). Although both activities were known (Fermi had made Mg27 by neutron capture), Henderson could claim the first case in which two different products resulted from the bombardment of a single isotope by the same charged particle. He determined the excitation functions for both, and consulted Oppenheimer. The sage authorized the conclusion that the Na24 came into existence by Gamow capture and the Mg27 by the mechanism of Oppenheimer and Phillips.
The Laboratory's appetite at its first sitting at the periodic table appears from the menu of the meeting of the American Physical Society held in Berkeley at the end of December 1935. Cyclotroneers gave twelve talks, only one of which concerned machinery. Otherwise the subjects were elements excited by deuterons: copper, nitrogen, and oxygen, whose excitation functions Newson followed to energies above the nuclear potential barrier, where the Gamow curve no longer holds; phosphorus, argon, nickel, cobalt, zinc, and arsenic, made radioactive by Paxton, Snell, Thornton, and Livingood; nitrogen, fluorine, sodium, aluminum, silicon, phosphorus, chlorine, argon, and potassium, whose beta and gamma emissions gave employment to Kurie, Richardson, Paxton, Cork, and their cloud chamber. For most of this work, deuteron energies ran about 3.5 MeV and the elements studied were no heavier than arsenic (atomic number, Z , = 33). This was a little tame and routine for the boss. Lawrence's name appeared on two papers at the APS meeting. In one, with Cooksey and Kurie, he described improvements in the cyclotron that resulted in 6 MeV deuterons; in the other, with James Cork, he announced the discovery that platinum nuclei (Z = 78!) "resonated" when hit by such rapid particles. This response from the tough platinum nucleus, which he thought he had "transmuted" to gold, was most gratifying. As Lawrence wrote the Macy Foundation in October 1935, six months earlier he would not have thought such alchemy possible with energies attainable in the Laboratory.
During 1936 the Laboratory worked its way forward from iron, using the faster deuterons then available and trusting in the efficiency of the Oppenheimer-Phillips process apparently so potent in aluminum. (In fact, as Bethe later showed in an elaborate, but approximate, calculation, the Oppenheimer-Phillips process would not have been detectable below Z = 30.) At the
meetings of the spring and early summer of 1936, Van Voorhis introduced a duplicitous copper, which, having imbibed a neutron perhaps in the manner of Oppenheimer-Phillips, decays by either a positron to nickel or an electron to zinc; he thereby found much, but missed more, since the predominant mode of decay of Cu64 is via a process, K-electron capture, then undetected. Livingood reported on the unseparated messes he made with 5 MeV deuterons on several metals and also on his attempt, fleetingly successful, to make the first artificial-natural radioelement (Bi210 , alias RaE) via the Oppenheimer-Phillips process Bi209 (d,p)Bi210 . He thought he glimpsed the faint beta decay of RaE, and also alpha particles of the right range to arise from RaE's descendent Po210 . The man who first identified RaE, Rutherford, was delighted to know that Lawrence could make a, or perhaps any, link of a naturally occurring radioactive series. "[It is] a great triumph for your apparatus."
Another triumph seemed in the offing. Cork had continued with the experiments on platinum. Together he and Lawrence identified four activities, two arising (according to them) from platinum isotopes excited by an unknown process more powerful than Oppenheimer-Phillips and two from irridium isotopes produced by an unlikely (d,a ) reaction. They disclosed further that the excitation function of platinum did not increase monotonically with energy, but showed several bumps or resonances. Oppenheimer developed a new theory to account for it all. At this point, in April 1937, Niels Bohr passed through Berkeley on his way to Japan.
Bohr had just put the finishing touches on his theory likening the nucleus to a liquid drop with modes of excitation incompa-
tible with Lawrence's platinum resonances. At a seminar arranged especially to discuss the latest curiosity of Berkeley experiment and theory, Lawrence announced that his measurements conflicted with Bohr's ideas, but agreed perfectly with Oppenheimer's, and Oppenheimer gave what Kamen remembered as "a typically stupefyingly brilliant exposition of its theoretical consequences." Bohr declared that the data had to be wrong. When he left, the resonances became sharper, the experiments more convincing.
Lawrence did not wish to repeat the saga of the disintegrating deuteron. He summoned McMillan, who had once traced an apparent activity of platinum under deuteron bombardment to radioactive nitrogen driven by recoil into the surface of the metal. McMillan realized that he needed chemical advice (the separations on which Lawrence and Cork had relied were hurriedly done by Newson during his last days at the Laboratory). He called on Kamen and a new graduate student in chemistry, Samuel Ruben. It took them over three months of strenuous chemical work—eighteen hours at a time—to separate the activities and to trace the exotic "resonances" to just plain dirt. By rubbing Laboratory grime into platinum foils before bombarding them, Kamen was able to reproduce most of Cork's measurements.
In the summer of 1936, Segrè, then newly appointed professor of physics at the University of Palermo, visited Berkeley, to see the cyclotron, to escape the heat at his main place of sojourn, Columbia, and to survey possibilities of escaping from the heat in Italy should war threaten. He returned to Palermo "still dreaming of the cyclotron" and carrying some bits of copper strip that he had scavenged from the chamber of the 27-inch. He and his associates separated radioisotopes of copper, zinc, and perhaps manganese from the scrap. 'Twas but antipasto. "We would like very
much to have more copper," Segrè wrote. "I think you can send any substance in a letter." Meanwhile the cyclotron had been opened for repairs. Lawrence salvaged more copper and the molybdenum strip that protected the dee edge at the exit slot. He had it all cut up and sent in several letters. It was an act of headstrong generosity. Lawrence suspected that the molybdenum contained an activity of long life but of too little promise to add its investigation to the rigorous Berkeley routine. "We are all very busy here, but there is nothing very exciting at the time to report." There would have been some excitement had they kept the hot molybdenum.
If the long activity arose via (d,n) on molybdenum, it belonged to element 43. Number 43, alias davyum, lucium, nipponium, and masurium, had been nondiscovered several times. No trace of it had turned up in the surveys of x-ray spectra by H.G.J. Moseley and his successors; the only evidence for its existence when Lawrence sent Segrè his second installment of scrap was three faint x-ray lines observed by Walter and Ida Noddack in 1925 in the course of their successful detection of element 75 (rhenium). Segrè and Carlo Perrier, Palermo's professor of mineralogy and an accomplished analytical chemist, took the Laboratory's molybdenum apart. They separated a large amount of radiophosphorus, which they found to contaminate everything from Berkeley, and handed it to colleagues in physiology to administer to rats. They tried to carry the residual activity on molybdenum and the elements immediately below it, niobium and zirconium, but to no avail; its chemistry was closer to that of rhenium, the heavy homologue of "masurium." In April Segrè notified Lawrence: "All the activity is due to some substances which have all chemical characters one would expect to find in the element 43." Perrier and Segrè saw indications of three different radioisotopes of 43, to which the Palermo group soon attached half-lives of 90, 50, and 80 days, in order of relative abundance. As for stable isotopes of "masurium," Perrier and Segrè declared
them to be "absent," indeed, nonexistent; no known element could be invoked to act as a carrier for the new activity. Consequently, just after the war, when weighable amounts of element 43 were created in nuclear reactors, Perrier and Segrè annihilated "masurium" and named their element, the first made by man before its discovery in nature, "technetium."
"The cyclotron evidently proves to be a sort of hen laying golden eggs." So Segrè wrote Lawrence at the start of the analysis of the molybdenum strip. He publicly acknowledged his gratitude not only by the usual professional thanks, but also, what Lawrence no doubt preferred, by advertising the cyclotron. Perrier and Segrè concluded their presentation of the radiochemistry of element 43: "We hope also that this research carried on months after the end of the irradiation and thousands of miles from the cyclotron may help to show the tremendous possibilities of this instrument." Segrè asked for more active long-lived material and sent some purified uranium oxide for irradiation by slow neutrons in the hope of making more unnatural elements, perhaps alpha emitters from transurania. "I think that when you are producing neutrons every point near to the cyclotron gets a stronger irradiation than with the most powerful sources available in Europe."
