The day after my arrival, I arranged my courses for the coming term. Naturally I signed up for Muller's Advanced Genetics—Mutations and the Gene. I was also urged by Fernandus Payne to take as soon as possible Microbial Genetics with Tracy Sonneborn, since he was zoology's brightest young star. But that term he was only teaching an elementary genetics class, and so I registered for Salvador Luria's course on viruses. Soon I heard faculty gossip that Luria treated his students like dogs. This worried me until I listened to his first several lectures and found them mesmerizing. Less comprehensible to my Zoology Department advisers was my desire to register for Advanced Calculus, a course usually taken only by physics and math majors. But unless I took it, I feared, I would never have the courage to learn more physics, without which I might be precluded from pursuing possible high-powered ways to probe the gene. Ironically, my teacher was to be Lawrence Graves, on sabbatical from the University of Chicago, where I never would have dared enter into one of his courses. But at the more low-key Indiana I would not be competing with real math whizzes— and besides, grades were rather beside the point.
The required text of Muller's course was the lucid and still highly relevant Introduction to Modern Genetics (1939) by the English biologist C. H. Waddington. The heart of the course, however, was Muller's lecture account of his career starting from his days as a student in the “fly room” of Columbia University between 1910 and 1915. Emanating from a short, heavyset man almost the shape of a Drosophila himself, Muller's lectures were streams of consciousness rather than prepared orations. His agitated speech mingled clever genetic reasoning with details of his frustrations over, say, not initially being accepted into T. H. Morgan's lab, and later when finally a member having his ideas given short shrift. Much less absorbing were the lab sessions, in which we were chaotically run through an increasingly complex set of genetic crosses. The insights of such experiments seemed rather arcane, pointing to a truth that could not be avoided: Drosophila's days as a model organism were over. Indeed, a new one would soon supplant it as the premier tool for studying the gene.
Through Luria's virus course lectures, I saw the genetic wave of the future unfolding. The key would be microorganisms, whose short life cycles would permit genetic crosses to be done and analyzed in a matter of days instead of weeks or months. Luria was particularly excited about the future of research using the common intestinal bacterium Escherichia colt and its parasitic viruses, the bacteriophages (or phages for short, as they were more often called). Soon after his 1943 arrival in Bloomington Luria, then thirty-one, was the first to systematically show that both E. coli and its phages gave rise to easily identifiable spontaneous mutants. Only three years later, in 1946, was genetic recombination between different E. coli strains demonstrated by the precocious twenty-one-year-old Joshua Lederberg, then a medical student in Edward Tatum's laboratory at Yale. The same year Alfred Hershey at Washington University found genetic recombination for the E. colt phages T2 and T4 and soon constructed the first genetic maps of phage chromosomes.
Until Luria's first lecture, I had no idea what a virus was. Soon I knew they were very small, infective agents that multiplied only within living cells. Outside of cells, viruses are essentially inert. But once they enter a cell, a multiplication process is initiated that leads to a generation of hundreds to thousands of new progeny viral particles identical to the original parent particle. Unlike bacteria, viruses cannot be observed using conventional microscopes. Their sizes and shapes first became known following the invention of the much more powerful electron microscope in Germany just prior to the start of World War II. The first phages so examined had unexpected tadpole-like shapes, with polygonal heads attached to much thinner, tail-like appendages.
More than two decades earlier, H. J. Müller had speculated that viruses were, in fact, naked chromosomes that had acquired special structures for being transported from one cell to another. Supporting his conjecture was the finding in the mid-1930S that DNA, a soon-to-be-discovered major component of all chromosomes, also was a major component of the phages. Even more important was the 1944 discovery by Oswald Avery and his coworkers at the Rockefeller Institute in New York that DNA could transmit genetic markers in pneumonia bacteria. Conceivably much, if not all, of the genetic specificity of phages also resided in their DNA components.
