Researchers at UC San Diego have demonstrated that a key cellular enzyme can accurately read an eight-letter genetic alphabet, doubling the four letters used by all known life on Earth. Detailed imaging revealed that RNA polymerase handles synthetic DNA letters in surprisingly similar ways to natural ones. The finding brings scientists closer to building expanded genetic systems that could perform entirely new biological functions.
All known life on Earth relies on the same four-letter genetic alphabet. Researchers at the University of California San Diego have now shown that one of biology's most important enzymes can accurately read and transcribe a much larger version containing eight genetic letters.
The finding suggests that cells can use their existing molecular machinery to handle synthetic genetic information. That marks an important step toward a long-standing goal in synthetic biology: expanding the language of DNA beyond the four letters found in nature. In the future, such systems could help scientists engineer biological machinery that carries out new functions or produces compounds that do not naturally exist.
How Cells Read an Eight-Letter Genetic Alphabet
The researchers focused on RNA polymerase, the enzyme that reads DNA and produces RNA -- the first step in gene expression. To see how the enzyme handles synthetic genetic information, the team combined biochemical experiments with high-resolution cryo-electron microscopy capable of revealing structures at scales smaller than the width of a single atom.
The researchers captured detailed structural views of RNA polymerase from Escherichia coli (E. coli) bacteria as it recognized and incorporated two synthetic base pairs. These artificial genetic letters are not found in nature.
The images showed that RNA polymerase identifies the synthetic DNA letters using many of the same biochemical and structural signals it relies on to recognize natural base pairs. That finding helps explain why the enzyme can accurately copy information written using an expanded genetic alphabet.
In a related study published in PNAS, the same research team found that RNA polymerase can also recognize another pair of synthetic base pairs even though they lack the hydrogen bonds that normally help hold DNA base pairs together.
Synthetic DNA Could Enable New Technologies
The potential applications extend well beyond understanding how DNA works. Earlier research has already used expanded genetic alphabets to create synthetic DNA molecules capable of recognizing liver cancer cells.
By showing in molecular detail how RNA polymerase reads and transcribes non-natural DNA letters, the new research provides an important foundation for technologies built around expanded genetic codes. Possible applications include new diagnostic tools, therapeutics, and engineered biological systems with capabilities that do not occur naturally.
Two Studies Explore Expanded Genetic Codes
The Nature Communications study ("Structural Basis of Transcription of the Hachimoji Eight-Letter Alphabet by E. coli RNA Polymerase"), led by Dong Wang, PhD, professor at the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, was published on Sept. 2, 2026 in Nature Communications.
The PNAS study ("Hydrophobic unnatural base pair promotes trigger loop closure and catalysis in cellular RNA polymerase independent of hydrogen bonding"), published on Aug. 12, 2026, was also led by Wang.
PS:
Natural DNA is composed of four molecules, called nitrogenous bases, that pair up with each other to form the code for life on Earth – A binds with T, and G binds with C. The Hachimoji DNA includes these four natural bases, plus four more synthetically made nucleotide bases which the researchers called P, B, Z and S.
The team, which included several different teams across the US, created hundreds of these Hachimoji double helixes with different combinations of the natural and synthetic nucleotide base pairs. Then, they conducted a series of experiments to see if the various double helixes had properties needed to create and support life.
Natural DNA has a hallmark property that no other genetic molecule seems to have – it’s stable and predictable. That means that researchers can calculate exactly how it will behave in certain temperatures and environments, including when it will degrade. But it turns out that the researchers were also able to do this with the Hachimoji DNA – they could come up with a set of rules that can predict the DNA’s stability when it is exposed to different temperatures.
All known life on Earth relies on the same four-letter genetic alphabet. Researchers at the University of California San Diego have now shown that one of biology's most important enzymes can accurately read and transcribe a much larger version containing eight genetic letters.
The finding suggests that cells can use their existing molecular machinery to handle synthetic genetic information. That marks an important step toward a long-standing goal in synthetic biology: expanding the language of DNA beyond the four letters found in nature. In the future, such systems could help scientists engineer biological machinery that carries out new functions or produces compounds that do not naturally exist.
How Cells Read an Eight-Letter Genetic Alphabet
The researchers focused on RNA polymerase, the enzyme that reads DNA and produces RNA -- the first step in gene expression. To see how the enzyme handles synthetic genetic information, the team combined biochemical experiments with high-resolution cryo-electron microscopy capable of revealing structures at scales smaller than the width of a single atom.
The researchers captured detailed structural views of RNA polymerase from Escherichia coli (E. coli) bacteria as it recognized and incorporated two synthetic base pairs. These artificial genetic letters are not found in nature.
The images showed that RNA polymerase identifies the synthetic DNA letters using many of the same biochemical and structural signals it relies on to recognize natural base pairs. That finding helps explain why the enzyme can accurately copy information written using an expanded genetic alphabet.
In a related study published in PNAS, the same research team found that RNA polymerase can also recognize another pair of synthetic base pairs even though they lack the hydrogen bonds that normally help hold DNA base pairs together.
Synthetic DNA Could Enable New Technologies
The potential applications extend well beyond understanding how DNA works. Earlier research has already used expanded genetic alphabets to create synthetic DNA molecules capable of recognizing liver cancer cells.
By showing in molecular detail how RNA polymerase reads and transcribes non-natural DNA letters, the new research provides an important foundation for technologies built around expanded genetic codes. Possible applications include new diagnostic tools, therapeutics, and engineered biological systems with capabilities that do not occur naturally.
Two Studies Explore Expanded Genetic Codes
The Nature Communications study ("Structural Basis of Transcription of the Hachimoji Eight-Letter Alphabet by E. coli RNA Polymerase"), led by Dong Wang, PhD, professor at the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, was published on Sept. 2, 2026 in Nature Communications.
The PNAS study ("Hydrophobic unnatural base pair promotes trigger loop closure and catalysis in cellular RNA polymerase independent of hydrogen bonding"), published on Aug. 12, 2026, was also led by Wang.
PS:
Natural DNA is composed of four molecules, called nitrogenous bases, that pair up with each other to form the code for life on Earth – A binds with T, and G binds with C. The Hachimoji DNA includes these four natural bases, plus four more synthetically made nucleotide bases which the researchers called P, B, Z and S.
The team, which included several different teams across the US, created hundreds of these Hachimoji double helixes with different combinations of the natural and synthetic nucleotide base pairs. Then, they conducted a series of experiments to see if the various double helixes had properties needed to create and support life.
Natural DNA has a hallmark property that no other genetic molecule seems to have – it’s stable and predictable. That means that researchers can calculate exactly how it will behave in certain temperatures and environments, including when it will degrade. But it turns out that the researchers were also able to do this with the Hachimoji DNA – they could come up with a set of rules that can predict the DNA’s stability when it is exposed to different temperatures.
