Synthetic Eight‑Letter DNA Alphabet Successfully Read by Cellular Machinery

All known life on Earth depends on a four‑letter genetic code. A team at the University of California San Diego has demonstrated that a key cellular enzyme can reliably read and transcribe an expanded, eight‑letter genetic alphabet.

The results indicate that living cells can employ their native molecular tools to process synthetic genetic data. This achievement represents a significant advance toward a longstanding synthetic‑biology objective: extending the DNA alphabet beyond its natural four‑letter repertoire. Ultimately, such expanded alphabets could enable the design of biological devices that perform novel functions or generate compounds unavailable in nature.

How Cells Read an Eight‑Letter Genetic Alphabet

The investigation centered on RNA polymerase, the enzyme that reads DNA and synthesizes RNA, the initial step of gene expression. To examine how this enzyme processes synthetic genetic sequences, the researchers integrated biochemical assays with high‑resolution cryo‑electron microscopy, which can resolve structures at sub‑atomic scales.

They obtained high‑resolution structural images of Escherichia coli (E. coli) RNA polymerase as it recognized and incorporated two synthetic base pairs—artificial letters absent from natural DNA.

The images revealed that the enzyme recognizes the synthetic nucleotides using many of the same biochemical and structural cues it employs for natural base pairs. This observation explains why the polymerase can faithfully copy information encoded with an expanded genetic alphabet.

In a companion study published in PNAS, the same group demonstrated that RNA polymerase can also accommodate a different pair of synthetic base pairs despite the absence of the hydrogen bonds that typically stabilize natural DNA duplexes.

Synthetic DNA Could Enable New Technologies

The implications go far beyond basic understanding of DNA. Prior work has already employed expanded alphabets to generate synthetic DNA strands that specifically target liver‑cancer cells.

By revealing, at the molecular level, how RNA polymerase reads and transcribes non‑natural nucleotides, this work lays a crucial foundation for technologies that leverage expanded genetic codes. Potential uses range from novel diagnostics and therapeutics to engineered biological systems that exhibit functions not found in nature.

Two Studies Explore Expanded Genetic Codes

The Nature Communications article, titled “Structural Basis of Transcription of the Hachimoji Eight‑Letter Alphabet by E. coli RNA Polymerase,” was led by Dong Wang, PhD, a professor at the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, and appeared on September 2 2026.

The PNAS paper, “Hydrophobic Unnatural Base Pair Promotes Trigger Loop Closure and Catalysis in Cellular RNA Polymerase Independent of Hydrogen Bonding,” was also led by Wang and published on August 12 2026.

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