Lawrence at first was more impressed by the salvage and application of P32 than by the news of element 43: "We are all amazed here to to see the amount of good work you have done with such a trivial amount of radiophosphorus." As for claims based on complex radiochemical analysis, he had reason to be wary: "Of course there are difficulties." By the fall of 1937, when sending P32 for Segrè's colleagues and more scrap for Segrè himself, he wrote, with his usual optimism: "We are only too glad to send you
material because you have accomplished so much with what little we have furnished." Indeed, although it was not known at the time, Segrè had accomplished precisely what Lawrence had prepared: the creation of new materials interesting in themselves and applicable to medicine. The element has been in clinical use since 1963. One isotope, Tc99 , which gives a useful gamma ray, is an important agent in visualizing tumors and abscesses of the liver, in imaging the living skeleton, and in brain scanning. Its production by accelerators became the basis of a multi-million dollar industry.
As Aristotle said, the road from Athens to Corinth runs also from Corinth to Athens. In the case of technetium, Europeans detected a new element in material made in Berkeley. In the case of the isobars of mass three, the Laboratory made a discovery prepared in Europe. Soon after Rutherford and his collaborators had identified the d-d reactions, the Cavendish and also Fritz Paneth and G.P. Thomson at Imperial College, London, sought to produce enough H3 and He3 in Cockcroft-Walton accelerators to investigate their physical and chemical properties. All failed. Rutherford supposed that the elusive isobars combined with stray protons and neutrons to form alpha particles, of which, however, no trace could be found. Efforts to detect He3 by the spectroscope also failed, except in passing and at Princeton, where physicists saw and then did not see lines in the spectra of the products of d-d reactions ascribable to a light helium isotope. By 1935 the case of the uncollectible isobars was attracting attention on both sides of the Atlantic.
The most promising route appeared to be the isolation of "triterium," as Rutherford called it, from heavy water. This quest rested on the assumption that H3 is stable. Weighing in its favor was a report by Tuve's group of the presence of tritium in the
heavy water made by Urey and F.G. Brickwedde and the apparent slight excess in mass of lightest helium over heaviest hydrogen. But Tuve's result had not been duplicated and the argument from the masses was far from secure. Although the Cavendish's values of the energies and masses entering into the reaction H2 (d,p)H3 were regarded as so reliable that the mass of H3 determined from them stood as one of the most certain of nuclear constants, the mass of He3 , deduced from the reaction H2 (d,n)He3 , stumbled over the difficulty of measuring the kinetic energy of the liberated neutron. Rutherford's group made He3 just slightly heavier than H3 ; analysis by the meticulous T.W. Bonner and W.M. Brubaker, who also used the reaction Li6 (d,a )He3 , made the masses the same within experimental error; and Hans Bethe and R.F. Bacher, scrutinizing it all in the spring of 1936, awarded He3 the tenuous excess of about two ten-thousandths of a mass unit. Excess in the atom, as in the human, may be a sign of instability. Already in 1934, the Cavendish physicists conjectured that He3 might transmute into stable H3 by emission of a positron, in the manner then just made fashionable by the studies of Joliot and Curie.
The first in the field were Walker Bleakney and his associates at Princeton, who had electrolyzed 75 tons of ordinary water down to its heaviest cubic centimeter before learning of the Cavendish evidence for the existence of H3 . They set their precious material free in Bleakney's mass-spectrometer, found traces of particles of mass five that they declared to be molecules of H2 H3 , and inferred that H3 constitutes about one part in a billion of ordinary water. Their colleagues at Princeton, G.P. Harnwell and H.D. Smyth, corroborated their finding by running the product of a gas discharge in deuterium into the spectrograph; and, in a further dividend, the Princeton mass-spectroscopists identified He3 in the d-d product as well. A year later Tuve's group again reported
"stable hydrogen atoms of mass 3 in numerous electrolytic deuterium samples" put through their magnetic analyzer.
The British were unable to duplicate the feats at Princeton and Washington. From Norsk Hydro, which by the mid 1930s had become the world's largest producer of deuterium, the Cavendish received 11 grams of the heaviest and most expensive remains of the electrolysis of 13,000 tons of water. (In 1935 Norsk Hydro-Elektrisk Kvaelstofaktieselskab sold almost pure heavy water for $1.25/g in quantities over 50 grams; in 1938, the price had declined to 75 cents/g for lots of 25 grams.) Aston could not find a drop of heaviest water in the Norwegian stock. Meanwhile, Mark Oliphant and Fritz Paneth and G.P. Thomson had failed to confirm Harnwell and Smyth, and guessed that the Princetonians, who had begun to doubt themselves, had been misled by the release of helium that had been dissolved into the glass walls of their discharge tube. By mid 1937 a consensus of sorts had been reached. "The claims of the Americans . . . were ill-founded," Thomson wrote Rutherford after visiting Princeton. "I am glad that you are coming to a similar conclusion." The next move appeared to Thomson to be to persuade Lawrence to devote a large amount of cyclotron time to irradiating a bucket of heavy water with deuterons in order to search for the spectrum of He3 . Nothing seems to have come of his proposal. The Laboratory had a more certain manufacture than the elusive isobars of mass three.
In July 1939 owing to the idleness of the 60-inch cyclotron as it awaited adequate shielding, the matter was reopened in Berkeley. Luis Alvarez thought to fuse deuterons in the 37-inch and feed the product into the 60-inch, which he would use as a giant mass-
spectrograph. He apparently accepted Bethe's revaluation of the mass data in 1938, which corrected in the wrong direction made He3 definitely heavier than H3 and allotted light helium a period of 5,000 years. "This would mean that He3 cannot be found in nature." This was to ignore the recomputation made by Bethe and Livingston in 1937, using revised values of the relevant parameters, which lowered the mass difference by a factor of ten; and also the reconsiderations of Bonner, who found that neutrons carried off more energy in H2 (d,n)He3 than he had thought, and lowered the mass of He3 below that of H3 . Rutherford thought it safest to assume the stability of both isobars. Holding with Bethe, Alvarez was alert to any anomaly that indicated that He3 does not have a period of five millennia.
When Alvarez and a graduate student, Robert Cornog, began their search, the magnetic field of the 60-inch cyclotron was set to accelerate alpha particles. As a preliminary check on the background radiation through the machine, Alvarez watched an oscilloscope that monitored the current to the target while the operating crew decreased the field. The current through the cyclotron fell to zero, as expected, when the field no longer held the alpha particles in phase with the radio frequency potential on the dees. At the end of the test, the crew turned off the field after readjusting it for accelerating alpha particles. As the rapidly changing field passed through the setting for mass three, a sudden burst of particles registered on the oscilloscope. The general phenomenon—a momentary spike in a cyclotron beam as the magnet current sweeps rapidly through the resonance point—had been noticed by M.C. Henderson and Milton White, who explained that the changing magnetic flux set up eddy currents in the pole faces that acted like shims.
Alvarez did not expect to see a spike. It made his day ("one of the finest moments of my scientific life"). It indicated particles of mass three in the cyclotron's source. The source was natural
helium from a deep well in Texas, where it had lain for geologic ages. Evidently He3 had a half-life greater than 5,000 years. In fact, as Alvarez proclaimed, it is stable. He and Cornog shimmed the 60-inch to give a He3 beam and estimated the relative abundance of the light and heavy isotopes as 10–7 for atmospheric, and 10–8 for well helium. (These numbers are low by a factor of ten; the higher percentage in the atmosphere arises from creation of He3 by cosmic rays.) That solved half the old problem. They then looked for radioactive H3 in the product of d-d reactions passed into an ionization chamber. A new long activity with chemical properties of hydrogen rewarded their search.
