In 1928, British medical officer Fred Griffith reported an experiment that exposed a problem biology could not yet explain. He mixed living, nonvirulent pneumococci with heat-killed cells from a virulent strain, injected the mixture into mice, and recovered living virulent bacteria afterward. The change persisted through subsequent generations of bacteria.
Something from the dead cells had permanently altered the living ones. Griffith had demonstrated transformation without knowing what chemical substance carried the information, and it would take another sixteen years before Oswald Avery, Colin MacLeod and Maclyn McCarty identified that substance as DNA.
The mouse that shouldn’t have died
Griffith was a medical officer at Britain’s Ministry of Health Pathological Laboratory, where pneumococcus was a serious public-health concern. His 1928 work compared forms of the bacterium that behaved very differently in mice.
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The smooth, or S, form carried a polysaccharide capsule and could be virulent. The rough, or R, form lacked that capsule and was generally nonvirulent in the experimental conditions Griffith used.
His controls behaved as expected. Living R bacteria did not kill the mice, living virulent S bacteria did, and heat-killed S bacteria by themselves did not.
Then came the combination that mattered. Griffith injected living R bacteria together with heat-killed S bacteria. The mice died, and living S-type bacteria could be recovered from them.
A permanent, heritable change
The striking part was not simply that virulent bacteria appeared. The transformed bacteria kept the new characteristics when they reproduced, showing that the change was stable rather than a temporary reaction inside the mouse.
Griffith called the phenomenon transformation. In modern terms, the experiment had revealed the transfer of hereditary information, but his work did not establish what molecule carried that information.
That distinction matters. Griffith had found the phenomenon, not DNA’s role in it, and he died in 1941 before the chemical identity of the transforming material was established.
Why DNA looked unlikely
To modern readers, DNA can seem like the obvious answer. It was not obvious in the late 1920s and early 1940s.
Most scientists who thought about the chemical nature of genes considered proteins the stronger candidate. Proteins were chemically varied and built from many different amino acids, while DNA appeared comparatively simple, with only four principal bases.
That apparent simplicity mattered. If heredity required a molecule capable of encoding enormous biological complexity, protein seemed to many researchers like the more plausible material.
Oswald Avery and the problem Griffith left behind
Across the Atlantic, Oswald T. Avery had been studying pneumococcus at the Rockefeller Institute since 1913. Avery was born in 1877, so he was about 50 when Griffith’s paper appeared, not in his mid-fifties.
Researchers gradually made Griffith’s phenomenon easier to study outside the mouse. Transformation was reproduced in laboratory culture, and subsequent work showed that material extracted from virulent pneumococci could produce the same change.
That made the mystery a chemical problem. If the transforming activity could survive in an extract, researchers could separate its components and ask which one carried the effect.
The chronology of the team is important. Rockefeller University’s history records that Colin MacLeod worked in Avery’s laboratory during the 1930s and developed a pneumococcal strain that could be transformed predictably. Maclyn McCarty joined Avery’s group in 1941 and took on much of the purification and chemical analysis of the transforming material.
The stringy white substance
As the material was purified, the case increasingly pointed away from protein and toward nucleic acid. Treatments that attacked protein did not eliminate the transforming activity, and neither did treatment directed at RNA. When DNA-degrading activity was introduced, transformation disappeared.
The active fraction behaved chemically like DNA. By the end of 1943, Avery and McCarty had concluded that the transforming substance responsible for the permanent hereditary change was deoxyribonucleic acid.
Avery understood that the result reached far beyond pneumonia. At about midnight on May 26, 1943, he wrote to his brother from his New York apartment about the material his laboratory had been studying, cautiously describing it as something that might be a gene.
The work was published with MacLeod as the third author. As The Scientist’s retrospective records, Avery, MacLeod and McCarty became the three names attached to the experiment that connected DNA with hereditary information.
A cautious paper, a major result
Their paper appeared on February 1, 1944, in the Journal of Experimental Medicine. Its title was characteristically restrained: “Studies on the chemical nature of the substance inducing transformation of pneumococcal types.”
The authors did not announce that they had solved heredity. They laid out the purification, chemical analysis and biological activity of the transforming fraction and concluded that its properties were consistent with a highly polymerized form of DNA.
