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Theranostic cells: emerging clinical applications of synthetic biology

Nature Reviews Genetics volume 22, pages 730–746 (2021)Cite this article

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Abstract

Synthetic biology seeks to redesign biological systems to perform novel functions in a predictable manner. Recent advances in bacterial and mammalian cell engineering include the development of cells that function in biological samples or within the body as minimally invasive diagnostics or theranostics for the real-time regulation of complex diseased states. Ex vivo and in vivo cell-based biosensors and therapeutics have been developed to target a wide range of diseases including cancer, microbiome dysbiosis and autoimmune and metabolic diseases. While probiotic therapies have advanced to clinical trials, chimeric antigen receptor (CAR) T cell therapies have received regulatory approval, exemplifying the clinical potential of cellular therapies. This Review discusses preclinical and clinical applications of bacterial and mammalian sensing and drug delivery platforms as well as the underlying biological designs that could enable new classes of cell diagnostics and therapeutics. Additionally, we describe challenges that must be overcome for more rapid and safer clinical use of engineered systems.

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Fig. 1: Synthetic biology shows promise for use in diagnostics and therapeutics.
Fig. 2: Bacterial diagnostics report on internal inflammatory markers.
Fig. 3: Bacterial therapeutics for treating diseases in vivo.
Fig. 4: Anatomy of a CAR.
Fig. 5: Theranostic cells for non-cancer applications.

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Acknowledgements

The authors acknowledge members of the Silver laboratory for helpful conversations and acknowledge support from Harvard Medical School’s Dean’s Initiative Award and DARPA (140D0420C0057).

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Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, Boston, MA, USA

    Monica P. McNerney, Kailyn E. Doiron, Tai L. Ng, Timothy Z. Chang & Pamela A. Silver

  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Monica P. McNerney, Kailyn E. Doiron, Tai L. Ng, Timothy Z. Chang & Pamela A. Silver

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  1. Monica P. McNerney
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  2. Kailyn E. Doiron
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  3. Tai L. Ng
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M.P.M., K.E.D., T.L.N. and T.Z.C. researched the literature and wrote the article. All authors contributed to discussions of the content and reviewed and/or edited the manuscript.

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Correspondence to Pamela A. Silver.

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Glossary

Off-target effects

Unintended therapeutic consequences that occur when a drug binds to molecules in the body that are not the intended target of the drug.

Synthetic biology

A multidisciplinary field of biological research that seeks to design and engineer biology akin to other engineering disciplines. Goals of the field are the development of molecules, cells and even organisms with novel functions.

Chimeric antigen receptor

(CAR). A synthetic receptor that combines the specific, extracellular antigen-binding ability of an antibody and the T cell-activating abilities of the T cell receptor (intracellular stimulatory domains) to redirect immune cell action towards a disease antigen of interest.

Cell-free systems

Mixtures of proteins, nucleic acids, salts and metabolites that resemble the cytoplasm of cells and can be used to enact genetic circuits.

Probiotics

Beneficial microorganisms that are used to promote health. Probiotics can be naturally occurring microorganisms or microorganisms that have been engineered to sense and respond to a specific condition.

Genetic circuits

DNA systems in which the presence of different combinations of signals leads to differential gene expression. Circuits usually consist of an input (that is, surface receptor binding to a ligand) and an output (that is, expression of therapeutics) that is enacted only after the input condition is satisfied.

Transcription factors

Proteins that control the expression of a gene, generally either by activating or repressing its expression.

Quorum-sensing systems

Cell to cell communication systems, prominent in prokaryotes, that use extracellular small molecules as signalling cues.

Dysbiosis

An imbalance of the gut microbiome community. Disruption to gut bacterial homeostasis has been associated with human diseases such as inflammatory bowel diseases and irritable bowel syndrome.

Chassis

The organism or cell line that houses a genetic circuit and is engineered to perform specific tasks.

Biofilm

A collection of microorganisms associated with a primarily polysaccharide-based matrix. Biofilms are recalcitrant to antibiotic treatments.

Alginate beads

Beads used to encapsulate cells to allow their implantation into the body while keeping them isolated from the host immune system. In addition to preventing an immune response, alginate encapsulation forms a semipermeable barrier to allow the diffusion of nutrients and gases.

T cell receptor

(TCR). The antigen-binding complex natively expressed on the surface of T cells. Binding of antigen to the TCR is necessary for T cell activation.

Antigen peptides

Short amino acid sequences that can be recognized by T cell receptors (TCRs) or antibodies expressed by cells of the adaptive immune system. Binding of an antigen to cell receptors or antibodies can trigger an immune response.

Single-chain variable fragment

(scFV). A fusion protein consisting of the variable domains of the heavy and light chains of an antibody connected by a small linker. scFvs confer antigen-binding specificity to the chimeric antigen receptor (CAR).

Autologous

A term to denote cells or tissue derived from a patient for the treatment of that same patient.

Cytokine release syndrome

A potentially deadly adverse effect of chimeric antigen receptor (CAR) T cell therapy, resulting from the mass release of pro-inflammatory cytokine expression from activated T cells.

Cytokines

Secreted proteins that bind to receptors on other cells that induce a change in that target cell, generally categorized as pro-inflammatory or anti-inflammatory.

Boolean logic gates

Systems of binary, on/off signals used to generate complex behaviours in a system (for example, an AND-gated circuit necessitates the presence of two inputs before expression of the output).

Allogeneic

A term to describe cells or tissue derived from one person used to treat a genetically different person (allotransplantation).

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McNerney, M.P., Doiron, K.E., Ng, T.L. et al. Theranostic cells: emerging clinical applications of synthetic biology. Nat Rev Genet 22, 730–746 (2021). https://doi.org/10.1038/s41576-021-00383-3

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