The most obvious next step was to determine the half-life of the radioactive hydrogen. A first estimate, made by Thanksgiving day, 1939, was 230 days, later diminished to 150 days, and then raised to perhaps ten years. The lower numbers may stand as a warning to unwary experimenters: as Cornog discovered to his chagrin, they measured the rate, not of decay, but of the leak of hydrogen through a rubber tube used in the apparatus. This last number came from McMillan, who had measured the half-life of H3 without discovering it. He had guessed that an activity he had noticed in 1936 and reckoned at ten years belonged to a suppositious Be10 made by (d,p) along with the B10 made by (d,n) in the usual cyclotron irradiation of beryllium. After the disclosure of the activity of H3 , physicists at the University of Chicago got a nice radioactive gas on dissolving a specimen similar to McMillan's. They supposed they dealt with the product of the reaction Be9 (d,H3 )Be8 and that McMillan's half-life characterized tritium. The period is, in fact, 12.6 years. Tritium is constantly
made in the atmosphere by cosmic rays. The heavy Norwegian rainwater examined by the Cavendish consequently contained radioactive hydrogen, which lived long enough to reveal itself to a Geiger counter after the war.
Lawrence was delighted with the identification of the isobars of mass three. He gave it pride of place in his report to the Research Corporation on the Laboratory's work for 1939. When the report was submitted early in 1940, negotiations with the Rockefeller Foundation over the 184-inch cyclotron had reached their critical phase. Lawrence gave the result a gloss that he doubtless expected Poillon to pass on to the Foundation. "Radioactively labelled hydrogen opens up a tremendously wide and fruitful field of investigation in all biology and chemistry."
Until the late spring of 1937, experimentalists knew only one way for artificial radioelements to decay: by the emission from their nuclei of a positive or a negative electron. Theorists had observed, however, that a nucleus liable to produce a positron might also transmute by capturing one of the two atomic electrons—the so-called K electrons—closest to it. The heavier the nucleus, the stronger the pull on the K electrons and the greater the likelihood of capturing one of them. The possibility was first aired by that inventive interpreter of Fermi's theories, Gian Carlo Wick. A means of detecting the process, should it occur, lay close to hand. An atom containing the stable nucleus created by K-electron capture would lack an electron in its innermost shell. An electron from the next shell is likely to fall into the hole and to emit an x ray, called a Ka ray, in the process. K-electron capture by an unstable nucleus of charge Z betrays itself by a Ka ray characteristic of element Z – 1. The higher the Z and the longer the life of a positron emitter, the more likely the competing K process is to occur. None of the naturally occurring radioelements, all of which have high Z , decay by releasing positrons. Hence the K-prospector looked as though it were among the longest-lived
emitters of positive electrons he could make as far up the periodic table as his means allowed.
Fermi's theory modelled beta decay and the competing capture process in analogy to the theory of electromagnetic radiation: just as an atomic electron can release or absorb a photon in leaving or reaching an excited state, so a proton can give rise to a positron or capture an electron while turning into a neutron. The analogy breaks down in that the energy of the beta particle created in the process is not equal to Emax , the difference in energy of the nucleus before and after the creation; rather, the energy may take any value up to Emax , as indicated in figure 8.2. To save the principle of energy conservation, physicists had supposed that a second particle is created in the beta decay, a "neutrino," whose lack of charge and vanishingly small mass (necessary to produce the asymmetry in figure 8.2) protected it from observation. With a neutrino mass of zero, the shape of the theoretical beta curve is determined chiefly by the value of Emax . Fermi's calculation, which took the strength of the interaction between electron and neutrino to be proportional to the amplitude of their fields, did not give quite the degree of asymmetry observed. Theorists at the University of Michigan, E.J. Konopinski and his professor, G.E. Uhlenbeck, came closer in the cases of P32 and Al28 by making the interaction proportional to the product of the amplitude of the electron field and the gradient of the neutrino field.
In 1936 Christian Møller in Bohr's institute compared the predictions of Fermi and of Konopinski and Uhlenbeck (K-U) for the total probabilities per second of positron emission (l+ ) and K-electron capture (lK ) in a hypothetical susceptible nucleus of high Z . (l is the inverse of the period of the activity.) His result: on both theories lK is much larger than l + , the disparity being the greater the smaller Emax . Then he specialized to the curious results of Cork and Lawrence, whose "platinum" decayed with a period of 49 minutes by emission of positrons of Emax = 2.1 MeV. Neither Fermi nor K-U could give enough positrons to fit these data. Møller supposed that K-electron capture must have occur-
red in the Berkeley experiments 9 times or 47 times as often as positron emission depending on whether events followed Fermi or K-U. He advised looking for x rays from the "iridium" formed from the "platinum" decay. Lawrence could not find the x rays and, as usual, thought he had caught out the theorists: "It looks to be a serious difficulty for the Fermi theory." Since Bohr's institute had no machine for making radioplatinum, experimentalists followed up Møller's lead by seeking Ka from the decay product of the heaviest available positron emitter. This was Sc43 (Z = 21, t = 4 hours), made by alpha particles from radon on (ancestor) calcium via (a ,p). A search for Ka from (descendent) calcium by J.C. Jacobsen failed. Calculations indicated that for Sc43 , lK /l+ = 5 according to K-U and 0.1 according to Fermi. Calculation and measurement in Copenhagen therefore favored Fermi.
Berkeley had by then plumped for K-U on the basis of its apparently better fit to measurements of beta decay. Here the primary instrument of research was Kurie's cloud chamber and the
primary researchers himself, J.R. Richardson, and Hugh Paxton. By using hydrogen, in which slow particles have a better chance to show their presence than in oxygen, then the usual medium in the chamber, they obtained close agreement with K-U for N13 , F17 , Na24 , and P32 . The cloud chamber men concluded that "[the K-U theory] completely describes the process of emission of a beta particle."
As they drifted further along the periodic table, however, their conviction dissipated. Active chlorine, argon, and potassium could not be fitted to K-U unless each contained two unresolved activities. And nothing fit unless Emax were put higher than the limit to which, as judged by the eye, the experimental curve tended. (They could not measure all the way to the maximum because they could not register enough of the very few fastest particles.) Ernest Lyman, another graduate student associated with the Kurie group, confirmed the disconfirming of K-U in the cases of P32 and RaE. As he observed, however, P32 and RaE have unusually long periods (14 and 5 days respectively), and might die in ways not dreamed of in the competing theories.
Fermi himself had pointed out that substances like RaE might escape his theory. He called attention to their position on the so-called Sargent curves, a plot of logEmax against logl for the naturally radioactive substances. Its author, B.W. Sargent, who took up the project while at the Cavendish, divided the empirical points into two classes, each of which fell roughly along a straight line (fig. 8.3). For a given Emax , an element of class II, which included RaE, has a much longer life than an element of class I. Their decay apparently required an inhibiting change of nuclear spin. At a meeting of the American Physical Society in Seattle in June
1936, Lawrence introduced Laslett to talk about a singularly long-lived positron emitter, Na22 (t = 3 years), first made by Otto Frisch by (g ,n) on F19 , then in comparative plenty by Laslett by (d,a ) on Mg24 . Its exceeding longevity interested Willis Lamb, who was brought forth at the same meeting by his mentor, Oppenheimer. Lamb reported that his calculations showed that if Na22 did require a change in nuclear spin, it would be twice as likely to decay by K-electron capture as by positron emission according to Fermi's theory, and thirty times as likely according to K-U. He proposed as a test not looking for the Ka line of neon but counting the relative numbers of alpha particles (one for each atom of Na22 created) and positrons (one for each positron decay) in the process. K-electron capture was not, and has not been, observed in Na22 .