The result attracted attention quickly. Joshua Lederberg, who would later become a Nobel laureate for work on genetic recombination in bacteria, was among the young scientists who recognized how far the finding could reach.
Acceptance was not universal, however. One persistent objection was that even highly purified DNA preparations could contain traces of protein, leaving room for skeptics to argue that an undetected protein might still be responsible for the biological effect.
The years of uneven acceptance
The period after 1944 was therefore not eight years of scientific silence. Avery’s work was discussed and praised soon after publication, while disagreement continued over whether the experiment had finally proved that genes were made of DNA.
Erwin Chargaff turned greater attention toward DNA chemistry and showed that the proportions of its bases were not the monotonous pattern earlier models had suggested. Geneticist Hermann Muller also recognized the importance of Avery’s evidence while remaining cautious about whether traces of protein had been completely excluded.
In 1945, the Royal Society awarded Avery the Copley Medal. He nevertheless never received a Nobel Prize, and he died in 1955 after the genetic role of DNA had become far more widely accepted.
The kitchen blender that strengthened the case
Another famous experiment arrived in 1952. Alfred Hershey and Martha Chase used bacteriophages, viruses that infect bacteria, whose protein and DNA components had been labeled with different radioactive isotopes.
After the viruses infected bacterial cells, the researchers used a Waring blender to separate viral coats from the bacteria. Most of the phosphorus label associated with DNA remained with the infected cells, while most of the sulfur label associated with protein stayed with the discarded viral material.
The experiment was not a simple replay of Avery’s work, but it gave researchers another system in which DNA, rather than protein, entered cells during the transfer of biological information.
Then came 1953. James Watson and Francis Crick proposed the double-helical structure of DNA, drawing on experimental evidence generated at King’s College London, including Rosalind Franklin’s X-ray work and data that reached the Cambridge group. The BBC Science Focus history describes how Franklin’s Photo 51 and other data contributed to the sequence of events that led to the model.
The structure was published in Nature in April 1953 alongside papers from the King’s College researchers. None of those three structure papers cited Avery’s 1944 work.
Sixteen years, one molecule
The distance from Griffith’s 1928 experiment to Avery, MacLeod and McCarty’s 1944 paper was sixteen years. During that interval, a puzzling observation in mice became a reproducible laboratory phenomenon, then a biochemical purification problem, and finally evidence that DNA could carry hereditary information.
The sequence was less tidy than retrospective accounts sometimes make it sound. Different researchers supplied different steps, and MacLeod and McCarty joined Avery’s work at different times rather than functioning as one fixed team for a decade.
But the scientific connection is clear. Griffith showed that a stable trait could pass from dead pneumococcal cells into living ones, and Avery’s laboratory eventually identified the material responsible for that transformation as DNA.
What Griffith’s transformation became
Natural transformation is now understood as a process in which some bacteria take up DNA from their surroundings and incorporate it into their genomes. It is also a powerful laboratory technique for introducing genetic material into bacterial cells.
In pneumococcus, transformation still matters outside the laboratory. A review in FEMS Microbiology Reviews describes natural transformation as an efficient route by which beta-lactam resistance determinants can spread between streptococcal strains and species.
That modern relevance makes Griffith’s result more than an elegant historical experiment. The same basic capacity to acquire DNA that puzzled researchers in 1928 remains part of how bacterial populations change and adapt.
Why acceptance took time
There was no single reason DNA took time to win broad acceptance as the genetic material. Protein had seemed chemically better suited to heredity, DNA chemistry was still poorly understood, and concerns about contamination gave skeptics a legitimate experimental question to keep asking.
Avery’s own style was cautious rather than promotional. The Guardian’s historical account notes that the significance of the work was recognized quickly by some scientists, even as many geneticists and chemists remained unconvinced well into the following years.
The image that survives from May 1943 is therefore powerful without needing embellishment. Avery, in his mid-sixties, was awake around midnight in his New York apartment, writing privately to his brother about a result his laboratory had spent years trying to understand.
He had not yet published the paper that would carry his name beside MacLeod’s and McCarty’s. Griffith had already supplied the mystery fifteen years earlier. What Avery’s laboratory now had was the chemical answer: the transforming material was DNA.