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Title: Biocontainment of genetically modified organisms by synthetic protein design

Abstract

Genetically modified organisms (GMOs) are increasingly deployed at large scales and in open environments. Genetic biocontainment strategies are needed to prevent unintended proliferation of GMOs in natural ecosystems. Existing biocontainment methods are insufficient because they impose evolutionary pressure on the organism to eject the safeguard by spontaneous mutagenesis or horizontal gene transfer, or because they can be circumvented by environmentally available compounds. In this paper, we computationally redesign essential enzymes in the first organism possessing an altered genetic code (Escherichia coli strain C321.ΔA) to confer metabolic dependence on non-standard amino acids for survival. The resulting GMOs cannot metabolically bypass their biocontainment mechanisms using known environmental compounds, and they exhibit unprecedented resistance to evolutionary escape through mutagenesis and horizontal gene transfer. Finally, this work provides a foundation for safer GMOs that are isolated from natural ecosystems by a reliance on synthetic metabolites.

Authors:
 [1];  [2];  [3];  [4];  [1];  [1];  [1];  [5];  [6]
  1. Harvard Medical School, Boston, MA (United States). Dept. of Genetics
  2. Harvard Medical School, Boston, MA (United States). Dept. of Genetics; Harvard Univ., Cambridge, MA (United States). Program in Chemical Biology
  3. Harvard Medical School, Boston, MA (United States). Dept. of Genetics; Boston Univ., MA (United States). Dept. of Biomedical Engineering
  4. Fred Hutchinson Cancer Research Center, Seattle, WA (United States). Division of Basic Sciences
  5. Fred Hutchinson Cancer Research Center, Seattle, WA (United States). Division of Basic Science
  6. Harvard Medical School, Boston, MA (United States). Dept. of Genetics; Harvard Univ., Cambridge, MA (United States). Wyss Inst. for Biologically Inspired Engineering
Publication Date:
Research Org.:
Harvard Univ., Boston, MA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1347113
Grant/Contract Number:  
FG02-02ER63445
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 518; Journal Issue: 7537; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; genetics; biotechnology; molecular evolution; computational biology and bioinformatics

Citation Formats

Mandell, Daniel J., Lajoie, Marc J., Mee, Michael T., Takeuchi, Ryo, Kuznetsov, Gleb, Norville, Julie E., Gregg, Christopher J., Stoddard, Barry L., and Church, George M. Biocontainment of genetically modified organisms by synthetic protein design. United States: N. p., 2015. Web. doi:10.1038/nature14121.
Mandell, Daniel J., Lajoie, Marc J., Mee, Michael T., Takeuchi, Ryo, Kuznetsov, Gleb, Norville, Julie E., Gregg, Christopher J., Stoddard, Barry L., & Church, George M. Biocontainment of genetically modified organisms by synthetic protein design. United States. doi:10.1038/nature14121.
Mandell, Daniel J., Lajoie, Marc J., Mee, Michael T., Takeuchi, Ryo, Kuznetsov, Gleb, Norville, Julie E., Gregg, Christopher J., Stoddard, Barry L., and Church, George M. Wed . "Biocontainment of genetically modified organisms by synthetic protein design". United States. doi:10.1038/nature14121. https://www.osti.gov/servlets/purl/1347113.
@article{osti_1347113,
title = {Biocontainment of genetically modified organisms by synthetic protein design},
author = {Mandell, Daniel J. and Lajoie, Marc J. and Mee, Michael T. and Takeuchi, Ryo and Kuznetsov, Gleb and Norville, Julie E. and Gregg, Christopher J. and Stoddard, Barry L. and Church, George M.},
abstractNote = {Genetically modified organisms (GMOs) are increasingly deployed at large scales and in open environments. Genetic biocontainment strategies are needed to prevent unintended proliferation of GMOs in natural ecosystems. Existing biocontainment methods are insufficient because they impose evolutionary pressure on the organism to eject the safeguard by spontaneous mutagenesis or horizontal gene transfer, or because they can be circumvented by environmentally available compounds. In this paper, we computationally redesign essential enzymes in the first organism possessing an altered genetic code (Escherichia coli strain C321.ΔA) to confer metabolic dependence on non-standard amino acids for survival. The resulting GMOs cannot metabolically bypass their biocontainment mechanisms using known environmental compounds, and they exhibit unprecedented resistance to evolutionary escape through mutagenesis and horizontal gene transfer. Finally, this work provides a foundation for safer GMOs that are isolated from natural ecosystems by a reliance on synthetic metabolites.},
doi = {10.1038/nature14121},
journal = {Nature (London)},
number = 7537,
volume = 518,
place = {United States},
year = {2015},
month = {1}
}

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