Having invented the chemostat, Szilard and Novick were eager to devise new ways to use it. One application was to study aging, since a bacterial population could be maintained for hundreds of generations and might serve as a model of a multicellular organism. At first, Szilard suspected that aging might be caused by accumulated deleterious mutations in a population of an organism’s cells, but when tested, this idea proved wrong. They discovered, instead, that the “lifetime” of the chemostat population was too quickly limited by “evolutionary” changes to show them much about aging.
Still, Szilard and Novick were able to make accurate measures of the rate of mutation of a bacterium. They demonstrated that in the absence of a virus, mutants that are resistant to the virus would accumulate in the chemostat population as mutations occurred and could be plotted along a straight line—as long as they grew at the same rate as the whole population. The slope of the straight line should give a measure of the rate of mutation far more accurately, in fact, than could be obtained by other methods then available. But, to their surprise, when they studied the effect of growth rate and mutation rate, they discovered that even at different growth rates the mutation rate stayed constant—per hour rather than per generation. This paradoxical artifact was finally rationalized fifteen years later.38
They also saw that after about forty generations, the number of mutants resistant to a virus dropped sharply, then rose again at the same rate observed initially. This, they showed, resulted from an evolutionary change. The original population in the chemostat, along with its accumulated virus-resistant mutants, was replaced by the selection of a new bacterial population arising from a mutant that could grow more rapidly at the low concentration of the limiting growth factor. When this “faster” strain became established, virus-resistant mutants again accumulated in it as they had in the original population, and at the same mutation rate. In one study, followed for about 650 generations over six months, ten to twelve such evolutionary steps occurred. “Here,” Newsweek reported about Szilard, “for the first time, as the bouncy, smiling physicist remarked, ‘evolution has been made visible.’”39
Realizing that their chemostat afforded a sensitive means to measure rates of mutation, Szilard and Novick began experiments to test several common substances as possible mutagens. First they tried caffeine at levels found in a cup of coffee or tea, and these raised the mutation rate tenfold. As expected, X-rays and ultraviolet light were also highly mutagenic, even at low intensities. But in the course of their work, they also found substances that were antimutagenic—a completely new concept. Their presence eliminated totally the effects of caffeine and, for some mutations, even reduced so-called spontaneous mutation rates.
Szilard enjoyed caffeine and drank Coca-Cola all day long to sate his habit (and, like his bacteria, to satisfy his need for sugar). On his way into the Quadrangle Club for lunch one day, he paused to buy a Coke from a machine in the coatroom and asked if his guest would like one, too. “No, thank you, not before lunch,” he said. Szilard swigged the Coke, and they walked upstairs to the dining room. On the way out, Szilard stopped at the machine again, bought a Coke, and offered one to his guest.
“But Szilard,” he said, “you just got through telling me that Coca-Cola is full of caffeine. And that caffeine is a mutagen.”
“That’s okay,” Szilard said. “I want to mutate into a native-born American so I can run for president.”40
Szilard and Novick also studied the regulation of gene expression. They found that this process could be regulated by controlling the rate of formation of the protein coded by the gene but also that the chemical activity of the proteins themselves could be controlled by substances that the proteins made. This latter phenomenon, now called feedback inhibition, plays a critical role in the ways that cells control the formation of the many substances used in their metabolism and growth.
Szilard was so impatient for new findings and so eager for the questions these findings might pose that he only performed experiments when the result seemed to offer a surprise. He was simply too anxious for answers. New ideas crowded out the old, and happily so. “The most important property of a man’s brain,” Szilard told John Platt, “is the ability to forget things.”41
Besides Szilard’s constant urge to plunge into new pursuits without finishing work at hand, Novick said that “lack of time or bad luck” kept them from fully developing many ideas. But Monod thought that Szilard’s creative nature itself kept him from performing decisive work. Had Szilard relentlessly pursued just a few of his ideas, Monod wrote, “his own specific achievements—written-up, formalized, and stamped—might have appeared greater, more definitely significant. Then however he would have been just as good, but no better, than many other highly distinguished scientists.
