Cas9-assisted biological containment of a genetically engineered human commensal bacterium and genetic elements

Naoki Hayashi, Yong Lai, Jay Fuerte-Stone, Mark Mimee () and Timothy K. Lu ()
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Naoki Hayashi: Massachusetts Institute of Technology
Yong Lai: MIT Synthetic Biology Center, Massachusetts Institute of Technology (MIT)
Jay Fuerte-Stone: The University of Chicago
Mark Mimee: The University of Chicago
Timothy K. Lu: Massachusetts Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Sophisticated gene circuits built by synthetic biology can enable bacteria to sense their environment and respond predictably. Engineered biosensing bacteria outfitted with such circuits can potentially probe the human gut microbiome to prevent, diagnose, or treat disease. To provide robust biocontainment for engineered bacteria, we devised a Cas9-assisted auxotrophic biocontainment system combining thymidine auxotrophy, an Engineered Riboregulator (ER) for controlled gene expression, and a CRISPR Device (CD). The CD prevents the engineered bacteria from acquiring thyA via horizontal gene transfer, which would disrupt the biocontainment system, and inhibits the spread of genetic elements by killing bacteria harboring the gene cassette. This system tunably controlled gene expression in the human gut commensal bacterium Bacteroides thetaiotaomicron, prevented escape from thymidine auxotrophy, and blocked transgene dissemination. These capabilities were validated in vitro and in vivo. This biocontainment system exemplifies a powerful strategy for bringing genetically engineered microorganisms safely into biomedicine.

Date: 2024
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DOI: 10.1038/s41467-024-45893-w

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