Programming gene and engineered-cell therapies with synthetic biology

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Science  09 Feb 2018:
Vol. 359, Issue 6376, eaad1067
DOI: 10.1126/science.aad1067

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Toward programmed therapeutics

Advances in synthetic biology are enabling the development of new gene and cell therapies. Kitada et al. review recent successes in areas such as cancer immunotherapy and stem cell therapy, point out the limitations of current approaches, and describe prospects for using synthetic biology to overcome these challenges. Broader adoption of these therapies requires precise, context-specific control over cellular behavior. Gene circuits can be built to give sophisticated control over cellular behaviors so that therapeutic functions can, for example, be programmed to activate in response to disease biomarkers.

Science, this issue p. eaad1067

Structured Abstract


Gene and engineered-cell therapies promise new treatment modalities for incurable or difficult-to-treat diseases. First-generation gene and engineered-cell therapies are already used in the clinic, including an ex vivo gene-replacement therapy for adenosine deaminase deficiency, chimeric antigen receptor (CAR) T cell therapies for certain types of leukemias and lymphomas, an adeno-associated virus gene therapy for inherited retinal diseases, and investigational therapies for β-thalassemia, sickle cell disease, hemophilia, and spinal muscular atrophy. Despite these early successes, safety concerns may hamper the broader adoption of some of these approaches: For example, overexpression of a therapeutic gene product with a narrow therapeutic window may be toxic, and excessive activation of T cells can be fatal. More-sophisticated control over cellular activity would allow us to reliably “program” cells with therapeutic behaviors, leading to safer and more effective gene and engineered-cell therapies as well as new treatments.


Recent advances in synthetic biology are enabling new gene and engineered-cell therapies. These developments include engineered biological sensors that can detect disease biomarkers such as microRNAs and cell-surface proteins; genetic sensors that respond to exogenous small molecules; and new methods for interacting with various components of the cell—editing DNA, modulating RNA, and interfacing with endogenous signaling networks. These new biological modules have therapeutic potential on their own and can also serve as building blocks for sophisticated synthetic gene “circuits” that precisely control the strength, timing, and location of therapeutic function. This advanced control over cellular behavior will facilitate the development of treatments that address the underlying molecular causes of disease as well as provide viable therapeutic strategies in situations where the biomolecular targets have been previously considered “undruggable.”

Recent publications have demonstrated several strategies for designing complex therapeutic genetic programs by combining basic sensor, regulatory, and effector modules. These strategies include (i) external small-molecule regulation to control therapeutic activity postdelivery, (ii) sensors of cell-specific biomarkers that activate therapeutic activity only in diseased cells and tissues, and/or (iii) feedback control loops that maintain homeostasis of bodily systems. Example therapeutic systems include a genetic circuit that senses two specific cell-surface markers to activate CAR T cells only in the presence of target cancer cells, a circuit that programmatically differentiates pancreatic progenitor cells into insulin-secreting β-like cells, and a gene network that senses the amount of psoriasis-associated cytokines to release immune-modulatory proteins only during flare-ups. These proof-of-concept systems may lead to new treatments that are dramatically safer and more effective than current therapies.


Rapid progress in synthetic biology and related fields is bringing therapeutic gene circuits ever closer to the clinic. Ongoing efforts in modeling and simulating mammalian genetic circuits will reduce the number of circuit variants that need to be tested to achieve the desired behavior. The platforms used to test genetic circuits are also evolving to more closely resemble the actual human environment in which the circuits will operate. Human organoid, tissue-on-a-chip, and whole-blood models will enable higher-throughput circuit characterization and optimization in a more physiologically relevant setting. Progress in nucleic acid delivery will improve the safety and efficiency with which therapeutic nucleic acids are introduced to target cells, and new methods for immunomodulation will suppress or mitigate unwanted immune responses. Together, these advances will accelerate the development and adoption of synthetic biology-based gene and engineered-cell therapies.

Programming gene and engineered-cell therapies with synthetic biology to improve human health.

Genetically encoded therapeutic programs can regulate the dosage, localization, or timing of therapeutic function by sensing and processing externally administered signals as well as cell-specific and systemic disease biomarkers. These synthetic gene networks may lead to gene and engineered-cell therapies that are safer and more effective and that can address a broader class of diseases than current approaches.


Gene and engineered-cell therapies promise to treat diseases by genetically modifying cells to carry out therapeutic tasks. Although the field has had some success in treating monogenic disorders and hematological malignancies, current approaches are limited to overexpression of one or a few transgenes, constraining the diseases that can be treated with this approach and leading to potential concerns over safety and efficacy. Synthetic gene networks can regulate the dosage, timing, and localization of gene expression and therapeutic activity in response to small molecules and disease biomarkers. Such “programmable” gene and engineered-cell therapies will provide new interventions for incurable or difficult-to-treat diseases.

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