The foundation of all life on Earth is the same: a four letter genetic alphabet that identifies a variety of three-letter words that identify 20 amino acids. These fundamental building blocks, the DNA components and their molecular interpretations are at the core of biology. Floyd Romesberg, a synthetic biologist with Sanofi, stated that it is difficult to imagine anything more fundamental.But life's foundational biochemistry is full of surprises. Researchers discovered viruses that swapped one of four bases in their DNA to create a new one a few decades back. Three teams of researchers have now identified hundreds of viruses that can make this substitution. They also discovered the mechanisms that enable it. These discoveries suggest that fundamental genomic changes could be more common and significant in biology than previously thought.Original story reprinted by permission of Quanta Magazine. This independent publication published by the Simons Foundation has an editorially neutral content policy. It aims to increase public understanding of science through the coverage of research developments and trends in mathematics, the physical and life sciences.This was a wonderful confirmation that nature is expanding right under our noses, stated Stephen Freeland, a biologist from the University of Maryland, Baltimore County.Romesberg stated that it speaks to the adaptability and flexibility of the genetic alphabet.The possibility that evolution might have taken a different path with DNA's four bases (adenine, thymine, cytosine and guanine) has long intrigued scientists. There could have been many more, or they might have had different chemical or binding properties or used different rules to represent information. Romesberg and other synthetic biologists have investigated this issue by creating artificial base pairs and adding amino acids to create novel proteins. However, survival of an organism depends on its genetic code and alphabet being intact. The exact ingredients of DNA's recipe have been frozen by evolution over billions of years, Francis Crick said.However, there have been some exceptions. For example, Soviet Union researchers discovered something unusual while studying a virus that infects photosynthetic bacterium. All of the As in the genome were replaced by 2-aminoadenine. This was later called Z. To form double-stranded genetic DNA, usually C pairs with G. T was paired with Z in this virus. (T-Z was treated during gene transcription as though it were T.The Z base appears to be a chemical modification to A. It is an adenine nucleotide that has an additional attachment. This small change allows Z to form triple hydrogen bonds with T. This is much more stable than the double bond which holds A-T together.Although the finding was interesting, it seemed to be an isolated one. Philippe Marlire (a French geneticist and leader of new research on Z genes) said that the discovery was made out of curiosity. It was almost forgotten about.He said that the chemical organization was altered at the most fundamental level. My instincts told me that this was not an anecdote. This is a grave violation.Marlire and his collaborators sequenced the genome of bacteriophage, which the Russian team had previously studied. They identified a sequence that was associated with the production of the Z-base in the early 2000s. They searched databases for other viral genomes over the next 15-years to find matches. A second group of researchers, led by scientists from China and Illinois, joined the effort independently.Scientists have reported that the Z substitution was found in over 200 phages. Further analysis of viral genomes revealed a key enzyme to make Z and an enzyme that destroys free-floating nucleotides. This makes Z more likely to be used in DNA synthesis.