The Search for Genetic Material

The central question that early geneticists faced was simple: what molecule inside the cell actually carries hereditary information? By the early twentieth century, scientists knew that chromosomes — made of both DNA and protein — were the physical carriers of genes. But which of these two components was the genetic material itself? The answer came from a series of elegant experiments, each narrowing down the possibilities.

The Transforming Principle: Griffith's Experiment (1928)

Frederick Griffith was working with two strains of the bacterium Streptococcus pneumoniae (then called Pneumococcus). One strain, the S strain (smooth), had a polysaccharide coat that made it virulent — injecting it into mice killed them. The other, the R strain (rough), lacked this coat and was non-virulent — mice survived.

Griffith performed four key injections:

• Live S strain → mouse died. The bacteria were recovered from the dead mouse's blood.
• Live R strain → mouse lived. No bacteria were recovered.
• Heat-killed S strain → mouse lived. The heat treatment destroyed the S strain's ability to cause disease.
• Mixture of heat-killed S strain + live R strain → mouse died. Crucially, live S strain bacteria were recovered from the dead mouse's blood.

Something from the dead S strain had "transformed" the harmless R strain into a virulent S strain. Griffith called this phenomenon transformation. He concluded that a transforming principle — a chemical substance — had been transferred from the dead S cells to the live R cells, permanently changing their hereditary character. He did not, however, identify what that substance was.

The Chemical Nature of the Transforming Principle: Avery, MacLeod, and McCarty (1933–44)

Oswald Avery, Colin MacLeod, and Maclyn McCarty set out to identify Griffith's transforming principle. They repeated the transformation experiment in vitro (in a test tube, not in mice) and systematically eliminated each major class of biomolecule.

They took a cell-free extract from the S strain (containing DNA, RNA, proteins, and polysaccharides) and treated it with different enzymes:

• Proteases (which break down proteins) — transformation still occurred.
• RNase (which breaks down RNA) — transformation still occurred.
• DNase (which breaks down DNA) — transformation did not occur.

Only when DNA was destroyed did the transforming activity vanish. They also purified the transforming substance and showed that its chemical composition and physical properties matched those of DNA. …