Frederick Griffith utilized two strains of Streptococcus pneumoniae bacteria. The R strain was not virulent, meaning it didn't kill mice. The S strain was virulent, meaning it did kill mice. When Griffith heat-killed S strain bacteria, and mixed them with R strain bacteria, the R strain bacteria became very similar to the S strain. Its outer capsule changed and it became lethal to the mice. Griffith determined some type of "transforming principle" must have caused the R strain to take on traits of the S strain.

Oswald Avery, Colin MacLeod, and Maclyn McCarty followed up on Griffith's work to figure out what molecule was acting as the transforming principle. They took the heat-killed S strain bacteria and treated them with proteases, lipases, and ribonucleases. These are enzymes that break down proteins, lipids, and RNA, respectively. When these different molecules were broken down, the dead bacteria mixture was still able to transform the R strain. Avery and his colleagues determined that DNA was the most likely candidate to be the transforming factor.