“Szilard was different,” Monod concluded. “He knew that meaningful ideas are more important than any ego, and he lived according to these ethics.” He was “a man to whom science was much more than a profession, or even an avocation” but “a mode of being.”42 Immunologist Melvin Cohn saw Szilard as a scientist more interested in discovering “how it might have worked than how it does work.”
This mode of being also prompted Szilard to bend and break scientific conventions. His behavior fell outside the dichotomy that says science moves by evolution or by revolution. For Szilard, science advanced by subversion, by rigorous challenge to every discipline’s most basic tenets, and by personal actions and reactions to ideas and events as they occurred. In Berlin, when he had seen Hermann Mark’s modern X-ray equipment for studying fibers in 1923, Szilard decided they were better used to study the X-rays themselves. At Cold Spring Harbor, when Szilard couldn’t keep bacteria at the right temperature and its gelatinous, agar-based medium solidified, he twisted the experiment into a study of agar and its properties. And, in Chicago, when impatient with the delays in peer-reviewed scientific journals, he bypassed them entirely by arranging regular meetings with the researchers he considered expert in particular topics.
In 1949 and 1950, Szilard organized the Midwest Phage, Marching, and Chowder Society, fortnightly brainstorming sessions at universities in Madison, Chicago, Urbana, Bloomington, and Saint Louis. A grant from the Rockefeller Foundation covered travel and meals, and Szilard used the encounters to question and challenge researchers at the forefront of molecular biology. Scientists described and discussed their latest results during these informal sessions, always under Szilard’s feisty interrogation. Besides Szilard, Novick, and cosponsor Salvador Luria, the meetings included Alfred Hershey, Leonard Lerman, James Watson, Joshua and Esther Lederberg, Max Delbrück, Theodore Puck, Sol Spiegelman, Joe Bertani, Roger Stanier, Renato Dulbecco, and Bernard Davis.
Because Szilard relished the give-and-take of informal discussion, most of his ideas were carried away and tested by others or simply forgotten. But a few thoughts intrigued Szilard so strongly that he pondered them for years. One was his attempts to understand the aging process in all living things, and for this he developed the concept of “aging hits.” In short, the number of chromosome defects that determine the natural length of life is set at birth.43
As with many of his ideas, Szilard merged fact and fiction in his brainstorming, and his fictional “Mark Gable Foundation,” written in 1948, described how people age and how those with incurable illness might be preserved cryogenically and revived for corrective treatment decades or centuries later. In 1955, Szilard wrote “Process for Slowing the Aging of Man,” in which he argued—this time, seriously—that life expectancy could be extended for persons with incurable diseases by alternating long states of low-temperature sleep with shorter periods of active living, since, when frozen, their body functions, including aging, are suspended.44 In this way, Szilard argued, a forty-year-old man with an incurable disease and only five years to live might choose to sleep nine months a year and live with his family for three, sharing his children’s development to adulthood.
In 1958, Szilard worked intens
ively on drafts of a paper on aging, proposing that aging hits determine our life span and that these occur randomly to deactivate chromosomes over time. “Thus, in its crudest form,” Szilard explained, “the theory postulates that the age at death is uniquely determined by the genetic makeup of the individual . . . [and] the main reason why some adults live shorter lives and others live long is the difference in the number of faults they inherit.”45 The New Scientist magazine published an account of Szilard’s aging paper, and Newsweek concluded from it that “females live longer because they receive a perfect 15,000 genes while men receive fewer . . . [and that] increased atmospheric radiation will make people of the future look older than they are.”46
In biology, as in physics, Szilard continued his practice of taking out patents: for a “Process for Producing Microbial Metabolites,” for the chemostat, for “Caffeine-Containing Products and Method of Their Preparation,” and for cheese made with unsaturated fats—an early form of “lite” dairy products.47 With Monod, Cohn, and Novick, Szilard developed a process for the industrial cultivation of microorganisms, based on the identical chemostat and biogen designs. During the 1950s, Monod used the proceeds of this patent to bribe border guards in order to secure the release of scientists from Hungary.48
While many of Szilard’s ideas were dismissed as mind play, tried and disproved, or simply forgotten in the rush of his busy life, one did earn him lasting credit: negative feedback regulation of enzyme activity. When Szilard attended Monod’s 1954 Jessup Lectures at Columbia University, he came away puzzled by what he heard about the induction in bacteria of the synthesis of betagalactosidase, an enzyme needed by bacteria for their consumption of lactose. The enzyme was only formed if lactose or an appropriate analogue was present in the bacterial growth medium.49 When visiting Monod in Paris in 1957, Szilard urged him to test an idea proposed by New York University microbiologist Werner K. Maas: whether “induced enzyme formation” is under the control of a naturally occurring repressor, a molecule that somehow inhibits synthesis of the enzyme. In this view, the inducer (here, lactose) interferes with the repressor and allows synthesis of betagalactosidase.
