Scientists expand genetic alphabet from 4 to 8 letters in functioning system

Researchers at the University of California San Diego, led by Dong Wang, PhD, have demonstrated that natural Escherichia coli RNA polymerase can accurately read and transcribe an expanded, eight-letter genetic alphabet. Using high-resolution cryo-electron microscopy, the team revealed that the enzyme recognizes synthetic base pairs using the same biochemical signals as natural ones. A second study showed this recognition can occur even without hydrogen bonds. These findings provide a molecular foundation for custom-engineered biological systems, novel therapeutics, and diagnostics.

Eight-letter genetic alphabet transcription

• ▪Researchers at the University of California San Diego demonstrated that Escherichia coli RNA polymerase can accurately read and transcribe an expanded, eight-letter genetic alphabet
• ▪The study demonstrating the transcription of the eight-letter genetic alphabet was published on September 2, 2026, in Nature Communications and led by Dong Wang, PhD, of UC San Diego

RNA polymerase structural mechanism

• ▪Researchers used biochemical experiments and high-resolution cryo-electron microscopy to capture detailed structural snapshots of Escherichia coli RNA polymerase recognizing synthetic base pairs
• ▪The structural snapshots revealed that Escherichia coli RNA polymerase recognizes synthetic DNA letters through the same biochemical and structural signals as natural base pairs

Synthetic base pair recognition

• ▪A study published on August 12, 2026, in PNAS, led by Dong Wang, PhD, reported that RNA polymerase can recognize a pair of synthetic base pairs that lack hydrogen bonds
• ▪The PNAS study demonstrated that a hydrophobic unnatural base pair promotes trigger loop closure and catalysis in cellular RNA polymerase independent of hydrogen bonding

Expanded genetic code applications

• ▪Previous research has utilized expanded genetic alphabets to create synthetic DNA molecules capable of recognizing liver cancer cells
• ▪The molecular foundation of how RNA polymerase transcribes non-natural DNA letters could enable future technologies including new diagnostics, therapeutics, and custom-engineered biological systems

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