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Bacterial Mutations

Luria and Delbruck Hit the Jackpot (1943)

Chris Evers

Today bacteria are an important tool in the study of genetics and biotechnology, but for 40 years after the rediscovery of Mendel's work and the rebirth of genetics, they were considered too simple to have genes, undergo mutation, or reproduce sexually. This is not surprising - bacteria are so small that it's very difficult to study individuals. Scientists had long observed differences between bacterial colonies, but had never realized that these differences were the results of mutations.

It was well known that if a bacterial virus was added to a flask containing bacteria, the liquid in the flask would become clear, as if the virus had killed all the bacteria. However, with time, the flask would once again become cloudy as the bacterial population rebounded - now composed of virus-resistant bacteria. This happened even when all the bacteria in the flask were the clonal offspring of a single bacterium. Although such bacteria should have all been genetically identical, some of them were susceptible to the virus while others were resistant.

Two explanations for this unexpected variation confronted the scientific community: either (1) exposure to the virus had caused some small proportion of the bacteria to become immune and able to pass this immunity on to their offspring, or (2) the virus-resistant form already existed in the colony prior to the introduction of the virus - having arisen through mutation - and it was selected for by the addition of the virus.

To determine which explanation was correct, Salvador Luria and Max Delbruck, working together at Cold Spring Harbor during World War II, devised a test. According to Luria, his inspiration for the test was his observation of a colleague playing at a dime slot machine at a faculty dance. After consistently losing for some time, his friend finally hit the jackpot. Luria realized that if the slot machine distributed payoffs randomly, according only to chance, the payoff would usually be zero, occasionally be a few dimes, and almost never be a true jackpot. However, the machine he was observing had clearly been programmed to return an excess of both zeros and jackpots.

Luria returned to the lab and set up a large number of bacterial cultures, starting each one from only a small number of cells. He allowed the cultures to grow for a while, then added virus and counted how many bacteria survived (were resistant). He reasoned that if resistance was induced in bacteria randomly, in response to contact with a virus, it would be expected to occur at a zero or low level in all cultures - like the zero or small payoffs from a slot machine operating by chance. Alternatively, if resistance was the result of a mutation, the results would be analogous to the payoff from a programmed slot machine. Most bacteria in most cultures would not mutate, but if one did, it would reproduce and when the virus was added there would be many survivors - a jackpot! By looking at the fluctuations in the pattern of payoff (viral resistance), he and Delbruck could determine whether they were governed purely by chance or if the game was "rigged" by mutation.

It turned out that the number of resistant bacteria varied greatly between cultures; the fluctuations in payoff were far too great to be accounted for purely by chance. These fluctuations proved that bacteria did undergo mutation - and that the resistance to the virus they used in the experiment (a T1 bacteriophage) arose through such mutation.

By analyzing their data further, Luria and Delbruck were also able to determine the rate of bacterial mutation from virus-sensitive to virus-resistant. The likelihood of any single bacterium mutating during each cell division was extremely low - only about one in a hundred million, explaining why it was so difficult to detect and study bacterial mutations. Luria and Delbruck were successful because they created a method that screened for the outcomes of such rare events. They screened for the mutation from virus-sensitive to virus-resistant by exposing the cultures to the fatal virus. Other mutations, for which there was no such screening method, would have been almost impossible to detect.

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