While Laslett wrote up his results, Alvarez entered the game and picked up the chips. He noticed that Sc43 lies on the first Sargent curve and looked around for a neighboring element with a radioisotope on the second. The cyclotroneers had been exploring the region. By the end of 1935 they had reached zinc and had studied at least one element, argon, carefully; but they did not stop to examine the transition elements below zinc closely enough to find the eligible positron emitters they had activated in them. Nor did Livingood's surveys of 1936 or a direct search among the activities of copper pick them up.
Harold Walke, who was so unsure of himself that he had to be careful, then looked closely at the activities of the first few elements in the fourth period. He found a strong positron activity induced on titanium; chemical separation pointed to an isotope of vanadium (later identified as V48 ) produced by (d,n). The period of decay, 16 days, placed the new activity on the second Sargent curve. That was the combination desired: a Z high enough, a life long enough. Alvarez attacked radiovanadium with McMillan close behind, opening loopholes, "following the job." Alvarez did not attend the Laboratory picnic on Sunday, June 20. That day he detected rays from the decaying vanadium with a penetrating power appropriate to the K rays of titanium. K-electron capture, long expected in theory, thus materialized in the laboratory. Alvarez made the ratio lK /l+ about 1, closer to Fermi's theory than to K-U. Lawrence praised the work as "especially significant."
Once the process had been seen everyone saw it. Livingood, now disciplined in collaboration with Seaborg and another chemist, Fred Fairbrother, a Leverhulme Fellow from the University of Manchester, found a positron activity in manganese. Later Livingood and Seaborg showed that this isotope (or rather isotopes: Mn52 and Mn54 ) decays by K-electron capture and that Zn65 , which Livingood had examined earlier, does so too. Then Otto Oldenburg, on sabbatical from Harvard, found a K process without positron competition in tantalum excited by neutrons (Ta180 , t = 8.2 hours). In all this there was a difficulty, however, which McMillan pressed on Alvarez. Perhaps the K electron does not jump into the nucleus but out into the world, driven by a gamma ray originating from an excited state of the stable final nucleus? If the probability for "internal conversion" (the release of an atomic electron that absorbs the gamma ray) were sufficiently high, only the x rays and the converted electrons would appear in the radiations. To decide the question, the experimenter must determine the element from which the K ray emerges: if from element Z (Z being the atomic number of the radioelement), then internal conversion; if from element Z – 1, then K-electron capture.
Alvarez took up this problem with the positron emitter Ga67 , which Wilfred Mann had made by (d,n) on zinc. The radiation from Ga67 consists of electrons, gamma rays, and x rays characteristic of zinc. Ernest Lyman and another graduate student showed that all the electrons had about the same energy. Alvarez explained: a nucleus of Ga67 swallows a K electron and ends in an excited state of Zn67 , which emits a monoenergetic gamma ray that has a moderate possibility of internal conversion; homogeneous electrons demonstrate the conversion and the zinc x rays the filling of the holes in the zinc atom's electronic structure. Walke found a better demonstration with long-lived V49 (t = 600 days), which decays only by K-electron capture and only into the ground state of titanium. No gamma rays or ionizing radiations
complicate the picture. Like the V48 in which Alvarez had made his discovery, V49 appeared to die out more closely to Fermi's than to K-U's specifications. By 1939 K-electron capture had been recognized in some twenty isotopes, including two of element 43. K-electron capture proved to be as common as theorists expected. Among other consequences of its ubiquity, it ruled out the possibility that platinum could be the source of the positrons seen by Cork and Lawrence.
Some pieces of the platinum puzzle fit well with the study of another nuclear process, in which, like the detection of K-electron capture, the Laboratory pioneered. This was the behavior of isomers, forms of the same unstable nucleus differing in internal energy. A pair of isomers can decay in several ways: each might emit a beta particle, or the more energetic isomer may relax into the lower by throwing off a gamma ray, or both processes might occur together. Isomerism first came to light in 1921, when Otto Hahn deduced that the third member of the radioactive chain descending from uranium UX2 (Pa234 ) consists of two beta emitters, both of which, he thought, arose directly from UX1 (Th234 ). No other instance was found. It took theorists some time to devise an explanation. In 1934 the inventive Gamow thought to trace the difference between Hahn's isomers UX2 and UZ to the presence in one of them of a hypothetical antiproton-proton pair in place of two neutrons. Another idea, put forward by a student of Heisenberg's, C.F. von Weizsäcker, in 1936, preserved the upper isomer long enough to emit a beta ray by supposing that a big difference in spin discouraged it from dropping immediately to the lower. Still, the matter was neither clear nor persuasive; Hahn's partner Lise Meitner expressed skepticism about isomerism and Bethe, though accepting the phenomenon, hedged over whether the pair UX2 and UZ was an example of it. The Cavendish's Norman Feather and Egon Bretscher cleared the matter up early
in 1938. They made UX2 the excited metastable state and the only direct descendent of UX1 , and UZ the rare result of UX2 nuclei that could not restrain their gamma radiation. By an appropriate attribution of the complex beta rays, they showed that UZ belonged on the first, and UX2 on the second Sargent curve.
Feather and Bretscher had the encouragement of the first unequivocal example of isomerism among artificially active elements. That was the work of Arthur Snell, the most complete and exact bit of radiochemistry accomplished at the Laboratory to that time (August 1937). He was inspired by the apparent existence of too many active bromines. Fermi's group had found two, with periods of 18 minutes and 4.5 hours, which they supposed to arise by slow neutron capture in the two stable bromine isotopes, Br79 and Br81 . Then a Soviet physicist, I.V. Kurchatov, found a third activity (t = 36 hr) in bromine hit by neutrons from a Rn-Be source, for which there was no obvious available antecedent in natural bromine. Kurchatov proposed that whereas Fermi reactions were of the ordinary type (n,g ), his occurred via the then still unestablished route (n,2n), giving rise to a suppositious active Br78 .
Snell checked these results by trying to make the Italian radioisotopes Br80 and Br82 and the Soviet Br78 in other ways than by neutron bombardment of natural bromine. He examined no fewer than twenty-eight different reactions involving As, Se, Br, Kr, and Rb activated by deuterons, alpha particles, and neutrons. Among his most significant results: Br78 does exist—he made it by (a ,n) on the single arsenic isotope As75 and by (d,n) on Se77 —but its period (6 min) and its decay mode (positron emission) exculpated it from responsibility for Kurchatov's activity; Br83 , hitherto
entirely unknown, also exists (t = 2.5 hr); and the three previously known activities had to be shared among Br80 and Br82 . From his inventory of twenty-eight reactions, Snell could show that both Fermi activities belong to Br80 . And, to complete his happiness, he created Kurchatov's activity (Br82 ) by deuterons on selenium. With the advice of Bohr—this result dates back to April 1937 or earlier—Snell pinned the reaction on Se82 , since Se81 , which could have given rise to Br82 by the familiar (d,n) reaction, does not exist naturally. On this explanation, Snell gave the first example of a (d,2n) reaction. The excitement of the discoverers of such arcana may be hard for outsiders to share. But in the breast of the nuclear physicist, they inspired "great joy."
The joy came also to McMillan, Kamen, and Ruben, who were still laboring on Lawrence's dirty platinum when Snell completed his work. Platinum appeared to have three periods, all activated by slow neutrons and decaying by fast electrons, and gold and iridium behaved similarly. It seemed too much of a good thing. "The results of this work so far [McMillan's group wrote] do not seem to be capable of any simple explanation without the introduction of a fantastic number of isomeric nuclei." Candidate isomeric nuclei turned up everywhere after the summer of 1937, and frequently for the first time in Berkeley; of the seventeen pairs of artificial isomers established by 1939, eleven were discovered or first confirmed by members of the Laboratory.
