All life on Earth rests on the same foundation: a four-letter genetic alphabet spelling out a repertoire of three-letter words that specify 20 amino acids. These basic building blocks—the components of DNA and their molecular interpreters—lie at biology’s core. “It’s hard to imagine something more fundamental,” said Floyd Romesberg, a synthetic biologist at the pharmaceutical company Sanofi.

Yet life’s foundational biochemistry can be full of surprises. A few decades ago, researchers found viruses that had swapped one of the four bases in their DNA for a novel fifth one. Now, in a trio of papers published in Science in April, three teams have identified dozens of other viruses that make this substitution, as well as the mechanisms that make it possible. The discoveries raise the thought-provoking possibility that this kind of fundamental genomic change could be much more widespread and important in biology than anyone imagined.

“Here was this wonderful validation that right under our noses, nature has been expanding,” said Stephen Freeland, a biologist at the University of Maryland, Baltimore County.

“It really speaks to the adaptability of the genetic alphabet,” Romesberg said.

Researchers have long been intrigued by the possibility that evolution could have gone in a different direction with DNA’s four bases: adenine (A), thymine (T), cytosine (C), and guanine (G). Perhaps there could have been more than four of them, or they could have had very different chemical or binding properties, or they could have used a different set of rules to represent information. Synthetic biologists like Romesberg have explored this by engineering artificial base pairs and additional amino acids to produce novel proteins. Even so, because an organism’s survival depends on keeping its genetic alphabet and code intact, the precise ingredients in DNA’s recipe are thought to have been largely locked in by evolution for billions of years—making them “frozen accidents,” in the words of Francis Crick.

But some exceptions have cropped up. In 1977, for instance, researchers in the Soviet Union found something peculiar while looking at a virus that infects photosynthetic bacteria: All the A’s in the genome had been replaced with an alternative base, 2-aminoadenine, which was later dubbed Z. Usually, C pairs with G and T pairs with A to form double-stranded DNA. But in this virus, with no A’s to be found, T paired with Z. (During gene transcription, T-Z was still treated as though it were T-A.)

The Z base looks like a chemical modification of A; it’s an adenine nucleotide with an extra attachment. But that modest change allows Z to form a triple hydrogen bond with T, which is more stable than the double bond that holds together A-T.

The finding was intriguing but seemed like an isolated case. “It came as a kind of curiosity, something really weird and of no general significance,” said Philippe Marlière, a geneticist at the University of Evry in France and one of the leaders of the new research on Z genomes. “And so it settled into oblivion, more or less.”

But since the alterations were “at the deepest level of chemical organization,” he said, “my instinct told me this is not just an anecdote. This is a profound violation.”

In the early 2000s, Marlière and his colleagues sequenced the genome of the bacteriophage that the Russian team had studied, and they pinpointed a genetic sequence associated with production of the Z base. For the next 15 years, they searched for matches in databases of other viral genomes. Another group, led by researchers in Illinois and China, independently joined the effort.