Researchers have shown that engineered bacteria can use synthetic DNA letters to encode extra amino-acid building blocks in proteins. The approach expands DNA’s alphabet and the set of codons a cell can read—but it requires specialized machinery, and it is not a routine capability of ordinary bacteria.
What does “unnatural DNA” mean?
DNA stores information in a sequence of chemical bases. Cells read that information in three-letter units called codons, which direct the protein-making machinery to add particular amino acids or stop building a protein. In the standard genetic code, four DNA letters form 64 possible triplet codons: 61 code for the 20 standard amino acids, and three signal stop.
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In this context, “unnatural DNA” means DNA that includes an engineered base pair beyond the four-letter natural alphabet. “Noncanonical” or “non-standard amino acid” means a protein building block outside the usual set of 20. These are different kinds of expansion: one changes the stored genetic alphabet; the other changes the chemical ingredients available for a protein.
How can synthetic DNA letters lead to a new protein?
Adding a base pair to DNA is only the first step. For the added information to affect a protein, it must be maintained in the DNA and made readable by the cell’s protein-production system. Researchers therefore need compatible components for copying or transcribing the sequence and an engineered decoding system that can match an added codon to the intended amino acid.
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- Store extra information. Researchers introduce an unnatural base pair into the organism’s DNA. The semisynthetic-organism work uses the synthetic bases dNaM and dTPT3.
- Create additional codons. The extra letters allow codons that cannot be written with only the natural DNA alphabet.
- Connect a codon to a building block. Engineered transfer RNA and aminoacyl-tRNA synthetase components help deliver the selected noncanonical amino acid in response to an added codon.
- Build the protein. When the cell translates the sequence, the amino acid can be placed at a specified position in the protein.
The key idea is not that synthetic DNA bases themselves become part of the protein. They provide extra information that an engineered translation system can interpret as instructions for adding a different chemical building block.
What did the expanded-alphabet study demonstrate?
A 2020 study by Zhang and colleagues in Nature Chemical Biology reported nine unnatural codons that produced protein with nearly complete incorporation of an encoded noncanonical amino acid. The study also reported that at least three unnatural codons could be decoded at the same time in the semisynthetic organism, producing a 67-codon system.
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Those results establish that an expanded DNA alphabet can support more than one added codon and can direct noncanonical amino-acid incorporation. They do not establish that every possible added codon works equally well, that any amino acid can be assigned to any codon, or that the method works uniformly in all proteins or bacterial strains. The reported performance belongs to the study’s engineered system and conditions.
How does this differ from other ways to expand the genetic code?
Researchers can expand what a cell translates without adding synthetic DNA letters. Other methods reassign a natural stop codon or use four-letter codons, with engineered decoding components. These approaches address the related goal of putting noncanonical amino acids into proteins, but they do not by themselves expand DNA’s alphabet.
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| Approach and reported study | Host | What changes in the code | Reported demonstration |
|---|---|---|---|
| Expanded DNA alphabet; Zhang and colleagues, Nature Chemical Biology (2020) | Semisynthetic organism | Unnatural DNA base pair enables additional codons | Nine unnatural codons produced protein with nearly complete incorporation of an encoded noncanonical amino acid; at least three were decoded simultaneously in a 67-codon system. |
| Quadruplet decoding; Costello and colleagues, Nature Biotechnology (2025) | Conventional E. coli | Four-letter codons, using the natural DNA alphabet | An in-vivo platform produced more than 100 new-to-nature peptide macrocycles containing up to three unique noncanonical amino acids. |
| Genetic-code expansion systems; Dunkelmann and colleagues, Nature Communications (2021) | Bacillus subtilis | Three system families; the study does not describe an expanded DNA alphabet | Reported incorporation of 20 distinct non-standard amino acids. |
The figures in the table are demonstrations reported by the named studies, not results from a standardized, head-to-head comparison. They should not be read as a ranking: the approaches differ in host, codon design, translation machinery, amino-acid range and experimental goal.
Why are engineered translation components important?
A cell’s existing translation machinery is optimized to read its own genetic code. A new codon must be recognized in a way that reliably supplies the intended amino acid without disrupting the rest of translation. Transfer RNA and aminoacyl-tRNA synthetase components are part of that engineered decoding system, while compatibility with the host affects whether the system works in a particular organism.
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Performance can also depend on the amino acid, its position in a protein and whether multiple noncanonical amino acids must be incorporated. A review notes that multiple or consecutive incorporation can be inefficient or unsuccessful in some in-vitro systems. That limitation is a reason to treat claims about one demonstrated construct as specific to that construct, rather than as a guarantee for other proteins or platforms.
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A 2020 Cell Chemical Biology study described an autonomous bacterial system that produced and incorporated 5-hydroxytryptophan as a 21st amino-acid building block. It also reported a fluorescently labelled antibody fragment for monitoring oxidative stress. This is a related example of bacteria making proteins with an additional amino acid, but it should not be conflated with the expanded-DNA-alphabet method: the available description does not establish that it used unnatural DNA letters.
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What can researchers use these systems for?
At a basic level, genetic-code expansion gives researchers a way to place chemical functionality at a chosen position in a protein, potentially enabling experiments or engineered molecules that standard amino acids alone cannot provide. The studies described here demonstrate different ways to achieve that goal, including unnatural DNA codons, quadruplet decoding and systems in another bacterial host.
The evidence supports specialized research platforms, not a claim that bacteria routinely make such proteins in ordinary conditions or that an application is already a marketed product. Each system’s demonstrated host, codons, amino acids and protein context matter when judging what it can do.
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