Livingood and Seaborg were the most successful hunters (plate 8.2). Earlier investigators had not carried their separations of zinc activated by neutrons very far. Seaborg went further. He and
Livingood in consequence added two new nickels to their treasury of isotopes, cleaned up earlier misattributions by Livingood and by Robert Thornton, and identified isomers of Zn69 . In all there were but three zincs, which Livingood and Seaborg prepared in a total of eleven different ways. Their attributions have stood. Then there were iron and its neighbors. With separated fractions from fifteen bombardments of iron, four of chromium, and two of manganese, all by deuterons, and several irradiations of the same with alpha particles and neutrons, Livingood and Seaborg straightened out a great many reactions and uncovered a pair of isomers in Mn52 . The most interesting and complex of the isomers came to light during a lengthy study of activated tellurium, which attracted Livingood and Seaborg not only as another radiochemical puzzle, but also as a possible quarry for a useful radioactive iodine.
Their first irradiation of tellurium with deuterons took place on March 26, 1938. They moved on to iodine, then back to tellurium, glimpsing, losing, and finally establishing the existence of an iodine with the biologically useful period of 8 days. That brought them through the summer. In September Livingood left for Harvard; he set up an electroscope in his kitchen to examine samples mailed him by the indefatigable Seaborg. There were too many telluriums. Joseph Kennedy, Seaborg's graduate student, helped to untangle them. He soon confirmed his collaborators' conjecture that the 8-day iodine, I131 , descended from not one but two telluriums, isomers of Te131 with periods of 1 hour and 1.2 days. But on further examination, the hour period shrank to 45 minutes and then split into two, of 30 and 55 minutes; and, in addition to the three telluriums that had replaced Kennedy's two, there were three more, of periods of 10 hours, 1 month, and several months. After
three weeks of hard work in January 1939, Kennedy and Seaborg proved that the 30-minute (corrected to 25-minute) activity was a parent of I131 and the lower of a pair of isomers whose upper level was the activity of 1.2 days.
To shorten a story already sufficiently long, Seaborg, Livingood, and Kennedy labored on the tellurium system until the end of December 1939, when they declared on the basis of sixteen different reconfirmed reactions that there exist precisely four radiotelluriums, three of which come in two isomers each. With a clever chemical technique, soon to be described, they showed which isomeric state was the lower; and, with the help of two graduate students, Carl Helmholz and David Kalbfell, who examined the specimens in a beta-ray spectrograph, they identified conversion electrons knocked out by the gamma rays emitted in transitions from upper to lower isomeric states.
After Livingood, Seaborg took up with an isomer hunter of even greater resourcefulness, Segrè, who brought the experience of identifying isomeric Cu65 in cyclotron scrap. Segrè required something in addition to Seaborg before he would begin their planned search for isomers of element 43: a better detector than Livingood and the Laboratory's other hunters of new activities employed. This detector consisted of an ionization chamber of a type used in Rome connected to a dc amplifier built by Lee DuBridge during a summer at Berkeley. Segrè's electrometer (plate 8.3) later served in the detection of H3 , C14 , and plutonium. It began by registering a beta ray, no gamma ray, and an x ray from activated molybdenum, which Seaborg and Segrè diagnosed as an electron converted from a gamma ray with almost 100 percent efficiency and the associated K radiation of element 43. They sent a letter to the Physical Review announcing these results; but
their pleasure suffered an interruption when Lawrence told them that Oppenheimer thought so high a degree of conversion impossible. Lawrence asked them to withdraw their report. The frequency with which the Laboratory had had to retract published results had declined since Lawrence had gone full time into fundraising and administration, and he did not wish to risk a throwback. Seaborg and "a rather agitated Segrè," who had lately been the master of his own ship, complied. Ten days after this contretemps, the Physical Review published a letter from Bruno Pontecorvo describing a similarly high conversion in rhodium. Lawrence conceded that Segrè and Seaborg should resubmit.
They soon confirmed their observations. They asked a graduate student, Philip Abelson, who had built a good spectrograph, to determine whether the x radiation they had found belonged to element 43 (it did), and they established that the lower isomer associated with the 6-hour activity had a life of at least forty years. These are the isomers of Tc99 (the lower has a life of almost a million years), the clinically important species of technetium. The collaboration was close and demanding. Segrè participated in the chemical separations and Seaborg in the physical measurements, and they wrote up their results together.
Since atoms of isomeric nuclei possess precisely the same chemical properties, it might not seem advisable to think about ways to separate isomers chemically. Segrè thought it could be done, however, by modifying the Szilard-Chalmers process, in which nuclei rendered active by an (n,g ) process (e.g., radioiodine) and knocked out of a compound (e.g., ethyl iodide) by the neutrons they absorb, are collected by combining them with suitable molecules (e.g., in a precipitate of silver iodide). His thought was at first received unenthusiastically because the recoil from the isomeric
transition seemed insufficient to free an atom from its chemical bonds. Ralph Halford, an instructor in the Chemistry Department, with whom Seaborg discussed the matter, thought that he might be able to effect a chemical separation. Segrè and Seaborg irradiated a liter of ethyl bromide, which, after treatment by Halford, gave a hydrobromic acid enriched in the lower isomer of Br80 . This isomer thus stood revealed as the 18-minute activity observed by Fermi's group, by Kurchatov, and by Snell. Seaborg and Kennedy immediately applied the scheme successfully to tellurium, confirming the double origin of 8-day iodine; and then, together with Segrè, tried hard, but with few positive results, to separate isomers of several other metals, from manganese to platinum.
The Groaning Board
The periodic table of the elements began as a sort of Ouija board, arranged on arbitrary principles and operating with mysterious powers. The concept of natural isotopes and the theory of the nuclear atom diminished the mystery by explaining that the principle of arrangement by weight was a happy approximation to the true regulation by atomic number. Why the natural isotopes have the weights they do remained a mystery. The discovery of means to split atoms and make natural isotopes radioactive made possible determination of the exact binding energies of nuclei and an understanding, or the beginning of one, of the genetic interrelationships among the elements.
The Laboratory made very material contributions to the new knowledge. The cyclotron plugged two holes in the periodic table, the spaces at 43 (technetium) and 85 "eka-iodine," later astatine. The first, we know, was found by Segrè and Perrier in
molybdenum irradiated by deuterons in the 27-inch; the second, found in an experiment that Segrè proposed, came from bombardment of bismuth by alpha particles in the 60-inch. At Hamilton's bizarre suggestion, astatine was fed to guinea pigs, who obligingly concentrated it in their thyroids to demonstrate its similarity to iodine; the Laboratory was nothing if not interdisciplinary.
The total record appears in figure 8.4. It indicates the percentage of reactions known in May 1935, July 1937, and December 1939 that the Laboratory either discovered or helped to clarify. The comparison with Cambridge is particularly striking: in 1935 Berkeley matched the Cavendish only in reactions initiated by deuterons; by 1937 the Laboratory dominated study of deuteron interactions and was extending itself vigorously into neutron and proton work; by 1939 it had risen to dominance in alpha- as well as deuteron-induced reactions, and to hegemony in neutron work, while Cambridge, under the management of W.L. Bragg, had lost its position in nuclear chemistry. Other laboratories, for example, Fermi's in Rome, Bothe and Gentner's in Heidelberg, and DuBridge's at Rochester, specialized in one sort of reaction only. A cruder, though perhaps more impressive index to Berkeley's contribution appears from comparison of the percentage of all reactions known at a given time for which Berkeley was credited or co-credited: in 1935, one reaction in ten; in 1937, one reaction in four; in 1939, almost one reaction in two.
Mice and Men
By the time the danger from neutron rays was appreciated, high-energy x rays no longer held promise for cancer therapy. The result obtained by Lauritsen and Packard of Columbia's Institute of Cancer Research in 1931—that 550 kV rays had no more deleterious effect on Drosophila eggs or the common mouse tumor "sarcoma 180" than an equal quantity of 50 kV rays—had been substantiated and extended. Lawrence had conceded to Wood that the 1 MV Sloan plants probably would have no greater curative properties than standard x-ray apparatus, and experience at the University's Medical School fully confirmed the concession. Hence the possible medical value of neutron therapy held unusual interest for Lawrence both for itself and as a replacement for a played-out technology. A principal objective of the very first experiments with neutron irradiation was to compare its biological effects with those of x rays.
