By the time he finished medical school in 1935, Luria knew he did not want to practice medicine. He had worked in the histology lab of Giuseppe Levi during medical school, became well-versed in laboratory techniques and procedures, and published several articles, but did not find histology very exciting. He was inspired to pursue biophysics by his friend Ugo Fano, a physics student who regaled him with tales of the revolutionary new ideas of Niels Bohr, Werner Heisenberg, Erwin Schrödinger, and Enrico Fermi. After a disappointing venture into radiology, Luria was able to spend much of 1938 studying physics at the University of Rome with a faculty that included Fermi. He experienced difficulty with the mathematics of physics and concluded that his interest in the field would remain amateurish rather than professional. But his "year among the physicists" was a critical turning point for him, first, in that it taught him to think more as a physicist, and second because it introduced him to radiation biology, specifically the work of a young German physicist--Max Delbrück.

Delbrück had for several years been working on a quantum model of gene mutation, in the wake of H. J. Muller's discoveries that X-rays and ultraviolet radiation could cause mutations in fruit flies. The paper he published in 1935 with Nicolai Timoféeff-Ressovsky and K. G. Zimmer constituted one of the earliest forays into what came to be called molecular biology. It included measurements of the radiation doses, a dose-response curve showing the relationship between the radiation dose and the number of mutations, and a quantum mechanical model to tie them together. The most important conclusion drawn from this study was that irradiating the genetic material caused a "quantum jump" which made itself visible as mutation. That is, genes might be stable in the same way that regular molecules were stable, having different energy states, and undergoing "quantum jumps" from the normal state to another stable state. By linking genes with the measuring systems of chemistry and physics, this research changed "the gene" from an abstract entity to a macromolecule.

Luria was excited by this idea of the gene as a molecule (which, he said later, seemed to "open the way to the Holy Grail of biophysics") and began thinking about ways to test the theory. He knew next to nothing about the young sciences of genetics and biochemistry, and wasn't sure how to start his quest for the biophysical grail. Fruit flies (Drosophila) were the classic organism for genetics research at the time, but Luria thought something smaller and simpler would be better. Ideally, it would be an organism on which effects of radiation could be measured with precision; therefore it had to be an organism that could be handled in large numbers, preferably a microorganism, so that even small effects would be detectable. A chance conversation with bacteriologist Geo Rita one day (aboard a stalled trolley car) led to a visit to Rita's lab. Rita was using bacteriophage--viruses that infect bacteria--to assess bacteria levels in the Tiber river. Working with Rita, Luria quickly learned how to grow and count the viruses, and believed that their small size and rapid growth would make them ideal organisms to test Delbrück's theories.

In July of 1938, Luria received an Italian government fellowship to work in the United States for a year. He hoped to spend it with Delbrück, who had already left Germany and had also begun investigating the possibilities of phages. Mussolini's "Racial Manifesto" went into effect the very next day, and Luria, as a Jew, was barred from taking the fellowship. As the persecution of Jews escalated in Germany, and Italy became firmly allied with that country, Luria decided to leave Rome and try his luck in Paris. There he was able to get a fellowship from the National Research Fund, and went to work in the laboratory of Fernand Holweck at the Institute of Radium. Holweck and several colleagues had also been working with radiation and microbes. Luria joined them and they ran experiments comparing the action of x-rays of various energies with that of alpha-rays on the C16 phage of E. coli.

When the German army closed in on Paris in June 1940, Luria, like many others, fled to southern France, continued on to Portugal, and then to New York. With a Rockefeller fellowship arranged by Enrico Fermi, he continued his phage irradiation studies at Columbia University with Frank Exner. They published several papers together, including an experiment showing that phage was more sensitive to x-ray damage in distilled water or salt solutions than in broth, gelatin, or albumin solutions--large protein molecules protected the phage to some extent.

Luria finally met Max Delbrück at the annual meeting of the American Physical Society on December 30, 1940. They spent New Year's Day in Luria's lab, playing with bacteriophage, and made plans to collaborate during the summer at Cold Spring Harbor Laboratory (CSHL) on Long Island. That summer was Luria's full initiation into the world of genetic science. He and Delbrück began their first investigation by asking what actually went on between the time the phage attacked the bacterium and the time the bacterium burst open and dissolved, liberating the new phage particles. They decided to add two types of viruses--one slower-acting, one faster-acting--to one bacterial strain, thinking that one virus might lyse (break open and dissolve) the cell while the other was still growing, giving them a look at an intermediate stage of virus growth. They discovered, instead, that only one of the phages could multiply: there was complete mutual exclusion. Interpreting these results was difficult, in the absence of specific knowledge of DNA structure and function. (It would later become clear that each phage attacking a bacterium reprograms the biochemical machinery to obey the phage genes. The programs of two different phages are generally as incompatible as phage and bacterium, so they exclude each other.) But these early experiments were an important step in the development of molecular biology, because they focused attention on possible mechanisms of phage multiplication, and shifted the interest of virus workers from the problem of cell damage by viruses to the life cycle of viruses themselves.

During the winter of 1941-42, Luria worked with biophysicist Thomas Anderson to take some of the first electron microscope pictures of bacteriophage and measure the tadpole-shaped particles. (When they showed these to J. J. Bronfenbrenner, the first American to work with phage after its discovery in Europe, he exclaimed, "Mein Gott! They've got tails!") Delbrück joined Luria and Anderson at CSHL that summer, and with the new electron microscope there confirmed their earlier conclusions regarding adsorption of the phage and the time it took for phage to lyse the cell and liberate new phage. It also showed that the complete phage never entered the cells. This work helped win Luria a Guggenheim fellowship, allowing him to spend much of 1942 at Vanderbilt University with Delbrück.

Luria and Delbrück then turned their attention to the development of phage-resistant bacteria. Bacteriologists had long noted that if a culture of bacteria is spread with a phage that attacks it, the phage will completely destroy all but a few bacteria within a day. Those few grow into colonies, and the cultures derived from them are specifically and permanently resistant to that phage. Does this result from the direct action of phage on a few bacterial cells, or from spontaneous mutation? If the latter, bacteria must have genes to mutate, though at the time many scientists doubted that bacteria had chromosomes.

They did not succeed in devising a critical experiment to approach the problem while Luria was at Vanderbilt, but he continued to work on it following his move to Indiana University in January 1943. His "eureka moment" came soon after, as he watched people play with a slot machine at a party. He drew an analogy between slot machines and bacterial mutations: an honestly programmed slot machine returns about 90% of money put into them, but distributed very unevenly--most trials produce nothing, some yield small amounts, and a few yield jackpots. And the variation of results will be much greater than random. In contrast, a completely un-programmed slot machine pays off at random, in a pattern technically called a Poisson distribution of rare independent events. Suppose Luria compared the numbers of resistant bacteria in each of 20 different cultures with the expected returns from different kinds of slot machines? If the phage produced the mutation, then all bacterial cells should be equally sensitive before the phage was introduced and cultures should have similar numbers of small resistant colonies after the phage has lysed the sensitive cells--like the random payoff of an un-programmed slot machine. If, however, mutation was occurring prior to phage exposure, there would be resistant colony clusters in some of the cultures, none in others, and very large ones in a few, after exposure to phage. That is, the number and size of resistant colonies would fluctuate much like the payouts of a programmed slot machine. This is exactly what Luria found.

Luria immediately wrote to Delbrück, who worked up a mathematical proof, providing two ways to calculate mutation rates from the number of mutants observed. Their description of this "fluctuation test"--"Mutations of Bacteria from Virus Sensitivity to Virus Resistance"--published in Genetics, marked the birth of bacterial genetics.