A bumpy road ahead for genetic biocontainment

George, D.R., Danciu, M., Davenport, P.W. et al,  Nature Communications,  2024.

The environmental release of bioengineered organisms is increasingly being suggested for a variety of applications, including bioremediation, biosequestration, bio-mining, environmental biosensing and conservation. The objectives of many environmental release applications shift the goals of biocontainment from preventing organism spread outside of closed spaces (e.g., laboratories or bioreactors) to managing the persistence of engineered organisms and their genetic material in open, dynamic environments. In the scientific literature, discussions of environmental release are often accompanied by calls for robust “intrinsic biocontainment”, where containment mechanisms are genetically engineered into the organism to limit and control its spread and persistence. A number of intrinsic biocontainment approaches have so far been proposed, and can be grouped into two overarching strategies. First, gene-flow barriers attempt to limit the spread of genetic material through lateral gene transfer, which refers to the ability of cells to directly exchange DNA molecules with one another or absorb DNA from external environmental sources. This can be accomplished through conditional lethality strategies (such as toxin anti-toxin systems or targeted DNA degradation), or through limiting plasmid replication or deleting natural competence genes from target cells. Second, strain/host control strategies seek to prevent survival and growth of engineered microbes outside specific environmental conditions using growth restriction and fitness control strategies such as metabolic auxotrophy, kill switches, and conditional essentiality. Over the past decade, researchers and developers have expanded the technical toolkit of intrinsic biocontainment techniques, with new approaches using orthogonal sequences, synthetic auxotrophy, CRISPR-based kill switches, sequence-entanglement, and “cell-free” systems.

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