RNA polymerase reads eight-letter DNA alphabet in UC San Diego studies

Overview

Updated Sep 7

All life on Earth runs on four DNA letters. Researchers at UC San Diego have shown that one of biology's core enzymes can read an eight-letter alphabet that includes four synthetic letters. The finding, published in Nature Communications, is a step toward engineered biological systems that use genetic information nature never wrote.

The work tests whether a cell's own machinery can process synthetic DNA. RNA polymerase from E. coli recognized the artificial letters through the same structural signals it uses for natural ones. That opens the door to expanded genetic systems for diagnostics, therapeutics, and data storage.

Why it matters

If expanded genetic alphabets work inside cells, scientists could build biological systems that produce compounds and functions not found in nature.

Questions about this story

Free account needed to ask — your question is kept and asked for you right after sign-up. Answers are public.

No questions yet — be the first to ask.

Key Indicators

Letters in the Hachimoji genetic alphabet

Four natural DNA letters plus four synthetic ones.

2.42–2.75 Å

Resolution of cryo-EM structures

Four enzyme structures captured at near-atomic resolution.

~2x

Rate difference for synthetic base pairs

Synthetic pairs incorporated roughly two-fold slower than natural ones.

Cryo-EM structures captured

Showing RNA polymerase interacting with synthetic nucleotides.

Voices

Curated perspectives — historical figures and your fellow readers.

People Involved

Dong Wang

Professor, UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences

Led the Nature Communications and PNAS studies

Steven Benner

Senior author and alphabet designer, Foundation for Applied Molecular Evolution

Co-designed the Hachimoji alphabet and the transcription experiments

Organizations Involved

UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences

Academic institution

Home of the research team

The pharmacy school at UC San Diego where Dong Wang's lab conducted the research.

Foundation for Applied Molecular Evolution

Research foundation

Designed the Hachimoji alphabet

Research foundation in Alachua, Florida, where Steven Benner designed the Hachimoji alphabet.

Timeline

February 2019 September 2026

5 events Latest: September 5th, 2026 · 2 months ago

Tap a bar to jump to that date

September 2026
ScienceDaily reports the finding
Latest Media

The university's research alert is republished, drawing wider attention to the eight-letter alphabet.
September 5th, 2026
Hachimoji transcription study published
Publication

Nature Communications paper showed E. coli RNA polymerase transcribes all eight letters at near-natural rates.
September 2nd, 2026
August 2026
Hydrophobic base pair study published
Publication

PNAS paper showed RNA polymerase recognizes a synthetic pair without hydrogen bonds.
August 12th, 2026
December 2023
RNA polymerase recognizes artificial base pairs
Publication

UC San Diego showed RNA polymerase can't distinguish synthetic AEGIS base pairs from natural ones.
December 12th, 2023
February 2019
Hachimoji alphabet introduced
Publication

Benner and colleagues published the eight-letter genetic alphabet in Science, adding four synthetic nucleotides.
February 22nd, 2019

Scenarios

Eight-letter transcription moves into living cells

Possible Resolves by End of 2028

Discussed by: Dong Wang and the research team

Wang said the in vitro study paves the way for an eight-letter transcription system in cells. A living cell would need to manufacture the synthetic letters and keep them available while competing with natural nucleotides. This requires solving the cellular supply problem for the four synthetic bases, a separate and unsolved challenge.

Eight-letter RNA aptamers target disease

Likely Resolves by End of 2028

Discussed by: The research team and earlier AEGIS work

Six-letter AEGIS DNA aptamers carrying P and Z have already been engineered to target liver cancer cells and carry chemotherapy drugs. The new work lets researchers build RNA aptamers with all eight letters. These could carry drugs to specific cells or serve as diagnostics.

Full eight-letter translation to protein

Unlikely Resolves by End of 2030

Discussed by: The research team; noted as further off

Making protein from an eight-letter message requires ribosomes and transfer RNAs that recognize the new codons. Researchers have done this with the B:S pair alone, but not with all eight letters. The Nature Communications paper marks this branch with transparent arrows to show it's not yet done.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

February 2019

Hachimoji alphabet introduction (2019)

Steven Benner and colleagues published the Hachimoji eight-letter genetic alphabet in Science. The alphabet added four synthetic nucleotides to DNA's natural four, and an engineered T7 RNA polymerase could transcribe it.

Then

The alphabet was demonstrated in vitro with a simple viral enzyme.

Now

It set the stage for testing whether cellular enzymes could handle the expanded alphabet.

Why this matters now

The 2026 study answers the question the 2019 paper left open: whether a cell's own multi-subunit RNA polymerase can read all eight letters.

May 2014

Romesberg's semi-synthetic organism (2014)

Floyd Romesberg's lab at Scripps Research created a semi-synthetic organism with an unnatural base pair (d5SICS-dNaM) in its DNA. The bacterium E. coli replicated the synthetic pair alongside its natural DNA.

Then

The semi-synthetic organism showed that cells can replicate DNA with unnatural letters.

Now

It demonstrated the feasibility of expanded genetic systems in living cells, though the pair was later refined.

Why this matters now

Romesberg's work showed replication of unnatural letters in cells; the new study addresses transcription, the next step in gene expression.

2000s–2020s

AEGIS six-letter system (2000s–2020s)

Benner's earlier AEGIS (Artificially Expanded Genetic Information System) added two letters to DNA's four. Six-letter AEGIS DNA aptamers carrying P and Z have been engineered to target liver cancer cells and carry chemotherapy drugs.

Then

AEGIS demonstrated practical applications of expanded alphabets in diagnostics and therapeutics.

Now

It provided the foundation for the eight-letter Hachimoji system.

Why this matters now

The new work extends AEGIS's P:Z pair to the full eight-letter alphabet and shows cellular RNA polymerase can read it.