Researchers get two genetic codes to work at the same time - Ars Technica

Overview

Researchers get two genetic codes to work at the same time

Messing with the genetic code might have gotten a bit easier to do.

Details

The genetic code is what life everywhere uses to convert the information contained in DNA into specific protein sequences. With minor variations, the same genetic code is used by every living thing on Earth, suggesting it was already present in the last common ancestor of all of it. It’s not an easy thing to change, because so many things in every cell depend on it.

Nevertheless, some preliminary steps have been taken. Researchers have managed to add some new amino acids to a bacterial cell and were able to make proteins that were one amino acid less than usual. But it’s a slog; for some of this work, people have had to re-engineer every single gene in a bacterial genome.

Now, researchers have found a way to operate two separate genetic codes simultaneously, avoiding the need to do any work to compensate for altering the code that every protein in a cell relies on. They didn’t test it in an actual cell, and it might cause some problems there. But it’s a creative solution that should accelerate some synthetic biology work.

To understand how this works, we need to go back to that high school biology class you might not have paid much attention to. In the genome, part of most genes is dedicated to encoding a protein. The linear arrangement of bases in the DNA gets directly translated into the linear sequence of amino acids that make up a protein. Each set of three bases in the DNA corresponds to a specific amino acid (with three exceptions, each of which signals the end of the protein).

That translation isn’t direct. DNA is first copied into a messenger RNA. Then, a complex of proteins and RNA called a ribosome latches on to the messenger RNA and starts translating it, one amino acid at a time.

That translation relies on yet another type of RNA, the transfer RNA (t Rna). While transfer RNAs fold up into a complex structure, they all have two key parts. On one side is a set of three bases that can pair with the messenger RNA, matching the three bases of the genetic code. At the other end, the t RNA is chemically linked to the corresponding amino acid. The ribosome simply ensures that the right transfer RNA is base paired, and then transfers the amino acid it carries to the growing chain of the protein.

A key part of this system is not directly involved in the process: the enzymes that chemically link the transfer RNAs to the correct amino acid. These enzymes need to recognize both the three-base code on the transfer RNA, and the appropriate amino acid to add to it. (This process is often referred to as “charging” a t RNA.)

So, to make comprehensive changes to the genetic code, you have to modify some combination of these factors: the sequence of genes, the sequence of transfer RNAs, and/or the enzymes that charge the transfer RNAs. (The only thing that doesn’t need to be changed is the ribosome itself.) And you have to do it in a way that either doesn’t impact every gene in an organism’s genome, or edit all the genes to compensate.

All of which is, not surprisingly, rather difficult. And, in most cases, you can’t just do things via intermediate steps, or the entire genome will end up producing malformed proteins. All of which has slowed down our attempts to experiment with artificial amino acids and alternative genetic codes.

The new work comes from a research group led by synthetic biologist and serial entrepreneur George Church. He’s definitely interested in exploring alternate genetic codes and found the slog needed to do so frustrating. A lot of the paper describing this work focuses on developing automated systems that could streamline some of the testing and screening. If those sorts of things interest you, the paper will be great. But for here, we’re going to focus on the biology.

The key insight behind the work is that the ribosome matters, but in a way that doesn’t really matter. Some parts of the ribosome’s RNA base pair with a group of bases near one of the ends of the transfer RNA, ensuring that it’s working with the correct type of RNA. While this is critical biochemically, it doesn’t matter practically because every single transfer RNA has the same sequence in that location.

But what, the new paper asks, if it didn’t? Since we know the precise locations that base pair on the ribosome and transfer RNA, we can potentially change the sequence of one of those—that breaks the normal base pairing, but we can then make a change in the other that restores it.

In theory, we can use this to create two populations of transfer RNAs that only differ at this small sequence. One of them would only be able to interact with the normal ribosomes, while the other could only interact with a separate population of ribosomes engineered to use a modified RNA. The paper converts this theory into practice.

One of the big questions was whether you could charge a transfer RNA after modifying this sequence. This seems like a simple question, but is quite a bit less so, since it’s seemingly not something anybody has asked previously. So the team here had to invent its own method for answering it, one involving a subtle difference in the chemical reactions that charged and uncharged amino acids can participate in. Detecting that required “cell-free translation, robotics, next-generation sequencing, and analytical chemistry.”

But it did provide an answer: depending on the specific changes made to the transfer RNAs, most of them could be charged, albeit typically at a lower efficiency than a normal transfer RNA. Some sequence changes were tolerated better than others.

With these charged alternative transfer RNAs in hand, the researchers confirmed that they were ignored by normal ribosomes. But if you used a ribosome with the corresponding changes that restored base pairing, it would happily make a protein using them. So, the researchers had two different populations of transfer RNAs, each compatible with a different population of ribosomes.

They designed a separate genetic code and used the alternative transfer RNAs to implement it. They then designed a messenger RNA that could be translated by both genetic codes, but would produce different proteins depending on which code was being used. They then put together a mixture of both populations of transfer RNAs, both populations of ribosomes, and all the chemicals needed to get translation to work.

Two different proteins were produced. So, both populations of ribosomes latched on to the messenger RNA but used different populations of transfer RNAs to make a protein using the messenger. And since the two populations implemented different genetic codes, the two populations of ribosomes made different proteins.

It also might be practically useful. After all, it’s extremely difficult to mess with the genetic code, because every protein in the cell depends on it. If that code will keep working happily while you mess with a second genetic code, then the cell will potentially be quite a bit happier.

Potentially. The researchers only do this work in a mixture of proteins and chemicals isolated from cells; they don’t try it in actual cells. And, to be clear, it might cause problems there. Afterall, the alternative ribosome would still try to translate any messenger RNAs that it comes across but will use the wrong genetic code, likely producing lots of truncated or malformed proteins. Collectively, these could interfere enough with normal processes to kill the cell.

I don’t see an obvious way around this problem. But of course I wasn’t clever enough to realize that having two genetic codes operating in parallel was possible, so it seems likely that some sharp biologist will ultimately find a way to work around this.

Nature, 2026. DOI: 10.1038/s 41586-026-10949-y  (About DOIs).

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Key Takeaways

• Researchers get two genetic codes to work at the same time

• Messing with the genetic code might have gotten a bit easier to do

• The genetic code is what life everywhere uses to convert the information contained in DNA into specific protein sequences

• Nevertheless, some preliminary steps have been taken

• Now, researchers have found a way to operate two separate genetic codes simultaneously, avoiding the need to do any work to compensate for altering the code that every protein in a cell relies on