Avery’s experiment was a landmark 1944 study that identified DNA as the molecule responsible for heredity. Oswald T. Avery, along with Colin MacLeod and Maclyn McCarty, published their findings in the Journal of Experimental Medicine under the title “Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types.” Their work provided the first strong evidence that DNA, not protein, carries genetic information from one organism to another.
The Problem Avery Set Out to Solve
Avery’s experiment built on a puzzling discovery made 16 years earlier. In 1928, British microbiologist Frederick Griffith was working with two strains of the bacterium Streptococcus pneumoniae. One strain, called “smooth” (S), had a thick sugar-based capsule on its surface and was deadly to mice. The other strain, called “rough” (R), lacked this capsule and was harmless.
Griffith’s key finding was this: when he injected mice with a mixture of live harmless R bacteria and heat-killed deadly S bacteria, the mice died. Something from the dead S bacteria had transformed the living R bacteria into killers, complete with the smooth capsule they’d never had before. Griffith called this mysterious substance the “transforming principle,” but he never figured out what it was. He suspected it might be leftover capsule material that the R bacteria could somehow absorb and use.
For the next decade and a half, no one pinpointed the identity of this substance. Most scientists at the time assumed proteins were the carriers of biological information, since proteins are large, complex molecules with enormous structural variety. DNA, by contrast, was considered too simple and repetitive to encode anything meaningful. Avery’s team set out to settle the question by isolating the transforming principle and determining exactly what it was made of.
How the Experiment Worked
Avery, MacLeod, and McCarty started with large cultures of heat-killed S-strain bacteria. Through a long series of biochemical steps, they progressively stripped away different cellular components, washing, separating, and enzymatically destroying them one by one. The goal was to purify the transforming principle down to its essence, then test whether it still worked.
The critical tests involved treating the purified substance with enzymes that specifically destroy one type of molecule at a time. Proteases, which break down proteins, had no effect on the transforming principle. Lipases, which digest fats, didn’t destroy it either. Ribonuclease, which breaks down RNA (a nucleic acid related to DNA), also left the substance fully active. But when the team exposed the transforming principle to enzymes that degrade DNA, its ability to transform bacteria was eliminated completely.
This process of elimination was powerful. If the substance were protein, proteases would have destroyed it. If it were RNA, ribonuclease would have stopped it. Only DNA-destroying enzymes knocked it out.
The Chemical Evidence
The enzyme tests alone weren’t enough to make a definitive case. Avery’s team also ran chemical analyses on the purified transforming substance to see whether its composition matched what DNA should look like. One of the most convincing results involved the ratio of nitrogen to phosphorus in the samples. DNA has a characteristic ratio of about 1.69 parts nitrogen to every 1 part phosphorus. Proteins, by contrast, contain very little phosphorus and have a much higher nitrogen-to-phosphorus ratio.
Four independent preparations of the transforming principle yielded nitrogen-to-phosphorus ratios ranging from 1.58 to 1.75, all clustering tightly around the theoretical DNA value of 1.69. This was strong chemical confirmation that the substance was DNA, not protein.
What the Results Meant
The experiment demonstrated that DNA alone could permanently change one type of bacterium into another. R-strain bacteria that absorbed purified DNA from S-strain bacteria didn’t just temporarily gain a capsule. They became S-strain bacteria and passed that trait to all their descendants. This was hereditary change driven by a specific molecule, and that molecule was DNA.
This was a direct challenge to the dominant view in biology. Through the 1930s and into the 1940s, most geneticists and biochemists believed that proteins, with their 20 different building blocks and enormous structural diversity, had to be the molecules encoding genetic information. DNA, built from only four chemical units, seemed far too simple. Avery’s results suggested otherwise, but the finding met considerable resistance.
Why Many Scientists Were Skeptical
Despite the rigor of the work, Avery’s conclusions were not immediately accepted. Many scientists in the emerging fields of biochemical genetics and phage research downplayed or simply ignored the paper. The skepticism wasn’t driven by flaws in the experiment so much as a disciplinary gap. Avery and his colleagues were chemically oriented microbiologists. The geneticists who might have been most interested in the identity of the genetic material were committed to physical methods like X-ray studies and remained attached to the idea that proteins were the sole carriers of biological specificity.
Some critics raised the concern that even tiny amounts of protein contamination in the purified DNA could be the real transforming agent. Though the enzyme tests strongly argued against this, the objection lingered until further experiments closed the door. The most famous of these was the 1952 Hershey-Chase experiment, which used radioactive labeling to show that when viruses infect bacteria, it is the viral DNA that enters the cell, not the protein coat. Together with Avery’s work, this made the case for DNA essentially airtight.
How It Shaped Modern Genetics
Avery’s 1944 paper reframed the central question of biology. Once DNA was recognized as the genetic material, the next obvious question became: how does its structure allow it to store and transmit information? That question drove James Watson and Francis Crick to build their famous double-helix model in 1953, which revealed how the four chemical units of DNA could encode an essentially infinite variety of genetic instructions through their sequence. Watson and Crick’s model shifted the entire field from asking what genes are made of to asking how genes actually work.
Avery himself was notably cautious in his published paper, careful not to overclaim. He was 67 years old when the study was published, and he never received a Nobel Prize for the discovery, a fact many historians of science consider one of the award’s most significant oversights. Still, the experiment stands as one of the most important in the history of biology: the first rigorous demonstration that DNA is the substance of heredity.