Synthetic organism that ‘speaks a different genetic language’ created at MRC LMB in Cambridge

The first synthetic organism to use a different genetic language to the rest of life on Earth has been created by researchers in Cambridge, writes editor Paul Brackley.

The astonishing achievement represents a new paradigm that protects valuable engineered organisms from natural invaders – and safeguards the natural world from engineered material.

It was achieved by Jason Chin’s group in the PNAC Division of the MRC Laboratory of Molecular Biology by altering the rules by which genetic information is encoded in DNA. The result is a genetically isolated organism, which cannot exchange information with the environment.

The genetic code is near-universal across all kingdoms of life. It is the set of rules by which genetic information is encoded in genes within DNA and enables the transfer of genetic information between different types of cells.

This has long proved useful for biologists, who have made use of the common code when engineering microbes, crops or even animals for research purposes.

Jason’s group at the LMB made a stunning breakthrough in synthetic biology in 2019, when they created the world’s first synthetic organism with fully recoded DNA.

They did so by developing methods to synthesise the genome of Escherichia coli (E. coli), creating Syn61, an organism with a compressed genetic code, and a further engineered organism, Syn61delta3, in which two transfer RNAs, or tRNAs, and one release factor had been deleted.

They knew that Syn61delta3 cells would be resistant to a range of viruses because they are unable to read viral genomes that use the full genetic code.

However, the team believed that it was possible that mobile genetic elements – such as transposons, viruses and plasmids – could complement the missing tRNAs, which would then make Syn61delta3 susceptible to viral infection. They also believe it might be possible for genetic information from synthetic organisms to be shared with natural cells via horizontal gene transfer.

In order to address these issues, Jerome Zürcher, a PhD student in Jason’s group, engineered tRNAs to reassign the codons – units of genetic information – that were removed when Syn61 was synthesised to different natural amino acids in Syn61delta3. This refactored the structure of the genetic code.

Jerome showed that genes that use the new synthetic code could only be correctly read in cells

which have the cognate – or corresponding – tRNAs.

Natural genes could not be correctly decoded in the synthetic cells in which codons had been reassigned. Nor could natural cells correctly read synthetic genes written in the altered code.

It means the natural cells and synthetic cells cannot share genetic material horizontally as they ‘speak’ different genetic languages.

The team then wished to test whether the newly-engineered cells were resistant to viral infection.

They collaborated with George Salmond’s group in the University of Cambridge’s Department of Biochemistry to identify pools of bacterial virus from the local River Cam that can infect Syn61delta3.

They found that when the cells with refactored genetic codes were challenged with these virus strains, no viral infection occurred.

It proved that cells with refactored genetic codes are protected from the invasion of mobile generic elements.

It means the team has effectively engineered cells with a genetic firewall, which isolated the synthetic organisms from the environment.

This could have many practical applications, as viral resistance is key when utilising engineered cells to manufacture drugs and materials.

If, for example, a virus gets into vats of bacteria used to manufacture drugs such as insulin, it can destroy the whole batch and disrupt vital supply chains. Genetic firewalls could also be useful in agriculture products.

Jerome said: “Genetic firewalls will allow for the safe application of engineered organisms outside the laboratory.

“In the future we could see genetic firewalls in other organisms, such as crops.”

The work, published in Science, was funded by UKRI MRC and UKRI BBSRC and also received funding from the European Union’s Horizon 2020 research and innovation programme.