John Lawrence and his technical advisor, Ernest Lawrence, who in July 1935 became "consulting physicist" to the Medical School, exposed $120 worth of rats near the beryllium target of the 27-inch cyclotron and at the Sloan machine in San Francisco. The neutrons appeared to be about ten times as effective as x rays per roentgen in altering the makeup of rodent blood, or five times as effective per unit of ionization since (they estimated) a roentgen of neutrons made twice the ionization in rat tissue that a roentgen of x rays did. Since the standard tolerable limit of x rays was 0.1 r/day, they recommended prudently that the maximum for n rays be 0.01 r/day. While the Lawrences zapped rats, Aebersold and Raymond E. Zirkle, a medical physicist visiting from the
University of Pennsylvania, tried the effects of the radiations on delaying the growth of wheat seedlings. Here one roentgen of neutrons did the damage of 20 r of x rays. Would neutrons prove ten or twenty times as effective as x rays in other biological contexts? "The general question is of more than theoretical interest, for it bears directly on the possibility of using very fast neutrons in the treatment of tumors."
John Lawrence returned to Berkeley early in February 1936 to take up the general question. With the help of Aebersold, the Lawrence brothers cooked some mice with 84 r/m of neutrons, and other mice with 32 r/m of x rays; neutrons killed with a third the dose (as measured in roentgens) needed for death by x radiation. The numbers fell out differently for sarcoma 180. About four times as large a dose of x rays as n rays was required to prevent pieces of tumor irradiated apart from the mouse from taking after implantation. Call the quantity of x rays needed to kill the tumor (mouse) Xt (Xm ) and the corresponding quantities for neutrons Nt (Nm ). Then Nt = (3/4)N m (Xt /Xm ). That is an exciting equation. It says that although the x radiation required to kill a tumor might exceed that required to kill its host, the lethal neutron dose for the tumor might not. The quantity X t /Xm has only to be less than 1.3. Unfortunately, according to the measurements of Aebersold and the Lawrences, Xt /Xm = 3.5. Still, neutrons appeared to hurt tumors more, and the body less, than x rays.
The doctor paid his next visit in the summer of 1936. "Things are humming," his brother wrote the Chemical Foundation, then eager for news relevant to their big commitment to the medical cyclotron. "The [27-inch] cyclotron is in operation daily, hundreds of mice and hundreds of tumors are being killed by neutron rays." John Lawrence and Aebersold repeated the work on
sarcoma 180 with another mouse tumor, obtained from Yale. It took 3,600 r of x rays, or 700 r of neutrons, to kill half the tumor particles before implantation; on healthy mice, 400 r of x rays had the same lethality as 120 r of neutrons. Hence neutrons killed Yale tumors 3,600/700 times, and Berkeley mice 400/120 times, as effectively as x rays. In this case, Nt = (2/3)N m (Xt /Xm ). Numbers were moving in the right direction. The addressee was William Crocker. John Lawrence's preliminary, but "highly significant," results had figured in Ernest Lawrence's declaration to Sproul in late February 1936 of the need for a clinical arrangement like Lauritsen's to test the efficacy of neutrons on human cancers. Now John Lawrence's firm comparative data about mouse tumors helped to convince Crocker to give the clinic. At the beginning of September, Sproul pitched effectively, as follows: "The newly [!] discovered neutron ray . . . seems to provide a means of overcoming the handicap which now limits the effectiveness of the x ray in the treatment of cancer. It appears that it can be used to increase the destruction of cancerous tissue without increasing the damage to the normal tissue." Greatly overplaying John Lawrence's results, Sproul suggested that neutrons might be three times more effective—wreak thrice the havoc to tumors for the same damage to the body—as x rays.
With Crocker's gift secured, the problem of staff for the clinic demanded solution. During the spring of 1936, the dean of the Medical School, Langley Porter, pressed by R.S. Stone to tighten ties with the Laboratory, met with Sproul and Ernest Lawrence for dinner at the Bohemian Club. Subsequently, Porter's assistant, Chauncey Leake, sought appointments for John Lawrence and Paul Aebersold in the Medical School. The business went slowly. As Poillon, himself a physician, had warned, "Medical men are extremely jealous of their prerogatives and . . . even to have a physicist suggest what they might do is received with anything but acclaim." By the time John Lawrence's appointment came through, he had decided to return to Yale; he kept up his work at
Berkeley on visits that totalled about six months during the academic year 1936/37. Neither he nor Stone wished to postpone neutron therapy until the Crocker cyclotron started up. Ernest Lawrence, concerned to show quick progress, agreed. The Lawrence brothers may have been especially, though irrelevantly inspired by the dramatic improvement of their mother under the rays of the Sloan tube. She had long complained of abdominal pain. In November 1937, the Mayo Clinic discovered an inoperable uterine tumor and gave her three months to live. John Lawrence brought her to San Francisco; Stone irradiated her several times with supervoltage x rays; the tumor melted away. Although the swelling may not have been a tumor at all, its erasure by x rays could not but have encouraged the Lawrences to press to make available an agent they had reason to believe would be still more powerful and beneficial.
As a preliminary to its clinical use, the diffuse neutron beam from the beryllium target of the 37-inch cyclotron had to be collimated and directed to a treatment port. Aebersold had the job, which he discharged by rearranging the water tanks of the cyclotron shielding and by lining the beam channel with lead (fig. 8.5). That kept the intensity within the channel almost twenty times that outside it at the port 70 cm from the beryllium target, where the patient received about 12 r/m. Carpenters transmuted a window of the Laboratory into a door opening into a demountable treatment room entirely screening the cyclotron; "the patients will hardly know they are next to such a monster." A parade of physicians, including one from the National Advisory Cancer Council, trooped through the Laboratory during the summer and gave their
blessings to the general work, if not to the therapeutic intiative. Their good judgment pleased and surprised Cooksey. "My opinion of doctors as a whole has risen tremendously." The first patients were exposed on September 26, 1938, just in time for a visit by the NACC's Arthur Compton. Their skin showed effects no worse than those caused by 12 r/m of x rays. Lawrence informed Sproul. "It gives me great pleasure to report an event of historic interest. . . . I personally believe, and my views are shared by my medical colleagues, that this will be the beginning of a new method of cancer therapy which in a few years will be as widespread as that of x rays and radium." What better time to ask for money? $2,000 for power and supplies, $1,400 for furnishings? "We could, of course, slow down our activities, including bringing to a halt the clinical therapy, but in view of the great immediate importance of this pioneering work it would be no less than tragic to do so."
After five months' experience with therapy at the 37-inch, Stone judged that the results of single erythema doses—doses sufficient to redden the skin—gave encouragement for "a complete course of therapy" and hope for "better results than are now being obtained." It would have been difficult to reach a different conclusion as the cyclotroneers began to fish for a beam in the 60-inch cyclotron. The first patient to absorb neutrons from the Crocker cracker, Mr. Robert Penney, received treatment on November 20, 1939 (plate 8.4). A regular clinical program did not begin until the end of January 1940. Then a few tumors vanished. "Dr Stone and John are very enthusiastic about the results." Thus brother Ernest. But John himself would not go beyond the meaningless formulation of the weather forecaster: "[There is] better than a fifty-fifty chance that neutrons are going to be of great value in therapy." He was therefore just better than half wrong when Stone evaluated the program in 1948. Only one of the 24 patients treated at the 37-inch cyclotron in 1938 and 1939 was then alive, and only 17 of the 226 treated at the 60-inch between 1939 and 1943. All but one of the 250 had been considered incurable. The survivors suffered what Stone described as "distressing late effects" that might not have occurred had they undergone x-ray rather than neutron therapy. He judged that he and John Lawrence had overexposed their patients. "Neutron therapy as administered by us has resulted in such bad late sequelae in proportion to the few good results that it should not be continued." Stone's negative evaluation put an end to fast-neutron therapy for two decades.
