All known life on earth utilizes the same genetic alphabet, consisting of four letters. Now, researchers at University of California San Diego have demonstrated that one of biology’s most essential enzymes can accurately read and transcribe an expanded, eight-letter genetic alphabet. The findings provide important evidence that cells can process synthetic genetic information using their natural molecular machinery, advancing a long-standing goal in synthetic biology to expand the language of DNA. It could also allow scientists to custom-engineer biological systems that perform functions or produce compounds not found in nature.

The study focused on RNA polymerase, the enzyme responsible for reading DNA and producing RNA — the first step in gene expression. Using biochemical experiments and high-resolution cryo-electron microscopy that can zoom down to smaller than the width of a single atom, researchers captured detailed structural snapshots showing how RNA polymerase from Escherichia coli ( E. coli ) bacteria recognizes and incorporates two synthetic base pairs, genetic letters that are not found in nature. These snapshots revealed that the enzyme recognizes synthetic DNA letters through the same biochemical and structural signals as natural base pairs, helping explain how expanded genetic information can be faithfully transcribed. In another related study, the same researchers reported that RNA polymerase can also recognize another pair of synthetic base pairs without hydrogen bonds to hold them together, published in PNAS.

This work has implications beyond basic biology. Previous studies have used expanded genetic alphabets to create synthetic DNA molecules capable of recognizing liver cancer cells. By revealing how RNA polymerase accurately reads and transcribes these non-natural DNA letters, the new study provides a molecular foundation for future technologies that use expanded genetic codes, including new diagnostics, therapeutics and engineered biological systems.