In his lecture when receiving the Nobel Prize for research on this idea and in later remarks, Monod noted that it was Szilard who had kept him on the path to success by insisting that normally the switch controlling formation of the enzyme would be “on” except in the presence of a repressor, which turned it “off.” Lactose induces the formation of betagalactosidase by inhibiting the repressor, Monod and his colleagues discovered, and Szilard had “decisively reconciled me with the idea (repulsive to me, until then) that enzyme induction reflected an antirepressive effect, rather than the reverse, as I tried, unduly, to stick to.”50
“We all looked forward to Szilard’s coming” to the Pasteur Institute, Cohn recalled. Right or wrong, Szilard’s ideas were always novel and often exciting. “He was given an office in Monod’s laboratory, and we all had to talk to him; everybody lined up for the chance.” Szilard organized discussion groups and seminars and impressed his colleagues with the way he absorbed what they said, then days later put it together with what he had heard from others. “He followed the thread of the discussion and picked out from what was said the seminal ideas.”51
Yet Szilard crushed bad ideas as eagerly as he cheered good ones, sometimes with dire results. In 1951 he convinced the Conservation Foundation to study advances in biological research that might be applied to human birth control and enlisted organic chemist William Doering from Columbia to help review current work. A grant from the foundation brought researchers to New York to explain their findings, and at one session a gynecologist from Boston proudly explained his discovery that hesperidin, a chemical in the rind of citrus fruit, was an effective birth-control agent in women. A charming man with a large practice, he had enlisted several patients to take part in his experiment, and to Szilard and Doering he reported proudly that none of the women studied had become pregnant while taking hesperidin. As proof that it worked, he said, when these women wanted to have children and stopped taking hesperidin, they became pregnant within a month or two.
“Leo jumped on that,” recalled Doering, “and asked the doctor whether he had followed very carefully the length of each pregnancy—that is, the relation between the date when they said they wanted to become pregnant and the date of delivery. This went on and on, and it gradually dawned on the poor guy that because his patients were so attracted to him, rather than say, ‘The hesperidin hasn’t worked and I’ve become pregnant!’ they came around instead with this reasonable story that they had to drop out of the experiment.” A few weeks after Szilard’s grilling, the doctor committed suicide.
“Leo was quite disturbed when he realized what he had done,” Doering recalled. “Where he thought he was carrying out an objective, intellectually based conversation, he had been unaware of the emotional impact of what he was telling this man, namely, that he had been deceived— through the best of human intentions—by his patients.”
Yet in other situations, Szilard’s aggressive mind gave way to deep concern about the personal cares of his friends and relatives. He chatted by the hour with their children and told stories to them that always had some clever twist. Many times Szilard offered consoling advice about personal decisions, once taking a day to visit Doering’s estranged wife in New Jersey just to be sure that their planned divorce was really the best action. Szilard also enjoyed brainstorming with young people, especially about their personal and career decisions.52
But a tension was always there between Szilard’s fiery reason and his cool emotions. “Leo is almost frightening when he’s on the trace of knowledge,” Doering said later. “He literally pulls men’s minds apart.”53 At conferences, Szilard’s behavior was notorious. To some he seemed rigorous and logical; to others, obnoxious and lazy. The “Szilard index” became a new standard among biologists as a way to gauge each speaker’s intellectual appeal. As John Platt recalled the procedure, whenever a dull speaker begins to talk, Szilard rises from his usual seat in the front row and marches majestically up the aisle—often through a slide-projector beam—to the door. Pausing there, he “stands with his hand on the knob for one sentence, nods as if to confirm his judgment, and departs.” This index was part of Szilard’s broader strategy for conference going: Don’t be overwhelmed by all the papers and talks, good and bad. Instead, focus on just a few, but think about them intensely.
