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A swapped genetic code prevents viral infections and gene transfer

Author

Listed:
  • 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
    Washington University School of Medicine in St. Louis)

  • Kamesh Narasimhan

    (Harvard Medical School)

  • Jorge A. Marchand

    (Harvard Medical School
    University of Washington)

  • 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
    Harvard University)

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.

Suggested Citation

  • 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 & Anus, 2023. "A swapped genetic code prevents viral infections and gene transfer," Nature, Nature, vol. 615(7953), pages 720-727, March.
    • Handle: RePEc:nat:nature:v:615:y:2023:i:7953:d:10.1038_s41586-023-05824-z
    DOI: 10.1038/s41586-023-05824-z
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    Citations

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    Cited by:

    1. Tomoshige Fujino & Ryogo Sonoda & Taito Higashinagata & Emi Mishiro-Sato & Keiko Kano & Hiroshi Murakami, 2024. "Ser/Leu-swapped cell-free translation system constructed with natural/in vitro transcribed-hybrid tRNA set," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Kasimir Kienbeck & Lukas Malfertheiner & Susann Zelger-Paulus & Silke Johannsen & Christian Mering & Roland K. O. Sigel, 2024. "Identification of HDV-like theta ribozymes involved in tRNA-based recoding of gut bacteriophages," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Tiantian Chang & Weichao Ding & Shirui Yan & Yun Wang & Haoling Zhang & Yu Zhang & Zhi Ping & Huiming Zhang & Yijian Huang & Jiahui Zhang & Dan Wang & Wenwei Zhang & Xun Xu & Yue Shen & Xian Fu, 2023. "A robust yeast biocontainment system with two-layered regulation switch dependent on unnatural amino acid," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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