Traits are inherited through 'genes' on chromosomes, but the physical molecule of heredity is unknown.

Gregor Mendel published his laws of hereditary transmission in 1866, in the journal of a regional natural history society in Brno that few biologists ever read. For three decades, the work sat in near-total obscurity. When it was rediscovered simultaneously in 1900 by Hugo de Vries, Carl Correns, and Erich von Tschermak, biology acquired a framework for thinking about how traits pass from parents to offspring. What it lacked was any idea of what physical substance did the passing.

The chromosome theory of heredity, developed through Thomas Hunt Morgan's work with Drosophila fruit flies at Columbia University in the 1910s and 1920s, located the genes on chromosomes and produced detailed genetic linkage maps. Morgan won the Nobel Prize in 1933. By the 1940s, textbooks across the United States and Europe taught that inherited traits were carried on chromosomes. The question of which molecule inside the chromosome was responsible for heredity, which substance actually encoded the information, remained, to most biologists' surprise, genuinely unsettled.

The candidate that most geneticists favored was protein. Chromosomes contain both DNA and proteins, but proteins came in enormous structural variety, twenty amino acids assembled into chains of arbitrary length and sequence, producing a combinatorial space large enough to encode the information needed for heredity. DNA, by contrast, was composed of just four nucleotides, and many biologists believed, incorrectly, that these nucleotides repeated in simple, unvarying patterns. Something so monotonous, the argument ran, could not carry complex information.

That assumption was challenged in 1944. Oswald Avery, Colin MacLeod, and Maclyn McCarty, working at the Rockefeller Institute in New York, published a paper identifying the transforming principle in bacteria, the substance that could transfer heritable characteristics from one strain of pneumococcus to another. Through painstaking chemical extraction and purification, they showed that the transforming substance was deoxyribonucleic acid. Treating it with DNase destroyed the transformation; treating it with proteases did not. The molecule of heredity was DNA.

The paper was received cautiously. Avery himself was restrained in his claims. Many biologists found reasons to doubt the result, in part because the conclusion forced a reconsideration of DNA's structural possibilities. The debate was not fully resolved until Alfred Hershey and Martha Chase published their 1952 bacteriophage experiment, using radioactive labeling to show that when viruses infect bacteria, it is the DNA component that enters the host cell and directs the production of new virus particles, not the protein coat.

By then, the structural question had become urgent. Watson and Crick solved it in April 1953. Their model of the DNA double helix, two antiparallel strands wound together, bases paired by complementary hydrogen bonds, adenine to thymine and guanine to cytosine, had an immediate explanatory payoff that Crick noted in the paper itself: the specific base pairing immediately suggests a possible copying mechanism for the genetic material. If each strand could serve as a template for a complementary strand, the structure explained how genetic information replicated.

The 1953 paper ran to barely 900 words in Nature. Students graduating that spring had almost certainly never heard of it. High school biology teachers, trained in curricula that predated even the Avery paper, were still presenting genetics as a property of chromosomes without specifying the molecule. The implications of the double helix would take years to filter into classrooms. In many schools, the question of what carried hereditary information was still being answered in terms of chromosomes without a chemical name.

What Watson and Crick had done was close an argument that had run for nearly a decade, and, in doing so, convert the question of how heredity worked from one about chemistry to one about information.