Luria's lectures were also particularly exciting for me because they frequently described his collaborations of the past six years with the German-born physicist Max Delbrück, whose ideas about the gene in the mid-1930S provided the essence of Erwin Schrödinger's What Is Life? How a gene is copied to yield an identical replica was now being extended by Luria and Delbrück to ask how a single phage particle gives rise to hundreds of identical progeny. In learning how phages multiply, Luria and Delbrück thought the fundamental mechanism of how genes are copied would also become known.
A key requirement of Luria's course was the term paper, which I chose to write on the effects of ionizing radiation on viruses. Luria had used X-rays to estimate the size of the then still submicroscopic phages when he worked in Paris in 1938-40, where he had fled when Mussolini, in an attempt to curry favor from Hitler, had begun his first serious persecution of Italy's Jews. Because only a single ionizing event is necessary to kill a phage, a minimal size of a phage can be calculated from the number of phage particles killed as a function of X-ray dose. The so-called target theory approach was previously used in 1935 by Max Delbrück to give an estimate of the size of Drosophila genes, and so I had no difficulty finding enough material to fill out my paper, as no original thought was expected. I was more worried I would be penalized for bad handwriting, but I got an A.
Not so easy was my math course, whose text was Advanced Calculus by Harvard's David Widder. Fortunately, Graves began to appreciate the much lower math aptitudes of his Indiana students in comparison to those he had been used to teaching at the University of Chicago.
What had threatened to be entirely above my head got easier, even occasionally satisfying toward the end. Helping matters was the presence in the class of a small, neat blonde with whom I could compare homework answers at the IU Union cafeteria. A grade of B was more than encouragement enough to continue the course through the spring term. Being able to pass a real math course was a big step forward for me, not only for its own sake but also for allowing me to hold my own with the growing number of physicists moving toward biology to find the secrets of the gene.
Not at all surprising, but nevertheless satisfying, was an A+ in animal ecology. Teaching it was Lamont Cole, a mathematical ecologist, newly recruited by Fernandus Payne to broaden the fish-dominated ecology outlook of IU. I loved learning details of animal adaptation to their environments as well as taking weekly field trips to observe how remarkably specific were the adaptations of certain species to certain niches. On a trip to one of the limestone caves that peppered the rolling hills near Bloomington, armed with rubber boots and several coal miner's lamps, we squeezed through narrow openings into sometimes vast, waterlogged cavities in search of blind cave fish. In the absence of light, there was no selective pressure against the emergence of mutant fish lacking not only scale pigments but also functional eyes. It was through studying blind cave fish that the Indiana zoologist David Starr Jordan rose to prominence. A scientist of great charisma, he would lead IU before being chosen in 1891 as the first president of Stanford University. By my time at IU, however, Jordan was locally best known for quipping that every time he learned the name of a student he forgot the name of a fish.
IU's traditional preoccupation with fish reflected the presence of thousands of lakes dotting the Indiana landscape, ranging from tiny farmer's ponds to lakes many miles wide whose shores were lined with vacation cabins. When I was a child, my mother's Gleason relatives occasionally took us fishing on lakes near Michigan City where on good days we would hook and later fry more bluegill, perch, and bass than we could easily eat. On other days, we would get no bites and go home bitter. The S
tate Department of Conservation began helping the university support its biological station at Winona Lake, where fish yield was measured in units called “fish pole hour.” While there were lakes generally yielding at least several fish per pole hour, there was also the very sad Oliver Lake, where more than ten hours would be needed to bring home a single fish.
By then I was routinely traveling on foot, three times daily, the two miles from my Rogers Center dorm to the science complex and back again. Because of the overcrowding, everyone in Rogers had a roommate and those of us with lab connections tended to avoid our dorm rooms except for sleeping. On these long walks, I liked to go by Jordan Avenue, site of the most desirable sororities, where I would spot girls much prettier than most to be seen in science buildings. For a break from homework or studying for exams, I would occasionally go birding with Palmer Skaar, a fellow new graduate student, who could identify the local birds as well as I. Best of all were the basketball games that began with IU predictably skunking neighboring DePauw. In contrast, most Big Ten games were cliffhangers until the tense closing moments of the last quarter. Also fun, though more intellectually demanding, were the informal Friday night seminars on protozoan genetics that Tracy Sonneborn had begun having at his home to interest the new group of graduate students in his lab's research.