After much experimentation, treatment of human cancers by neutron rays recommenced around 1970, at, among other places, the Hammersmith Hospital in London, which used a cyclotron constructed in 1952. By 1978 over 3,000 patients had been treated at eleven centers in Europe, Japan, and the United States. The therapy proved effective against advanced, superficially placed
tumors that could be irradiated with little damage to neighboring normal tissue. The experience at Hammersmith through 1984 was that 70 percent of such tumors regressed after treatment with 7.5 MeV neutrons in comparison with 35 percent after treatment with x rays. Stone and the Lawrences had the right idea but the wrong dosage.
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." 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.
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. 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.
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. With this I131 , Hamilton and Myron Soley of the Medical School
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.
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. 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.
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. 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.
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. 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]."
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. 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.
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 . 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."
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. Lawrence and his associates
at the Crocker Laboratory confirmed the phosphorophyllic tastes of leukemic tissue. 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."
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.
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. 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. 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. 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. 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.
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.
On May 25, 1939, the "University Explorer," reaching deep to advertise the Laboratory, announced the arrival of radioactive fertilizer in Hawaii. A professor at the University there had imported P32 from Berkeley by Pan American clipper to test its power on pineapples. An explorer of the consequences of the innovations of the Laboratory had (and has!) his work cut out: "The influence of the cyclotron has been felt in so many different fields of science that no one can predict its ultimate value to mankind."
The influence began to spread at home, in 1937/38, among members of Berkeley's Chemistry Department. The first practitioners of radioactive tracing were Libby, Seaborg, and, above all, Ruben, through whose efforts University biologists took up the technique. Purely chemical applications, which were not irrelevant to the biologist, included the vast fields of exchange reactions and reaction mechanisms; the nature of the inquiry may be indicated by studies by Libby's students of exchanges between various valence forms of sulphur and of photochemical processes in solution, and by Libby himself of the reactions of recoil nuclei activated by neutrons. Another conspicuous line, detection of impurities by their radioactivity, which had been an unwelcome and misleading annoyance, was practiced for a time by Seaborg and Livingood, who found copper in nickel, iron in cobalt, and phosphorus and sulphur everywhere.
Ruben and P32 inspired a major direction of research in the Physiology Department on the metabolism of phospholipids or phosphatides, which occur in all living tissues in connection with fatty deposits. Ruben, Chaikoff, and their students and colleagues, who included the chemist I. Perlman and, occasionally, John Lawrence, ground up rats and birds fed radiophosphorus under various regimes—fasting, normal diets, fatty diets—to learn the loci of the creation and destruction of phospholipids. Following John
Lawrence's interests, they also examined cancerous mice. They extended the findings of Segré's associates in Palermo, who, with an Italian touch, had fed olive oil and Berkeley phosphorus to their rats; which, when anatomized, disclosed that the liver is the fastest metabolizer of phospholipids. The Berkeley group further showed that excised bits of liver, kidney, and intestine continued to work at phospholipid metabolism in vitro, and that the rate of its metabolism in tumors transplanted from one animal to another was characteristic of the tumor, not the animal.
Two other sustained programs in radioactive tracing that thrived on the Laboratory's output deserve mention. One grew in the Biochemistry Department around David Greenberg's ongoing investigations of mineral metabolism. Inspired, he said, by the "revolutionary nature and potential importance" of radiotracing, Greenberg and his associates began as others did, feeding radiophosphorus to rats and examining deposits in tissue and feces. They went on to the phosphorus metabolism of rachitic animals. They were the first to use radiocalcium (Ca45 ), a commodity more costly than Fe59 , as a tracer. In 1940 and 1941 they published information on the metabolism, deposition, and elimination of manganese, iron, and cobalt, the last, as they found, a possible cause of polycythemia. The second program, conducted by S.C. Brooks at the Medical School, studied the transport of ions into and within plant cells. Here radioactive indicators brought light where darkness had long prevailed. According to an authoritative reviewer, the results of Brooks and his associates released biologists from "the necessity of postulating mysterious properties for cellular membranes and protoplasm." Further
attacks on these mysteries occurred at the School of Agriculture, where Perry Stout and his co-workers made the uptake of alkali and halide salts by growing trees and shrubs their subject of study. They settled the vexed question whether salts rise through the bark as well as through the xylem (the answer is no) and demonstrated by persuasive autoradiography the deposit of P32 in the leaves and fruit of growing plants (plate 8.5).
It did not take much, apart from the material, to set up with radioactive tracers and to get quick, publishable results. There were so many animals and plants, so many elements, so many permutations of experimental circumstances. Hence the Laboratory received many requests for its products, which, if they did not save lives, might improve careers. Lawrence honored requests from outside the University on the basis of merit, other factors being equal. His most generous support went to workers in Rochester and in Copenhagen, the two places where, in the opinion of Merle Tuve, no fan of the Laboratory, work with tracers second only to Berkeley's was being done. In Copenhagen, Hevesy's group continued work with P32 , following it throughout the body and its products, into blood, eggs, milk, across cell walls, to and from the liver, and into the brain. Like Chaikoff's group, they paid much attention to phospholipid metabolism; and they worked out other biochemical pathways, notably the role of phosphorus compounds in the enzymatic breakdown of carbohydrates (glycolisis). Lawrence encouraged Hevesy to ask for "as much [P32 ] as he can use. . . . We are more than eager to help his important work."
Hevesy received the Nobel prize in chemistry in 1944 for his contributions to the tracer method. The leader of the Rochester
group, George Whipple, already had a Nobel prize, that of 1934 in physiology and medicine, for work on anemia. Radioiron sent from Berkeley allowed him to wallow more deeply in his favorite subject. His group, in which P.F. Hahn took the lead, showed that anemic dogs accepted iron in any form, collected it rapidly in the bone marrow, and disbursed it rapidly in blood cells. A normal dog would absorb almost no iron at all. It appeared that ingested iron entered the blood stream only if the body's iron store had been depleted; otherwise it passed directly through the intestines. Whipple expected to devise a satisfactory treatment of anemic patients using ordinary iron on the basis of the knowledge labelled iron gave him. The information did not come easily. Most of the time Whipple's group were as deprived of iron as their dogs. The cyclotron could not keep up the supply: the 37-inch made less than 1 mµCi of Fe59 per µAh, the 60-inch only 0.03 µCi. A radioiron with suitably high specific activity, Fe55 (t = 4 years), can be made by (d,n) on manganese, but it was not available before the war.
The Rochester iron men hoped that the radioisotopes furnished by physicists would turn out to be the "'Rosetta Stone' for the undertaking and study of body metabolism." That was to be very optimistic. The Stone then had nothing to say about the largest part of the bodies of plants and animals: no useful radioactive tracer for hydrogen, carbon, oxygen, or nitrogen had yet been found. No one felt this difficulty more than Kamen and Ruben, who had boldly set forth in 1938 to find the way through photosynthesis armed with C11 , which has a half-life of about 21 minutes. An experiment consisted of making the isotope, burning it to carbon dioxide, feeding it to plants, chopping the leaves into a beaker, adding as carrier any substance they guessed might have been labelled with C11 by the plant, and examining the various
carriers. All in an hour or two. The pace forced out their first collaborator, Zev Hassid, who suffered from high blood pressure. They made three of these hectic runs a week for three years.
