The 1943 Luria–Delbrück fluctuation experiment showed that bacterial resistance mutations occur before exposure to the selecting virus.
Salvador Luria and Max Delbrück grew separate cultures of Escherichia coli and then exposed them to bacteriophage T1. If the virus caused resistance directly, the numbers of resistant bacteria should have been similar across cultures. Instead, the cultures showed large fluctuations: some had many resistant colonies, while others had few or none.
The pattern indicated that random mutations arose during bacterial growth before the phage was encountered. The virus selected resistant cells rather than instructing ordinary cells to become resistant.
This experiment established a central principle of evolution: mutation is random with respect to need, while natural selection changes the frequency of variants. Luria and Delbrück received the 1969 Nobel Prize in Physiology or Medicine.