A swapped genetic code prevents viral infections and gene transfer

Nature. 2023 Mar;615(7953):720-727. doi: 10.1038/s41586-023-05824-z. Epub 2023 Mar 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids* / genetics
  • Amino Acids* / metabolism
  • Codon / genetics
  • Ecosystem
  • Escherichia coli* / genetics
  • Escherichia coli* / virology
  • Gene Transfer, Horizontal* / genetics
  • Genetic Code* / genetics
  • Genome, Bacterial / genetics
  • Host Microbial Interactions* / genetics
  • Leucine / genetics
  • Leucine / metabolism
  • Organisms, Genetically Modified / genetics
  • Protein Biosynthesis* / genetics
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism
  • Serine / genetics
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Diseases* / genetics
  • Virus Diseases* / prevention & control

Substances

  • Amino Acids
  • Codon
  • Leucine
  • RNA, Transfer
  • Serine
  • Viral Proteins