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Engineering living therapeutics with synthetic biology

Abstract

The steadfast advance of the synthetic biology field has enabled scientists to use genetically engineered cells, instead of small molecules or biologics, as the basis for the development of novel therapeutics. Cells endowed with synthetic gene circuits can control the localization, timing and dosage of therapeutic activities in response to specific disease biomarkers and thus represent a powerful new weapon in the fight against disease. Here, we conceptualize how synthetic biology approaches can be applied to programme living cells with therapeutic functions and discuss the advantages that they offer over conventional therapies in terms of flexibility, specificity and predictability, as well as challenges for their development. We present notable advances in the creation of engineered cells that harbour synthetic gene circuits capable of biological sensing and computation of signals derived from intracellular or extracellular biomarkers. We categorize and describe these developments based on the cell scaffold (human or microbial) and the site at which the engineered cell exerts its therapeutic function within its human host. The design of cell-based therapeutics with synthetic biology is a rapidly growing strategy in medicine that holds great promise for the development of effective treatments for a wide variety of human diseases.

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Fig. 1: Endowing biological scaffolds with therapeutic capabilities.
Fig. 2: Development of living therapeutics with engineered genetic circuits.
Fig. 3: Human cell therapies with engineered genetic circuits.
Fig. 4: Human circulating CAR-T cell therapies with engineered genetic circuits.
Fig. 5: Bacterial cell therapies with engineered genetic circuits.

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Acknowledgements

T.K.L. was supported by the US Department of Defense (W81XWH-17-1-0159, W81XWH-16-1-0565) and National Institutes of Health (5-R33-AI121669-04). T.G. was supported by a postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada. J.J.C. was supported by the National Institutes of Health grant 1RC2DK120535-01A1 and the Defense Threat Reduction Agency grant HDTRA1-14-1-0006. The authors apologize to those authors whose work was not cited directly owing to space limitations.

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A.C.-R. and T.G. wrote and edited sections of the manuscript, generated artwork and researched references. A.C.-R. and T.G. are equal contributors. A.S. edited the manuscript, generated artwork and researched references. J.J.C., T.K.L. and P.F.M. contributed to the writing and editing of the manuscript. J.M.L. conceived and coordinated the project, wrote several sections, edited the manuscript and researched references.

Corresponding author

Correspondence to Jose M. Lora.

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Competing interests

A.S. is an employee at Synlogic. J.J.C. is a co-founder and adviser of Synlogic and Senti Bio. T.K.L is an employee at Senti Bio, and co-founder and adviser of Synlogic and Senti Bio. P.M is a member of the advisory board of Synlogic. J.M.L. is a former employee at Synlogic. T.G. and A.C.-R. declare no competing interests.

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Nature Reviews Drug Discovery thanks Howard Salis, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Boolean gates

A system or device that performs a logical operation on one or more binary inputs, which results in a single binary output.

AND gate

Output is actuated only if all of the specified inputs are received.

Synthetic promoters

Recombinant DNA elements that enable the binding of transcription factors and RNA polymerase enzyme to initiate transcription of RNA molecules.

Prosthetic gene network

Synthetic gene circuit that senses the bioavailability of a metabolite or hormone and autonomously corrects the physiological level of the molecule when it deviates from a targeted set point.

Payloads

Exogenous therapeutic molecules delivered by engineered cells.

OR-gate

Output is actuated if any of the specified inputs are received.

NOT-gated

Output is negated if a specific input is received.

Toggle switch

A synthetic, two-gene regulatory network in which either of two gene products represses the expression of the other gene, resulting in bistable equilibrium states.

Repressilator

Regulatory cycle of multiple genes whereby each gene represses its successor in the cycle, which is used to build an oscillating biological network.

Curli nanofibres

The amyloid fibre component of Escherichia coli biofilms.

Trefoil factors

(TFFs). Disulfide-rich mucosal peptides that promote epithelium protection by stimulating cell migration and increasing the viscoelasticity of the mucosa.

Curli operon

Gene cluster that encodes and regulates curli proteins.

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Cubillos-Ruiz, A., Guo, T., Sokolovska, A. et al. Engineering living therapeutics with synthetic biology. Nat Rev Drug Discov 20, 941–960 (2021). https://doi.org/10.1038/s41573-021-00285-3

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