Abstract
Synthetically engineered organisms hold promise for a broad range of medical, environmental, and industrial applications. Organisms can potentially be designed, for example, for the inexpensive and environmentally benign synthesis of pharmaceuticals and industrial chemicals, for the cleanup of environmental pollutants, and potentially even for biomedical applications such as the targeting of specific diseases or tissues. However, the use of synthetically engineered organisms comes with several reasonable safety concerns, one of which is that the organisms or their genes could escape their intended habitats and cause environmental disruption. Here we review key recent developments in this emerging field of synthetic biocontainment and discuss further developments that might be necessary for the widespread use of synthetic organisms. Specifically, we discuss the history and modern development of three strategies for the containment of synthetic microbes: addiction to an exogenously supplied ligand; self-killing outside of a designated environment; and self-destroying encoded DNA circuitry outside of a designated environment.
Highlights
Engineered organisms hold promise for a broad range of medical, environmental, and industrial applications
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty
If engineered organisms require a synthetic compound for survival, they will be unable to survive outside of a laboratory or other highly specialized environment in which the chemical is supplied. This engineering feat is more difficult than generating organisms with a “broken” ability to produce a naturally occurring metabolite. It requires engineering some sort of metabolic or functional connection to a synthetic chemical that was previously irrelevant to the organism’s biology
Summary
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. Lopez and Anderson engineered benzothiazole-dependent “SLiDE” mutant proteins for the essential genes for phenylalanine tRNA synthetase, tyrosyl tRNA synthetase, methionyl tRNA synthetase, DNA polymerase III, and adenylate kinase, which require the synthetic ligand benzothiazole to bind as a cofactor to stabilize the hydrophobic core and the folded, functional form of the protein[23] (Figure 1, bottom right) Strains containing three such mutants in parallel achieved escape frequencies of less than 3 × 10−11 after two days in culture. Collins and colleagues developed several architectures for highly robust kill switches consisting of networks of multiple component switches that interact to reinforce the “killing” state in the absence of a strong, highly specific “don’t kill” environmental signal, providing backup in case one component is mutated or otherwise non-functional[31] Their “DEADMAN” switch employs a bistable regulator with mutually reinforcing feedback loops to actively drive both the expression of a toxin and the degradation of an essential cell protein in the absence of a specific effector (Figure 2, bottom left).
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