They made some progress. A plant fed in the dark attached labelled CO2 to a big molecule RH, R is an unknown radical, making a compound RCOOH. The reaction appeared to be reversible. In the light, however, and the presence of chlorophyll, RCOOH gained water and lost oxygen, irreversibly, to become RCH2 OH. This structure may be considered a molecule R'H, which can fix another CO2 molecule in the same way to become RCH2 OCH2 OH, and so on. R might then break off, leaving a sugar. The scheme was novel and, in keeping with the requirements of philosophers, had an easily testable consequence that distinguished it from older theories. The consequence: that RH be a very big molecule. For evidence, Kamen and Ruben turned to the ultracentrifuge. The best local setup was at Stanford. Ruben stationed himself there, awaiting with counters ready the delivery of the labelled samples Kamen rushed down from Berkeley. Their lives eased with the discovery that Shell Development Company in Emeryville, adjacent to Berkeley, had a similar centrifuge. The machine showed RH to have a molecular weight between 500 and 1,000. To go farther, to identify the heavy molecule and the intermediates in photosynthesis, Kamen and Ruben needed a longer-lived isotope of carbon. A bout with N13 , which has a half-life of 10.5 minutes and which did not quite enable them to decide whether nonleguminous plants can fix nitrogen, further indicated the limits on biochemical research placed by lack of tracers for organic reactions.
Another path lay open. For many years biochemists had been following reactions by tagging compounds with naturally occurring isotopes. They would introduce a substance artificially enriched with deuterium or with C13 , which makes up a little over 1 percent of ordinary carbon. They had then only to take the final
products of interest and assay them for the relative abundance of the rare isotope in a mass spectrograph. Urey's colleague at Columbia, Rudolf Schoenheimer, the great master of the technique, routinely detected changes of 1 percent in isotopic abundance, which, in the case of carbon, meant one part in ten thousand. With some encouragement from the Research Corporation, Urey had perfected a method to enrich the concentration of C13 , which he turned over to Columbia University to patent at the end of 1939. At about the same time, the Eastman Corporation sought advice about the likely market for the stable isotope N15 as a tracer for nitrogen. Urey formed and did not hide the opinion that any foundation truly wishing to advance biochemistry and biology should assist in making rare natural isotopes available and not throw its money into cyclotrons.
Lawrence was then at the beginning of his negotiations with the Rockefeller Foundation for what became a request for a million dollars. Around October 1, 1939, Lawrence summoned Kamen and ordered him to find a radioactive carbon, nitrogen, and/or oxygen to silence Urey. "He said I could have both the 37-inch and the 60-inch cyclotrons and all the time I needed, as well as help from whomever I requested—Segrè, Seaborg, anyone!" Naturally Kamen chose to center his all-out search on carbon, and all the more after he had demonstrated with Segrè's help that no useful oxygen or nitrogen could be made by irradiating oxygen with alpha particles or deuterons. He pinned his hopes on an internal target of graphite, which he baked with deuterons for 5,700 µAh during the first six weeks of 1940. On February 13, Kamen terminated his exposure and left the hot target for Ruben to analyze.
Kamen recalled that he had turned to deuterons on graphite in "desperation and resignation." The only likely candidate for a useful radiocarbon was C14 made by (d,p) on the rare isotope C13 .
But for reasons similar to those that inhibited the discovery of the activity of H3 , C14 did not appear to possess the characteristics desired by radiobiologists. For C14 had already been discovered at the Laboratory. In 1934, in one of his first observations with his cloud chamber, Kurie had seen half a dozen tracks that indicated a new sort of radiation stimulated by neutrons. In addition to the then known (n,a ) process, he saw what he interpreted as (n,p) reactions on air, either N14 (n,p)C14 or O16 (n,p)N16 . His attribution, challenged by the Cavendish, was established by Bonner and Brubaker in 1936. Kurie and Kamen then studied the profusion of (n,p) events made possible by the cyclotron's enlarged neutron flux; they found the recoil tracks of the C14 ions and the liberated protons to be plentiful and conspicuous enough to serve as a measure of the stopping power of the air in the cloud chamber.
From general considerations set forth by Bethe and Bacher, not more than one of a set of isobars can be stable. But N14 is stable. The beta decay of C14 to N14 would depend upon their difference in mass, which Bethe and Bacher estimated at 100 or 200 MeV. "Assuming the b -transitions to be allowed, the lifetimes would be between 1/2 and 20 years." In the same bit of beryllium irradiated by deuterons in which he identified Be10 (in fact H3 ), McMillan had also noted a weak activity of about three months, which he ascribed to C14 made via (d,p) on a carbon impurity in the target. He then tried to make C14 in quantity by (n,p) by exposing ammonium nitrate to neutrons from the 37-inch cyclotron; the experiment ended with the accidental breakage of the salt's container and was not renewed. Livingston and Bethe accepted McMillan's estimate of a half-life of several months and Oppenheimer's student Phillip Morrison refined and confirmed their calculations. But careful search, notably by Ernest Pollard of Yale, who tried (d,p) on C13 and (a ,p) on B11 , found the product
protons, and calculated that C14 should yield soft beta rays, disclosed no activity ascribable to any carbon isotope. Hence Kamen's doubt that anything interesting would result from bombarding charcoal with deuterons.
The first tests confirmed his pessimism. Carbon removed from a target of calcium carbonate did not excite a thin-walled Geiger counter. When placed inside a screen-walled counter devised by two of Ruben's colleagues, however, it gave some weak signs, about half the usual background count. That equivocal message marked the discovery of the most important radioactive tracer found at the Laboratory. On leap-year day 1940 the good news was sent for publication. The reason that the decay of C14 had been so difficult to detect is that its period is very long. Ruben and Kamen first estimated "years;" a larger irradiation (some 13,000 µAh) of a better probe target enriched in C13 allowed a much higher and better estimate, thousands of years. That was a puzzle for the theorists, who, however, in the persons of Oppenheimer and L.I. Schiff, helpfully remarked that the nuclei of C14 and N14 must differ enough in angular momentum to retard the decay by the amount observed. In any case, the long-sought long-lived carbon was in hand, and it remained only to discover how to make it in sufficient amounts to satisfy the expected large demand. Kamen and Ruben returned to Kurie's process, N14 (n,p)C14 , irradiating large carboys of concentrated ammonium nitrate with neutrons from the 60-inch cyclotron. Although the yield was greater and the recovery easier than with deuteron-irradiated graphite, Lawrence ordered the process discontinued. He had heard that ammonium nitrate presented a serious hazard of explosion and no weight of chemical opinion could persuade him of its safety in solution.
Lawrence lost no time informing Urey of the miraculous appearance of C14 and in asking him for a sample of purified C13 to serve as a target for Kamen. That, he intimated, would be the true value of Urey's separation process; C14 would not depress the market for C13 ; "quite the contrary." The rules of science are strict. "Needless to say [Urey replied] we will surely send him the material he wants." But then the obvious question arose: why go to the trouble and expense of transmuting C13 into C14 for tracing if C13 will serve au naturel? Calculations by Urey, Kamen, Ruben, and Tuve concurred. As Kamen put it, C14 was "an ace in the hole," something for very special applications, such as the study of photosynthesis, where the big molecules involved might dilute the natural isotope past detection. To make a quantity of C14 useful for the purpose would require a long time on the machine. "It is quite beyond all probability to make more than one or two such strong samples in your or my lifetime as conditions are at present." Urey gave Kodak his apparatus and encouraged them to proceed. They agreed to make N15 and, if that succeeded, to try C13 . Kodak did not like Urey's method of separation, which used deadly hydrogen cyanide gas, and they worried that the more prolific route via N14 would make C13 unnecessary.
Although Lawrence, Kamen, and Ruben joined Urey and others in urging the commercial production of C13 , Kodak did not move to serve the mass market of biotracers before the war. The frustration of having too little heavy carbon to unlock the secrets of life was eased by war. In 1945 Urey again tried to enlist Kodak. Again the question: if C14 can be made plentifully without separated C13 , why invest in a heavy-carbon plant? But if not,
Kodak should come to the rescue, lest the country "lose years in applying the tracer technique to chemical and biological problems." Kodak wisely remained out of the picture. The tremendous neutron fluxes in the piles built during the war created C14 in plenty. Thus the sciences of life gained "the most important tracer available among the artificial radioactive elements."