“There is a legend that I sleep in seminars but that I always wake up to ask a question that shows I have been listening and sleeping at the same time,” Szilard told Platt over lunch at a 1958 biology conference in Boulder. “But it is only a legend—the truth is that I sleep; but when I wake up, I don’t open my eyes until I am ready to ask the question.”54
Outside formal meetings, Szilard enjoyed staging rump sessions: At Boulder, he bought two aluminum beach chairs, set them on the lawn or on the roof of the student union building, and sat there talking with one person at a time. He played mentor to a circle of younger scientists, whom he found more creative than colleagues his age, among them Leslie Orgel from Cambridge and Matthew Meselson from Cal Tech. Meselson later said that Szilard had changed his life with advice given at Boulder: Don’t be driven by conscience to “finish up” dull projects, but plunge into work on your next appealing idea.55
“When I would tell Leo I was going to a seminar,” Novick recalled, “he would later ask me if it was interesting. If I said yes, he would call the speaker and invite him for dinner, thereby getting a personal seminar and avoiding the chance of wasting time at a bad talk.”56
Szilard’s own freewheeling style, his zest for brainstorming, his need to push and probe and ponder ideas, set him apart from colleagues who toiled on well-focused research projects and doggedly saw them to conclusion. Scientists can cite few of Szilard’s papers, for there are few, but will recount by the hour their exciting conversations with him. During his first visit to the United States, in
1954, Austrian zoologist Konrad Lorenz met Szilard at a party in the apartment of law professor Hans Zeisel, on Riverside Drive in New York. For half an hour, Szilard sat next to Lorenz in an armchair, staring morosely across the room, but then turned abruptly to say, “I was reading the other day . . .” and suggested an experiment in animal behavior. Lorenz looked at his wife in amazement. “That was the experiment I suggested to you last week,” he said. For fifteen minutes Lorenz and Szilard began talking, soon in half sentences, neither waiting for the other to finish—or needing to. Zeisel’s daughter, Jean, was so excited by the intellectual frenzy that she burst into tears.57
Recalling that episode, Lorenz remembered Szilard as “one of the most intelligent men I ever met.” Later that night, he said, while riding in a taxi, Szilard asked him about Erich von Holst’s “reafference principle,” which explains sensations produced by the movements of a sensory organ, as when we detect after spinning around that the room is spinning in the opposite direction. “After moving only about two blocks, he had completely grasped the . . . principle and proved it by giving a striking example of its working which was entirely new to me.”58
At a party in biologist Bernard Davis’s New York apartment, as Monod, Jacob, Novick, and other distinguished researchers chatted in the living room, Szilard refused to join them. Instead, he took over a bedroom and, in turn, invited each guest in for a private chat, quizzing them on their latest work and findings, suggesting new experiments and novel interpretations of their research data, and reporting how that might relate to the work of others.59 Participants found these interviews exhilarating, but also exhausting.
In New York another time, Szilard rushed into Maurice Fox’s laboratory at the Rockefeller Institute, excited to report that “biological clocks”—cyclic activities in the behavior of living organisms—are not affected by tempera ture. “If there’s no temperature coefficient, that means it’s unlikely to be a chemical process. . . . Could it be an electrical circuit that is independent of temperature?” he wondered. Suspecting that an immutable law of biology might lie behind this fact, Szilard said, “If there’s an undiscovered principle of physics, it seems likely that the biosphere will have employed it,” and asked Fox to arrange a talk with some neurobiologists. Fox called a colleague, Theodore Shedlovsky, who offered to invite some electrophysiologists to lunch. And, he reported, Norbert Wiener, a pioneer in cybernetics, was around the institute and might also join them; at the time, Wiener was studying alpha rhythms in the brain, another cyclic phenomenon.
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