The more I learned about phages, the more I became ensnared by the mystery of how they multiplied, and even before the fall term was half over I knew I did not want to do my degree with Müller. Nor did Muller's work, which seemed increasingly outdated, attract any of the new students his famous presence had drawn to IU that year. Most were captured by Tracy Sonneborn's infectious enthusiasm for the tiny, one-celled, ciliated protozoan Paramecium. I, however, could see no way for paramecia to compete with phages in pursuit of the fundamental nature of the gene. I therefore had to tell Sonneborn, somewhat sheepishly, that I would be working with Luria, fearing that this would spell the end of my welcome at his Friday night protozoan soirees. But he very graciously gave no evidence of feeling spurned and told me that I could keep coming as long as I wanted.
As soon as spring term started, I began learning how to infect E. coli cultures with the T2 phage and to count the number of bacteria that had phages multiplying within them. To my great benefit, I also became friends with thirty-three-year-old Renato Dulbecco, who, like Luria, had trained as an M.D. in Turin and who had come the previous fall to learn how to work with phages. With his family still in Italy, Renato was almost always in the lab and could give me needed advice when the phage counts were not what I expected.
With a light spring course load, I started assisting in the bird course, where help was clearly needed given the prevailing fish bias. There was no real bird expert among the zoology faculty, and so the course was taught by Bill Ricker, the department's best fish man. Long regarded as a gut course—anyone who went on the field trips could expect a passing C—it was now used by physical education majors in the new academic division called Health, Physical Education, and Recreation (HPER) to fulfill their science requirement. In fact, this division came into existence the year before to prevent a repetition of the worst tragedy in IU's history. Robert Herchenmeyer, the best football player ever to attend IU and who in the fall of 1945 led it to its first and only Big Ten championship, flunked out the following spring. Yet for the sake of appearances, HPER majors had to take several courses with nonathletes. And so I found myself helping two jocks learn to identify birds seen on previous Saturday morning field trips and thereby pass the final. For my trouble, I got a look at a number of birds virtually unseen in Chicago, such as the Kentucky warbler, the Bachman sparrow, and the pileated woodpecker, the most impressive of all the birds of southern Indiana.
Back in the lab my first research problem from Luria was to see whether phages inactivated by X-rays could still undergo genetic recombination and produce viable recombinant progeny lacking the damaged genetic determinants present in the parental phages. Two years earlier, Luria had discovered that phages inactivated by ultraviolet light did so recombine when two or more infected the same E. coli host cell. It was to further analyze “multiplicity reactivation” that Luria had brought Dulbecco over from Italy, and he now hoped I could extend his discovery by using X-rays to produce genetic damage. From my first experiment, I began to get positive results, and Luria would regularly look over my notebooks to convince himself that I had done the experiments correctly.
I had to briefly interrupt my experiments when my turn came to give a formal lecture before the zoology faculty. All beginning students were expected to give one during their first year as practice for later careers likely to involve some form of teaching. Since I had come to IU for a zoology degree, I prepared a talk on birds that summarized the conclusion of Darwin's Finches, the new book by the English ornithologist David Lack. Just before the war, he had lived on the Galapagos Islands to follow up Charles Darwin's bird observations of a hundred years before, which had led Darwin to question the immutability of species.
