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


  • 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.

  • Fig. 1 Building blocks for therapeutic programs.

    (A) Logic gates with inputs (A and/or B) and outputs (X) can be used to represent molecular processes and reactions. (B) Conventional gene and cell therapies require just one exogenous molecular input and lack precise control over the output. Such modules function as buffer gates (i.e., control devices whose output levels correspond to their input levels), because the RNA output will be produced in any cell that the DNA input is delivered to and the therapeutic protein will be translated correspondingly. (C) Engineerable modules can regulate the production, conversion, or loss of specific DNA (blue), RNA (red), or protein (yellow) species by using more than one molecular input. TF, transcription factor; RBP, RNA-binding protein.

  • Fig. 2 Small-molecule regulation enables control over strength of therapeutic activity and facilitates new applications.

    (A) Traditional CARs are activated when the T cell encounters a target antigen. ON-switch CARs respond to antigens only when a small molecule, such as rapalog, is administered. (B) The pancreatic progenitor-to–β-like cell differentiation circuit is controlled by VA. Increasing levels of VA establish three different gene-expression profiles for the transcription factors PDX1, NGN3, and MAFA to drive differentiation. The final concentration of PDX1 is a summation of translation from two mRNA sources akin to a wired-OR operation in electronic logic circuits. Dashed arrows indicate multiple steps. The same drawing conventions are used as in Fig. 1.

  • Fig. 3 Genetically encoded therapeutic programs incorporate cell-specific biomarkers for localized activity.

    (A) In an AND-gate CAR T cell, the activation of a synNotch receptor by a first antigen induces the expression of a CAR, which in turn is activated by a second antigen to ultimately activate the T cell. (B) RNA-encoded miRNA-classifier circuit selectively kills cancer cells characterized by high levels of miR-21 and low levels of miR-141, miR-142(3p), and miR-146a. The same drawing conventions are used as in Fig. 1.

  • Fig. 4 Gene circuits that use feedback regulation to sense systemic biomarkers and secrete systemically acting effector molecules enable homeostasis.

    (A) A closed-loop circuit to treat obesity responds to fatty acids and produces pramlintide to slow gastric emptying, reduce glucagon, and modulate satiety. (B) A cytokine converter circuit to treat psoriasis responds to inflammatory signals TNF-α and IL-22 and produces anti-psoriatic and anti-inflammatory cytokines, IL-4 and IL-10, respectively. Dashed arrows indicate multiple steps. The same drawing conventions are used as in Fig. 1.

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