A swapped genetic code prevents viral infections and gene transfer

Akos Nyerges (), Svenja Vinke, Regan Flynn, Siân V. Owen, Eleanor A. Rand, Bogdan Budnik, Eric Keen, Kamesh Narasimhan, Jorge A. Marchand, Maximilien Baas-Thomas, Min Liu, Kangming Chen, Anush Chiappino-Pepe, Fangxiang Hu, Michael Baym and George M. Church ()
Additional contact information
Akos Nyerges: Harvard Medical School
Svenja Vinke: Harvard Medical School
Regan Flynn: Harvard Medical School
Siân V. Owen: Harvard Medical School
Eleanor A. Rand: Harvard Medical School
Bogdan Budnik: Harvard University
Eric Keen: Washington University School of Medicine in St. Louis
Kamesh Narasimhan: Harvard Medical School
Jorge A. Marchand: Harvard Medical School
Maximilien Baas-Thomas: Harvard Medical School
Min Liu: GenScript USA Inc.
Kangming Chen: GenScript USA Inc.
Anush Chiappino-Pepe: Harvard Medical School
Fangxiang Hu: GenScript USA Inc.
Michael Baym: Harvard Medical School
George M. Church: Harvard Medical School

Nature, 2023, vol. 615, issue 7953, 720-727

Abstract: Abstract Engineering the genetic code of an organism has been proposed to provide a firewall from natural ecosystems by preventing viral infections and gene transfer1–6. However, numerous viruses and mobile genetic elements encode parts of the translational apparatus7–9, potentially rendering a genetic-code-based firewall ineffective. Here we show that such mobile transfer RNAs (tRNAs) enable gene transfer and allow viral replication in Escherichia coli despite the genome-wide removal of 3 of the 64 codons and the previously essential cognate tRNA and release factor genes. We then establish a genetic firewall by discovering viral tRNAs that provide exceptionally efficient codon reassignment allowing us to develop cells bearing an amino acid-swapped genetic code that reassigns two of the six serine codons to leucine during translation. This amino acid-swapped genetic code renders cells resistant to viral infections by mistranslating viral proteomes and prevents the escape of synthetic genetic information by engineered reliance on serine codons to produce leucine-requiring proteins. As these cells may have a selective advantage over wild organisms due to virus resistance, we also repurpose a third codon to biocontain this virus-resistant host through dependence on an amino acid not found in nature10. Our results may provide the basis for a general strategy to make any organism safely resistant to all natural viruses and prevent genetic information flow into and out of genetically modified organisms.

Date: 2023
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DOI: 10.1038/s41586-023-05824-z

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