A week after my talk, I first met Max Delbrück. On his way back from a visit at Princeton with his great hero, the Danish theoretical physicist Niels Bohr, he came to spend several days with Luria to learn how the experiments on multiplicity reactivation were progressing. Max was not at all the middle-aged, balding, somewhat overweight German academic I was expecting. Instead my first visit to Luria's flat, several blocks to the south of the main campus, brought me face-to-face with a man who looked more like a fellow student. Max, then forty-one, had come to the United States in 1936, when he was thirty. As a member of the German Protestant academic elite, he was first excited by astronomy. But by twenty, his interests had shifted to theoretical physics, as quantum mechanics was coming into existence. After obtaining at Göttingen his Ph.D. at twenty-four, he spent several years at Copenhagen, the world center for theoretical physics, under Bohr's tutelage. Returning in 1932 to Berlin to work in the great chemist Otto Hahn's Kaiser Wilhelm Institute, Delbrück became acquainted with the Russian-born Drosophila geneticist N. Timofeeff-Ressovsky, who was then using X-rays to induce mutations in Drosophila with the help of the physicist K. G. Zimmer. Discussions among the three of them led to their seminal 1935 paper “On the Nature of Gene Mutation and Gene Structure,” whose ideas formed the core of Erwin Schrödinger's What Is Life?
To move up the German academic ladder, Delbrück needed to demonstrate ideological correctness to the Nazi bureaucracy. Failing to do this, in the fall of 1936 he seized upon an offer from the Rockefeller Foundation of a fellowship that would let him work at Caltech. There T. H. Morgan and his now also famous coworkers, Alfred Sturtevant and Calvin Bridges, had moved in 1929. But after his arrival in Pasadena, Delbrück found Drosophila boring and instead turned to working with the physical chemist Emory Ellis on phages in the basement of the biology building. When the war came, as a German alien he was not eligible for war research. Instead, with continuing Rockefeller support, he moved to Vanderbilt University as an instructor of physics. His collaboration with Luria began soon after Luria's arrival in New York City from Italy. During the summers of 1941 and 1942, they did research at the Biological Laboratory at Cold Spring Harbor on Long Island's North Shore. During the following winter months, Luria came temporarily to Nashville as a Guggenheim Fellow before assuming his position at IU early in 1943.
At supper, Delbrück and Luria talked fondly of their collaboration, particularly at Cold Spring Harbor. Earlier Luria had told me that he would be spending the following summer there and invited Dulbecco and me to accompany him. Delbrück also would be returning, as he had done every summer since 1941.1 listened attentively to talk about the summer course on phages that Delbrück had started in 1945. The summer before, the course had attracted Leo Szilard, the Hungarian physicist, whose name would be forever linked with Enrico Fermi's for their creation of the first sustained nuclear reaction at the University of Chicago in 1942. Luria and Delbrück spent the day after that dinner talking about phages before
playing doubles tennis with Dulbecco and me. I became acutely aware that I would have to elevate my game greatly if I was ever to play singles with Delbrück.
Summer had effectively arrived in Bloomington, with the late May daytime temperatures in Luria's inadequately air-conditioned attic lab often too high for our agar plates to gel quickly. Doing more experiments that term made little sense, even when the temperatures temporarily dipped, and besides, I was preparing for my math finals. I wasn't worried about Advanced Calculus. Graves had let us know that all graduate students would get at least a B for staying in the course (by then all the undergraduates had dropped out). But Differential Equations with Professor Kenneth Williams was another matter. Everyone knew that his real passion had long since become the Civil War and his books on the topic, for which he had received much acclaim. I had no rapport with him, finding him mean-spirited when not boring, and was relieved to get off with a B-.
Max Delbrück with Salvador Luria and his coworker Frank Exner at Cold Spring Harbor symposium, 1941
I was in high spirits when I briefly returned home on my way to Cold Spring Harbor and my first trip to the East Coast. The year had exceeded even my highest hopes, since I was now in the thick of the quest to understand the gene. I became more than aware of the advantages of having attended the University of Chicago, where I had learned the need to be forthright and call crap crap. It was not that I was inherently brighter than my fellow graduate students; I was just much more comfortable challenging ideas and conventional wisdom, whether it concerned politics or science. And never forgetting Robert Hutchins's wisdom that the academic world abounds in triviality, I was ever mindful of what sort of work would further my career and what would be merely idle learning.
Avoid Boring People: Lessons from a Life in Science Page 5