Light‐Controlled Mammalian Cells and Their Therapeutic Applications in Synthetic Biology

Abstract

The ability to remote control the expression of therapeutic genes in mammalian cells in order to treat disease is a central goal of synthetic biology‐inspired therapeutic strategies. Furthermore, optogenetics, a combination of light and genetic sciences, provides an unprecedented ability to use light for precise control of various cellular activities with high spatiotemporal resolution. Recent work to combine optogenetics and therapeutic synthetic biology has led to the engineering of light‐controllable designer cells, whose behavior can be regulated precisely and noninvasively. This Review focuses mainly on non‐neural optogenetic systems, which are often used in synthetic biology, and their applications in genetic programing of mammalian cells. Here, a brief overview of the optogenetic tool kit that is available to build light‐sensitive mammalian cells is provided. Then, recently developed strategies for the control of designer cells with specific biological functions are summarized. Recent translational applications of optogenetically engineered cells are also highlighted, ranging from in vitro basic research to in vivo light‐controlled gene therapy. Finally, current bottlenecks, possible solutions, and future prospects for optogenetics in synthetic biology are discussed.

Light-Inducible Recombinases for Bacterial Optogenetics

“…Optogenetic tools enable novel applications for synthetic biology. [1][2][3][4][5] These tools typically use light to control expression of genes, often relying on light-dependent changes in protein state to control protein-protein interactions, 6,7 promoter systems, 8,9 and ion channels. 10 Optogenetic systems offer many advantages over traditional chemical approaches for controlling gene expression due to the direct and programmable nature of light as an input.…”

Components from the Human c-myb Transcriptional Regulation System Reactivate Epigenetically Repressed Transgenes

“…The ability to quickly toggle between enhanced and repressed states is a fundamental feature of engineered transgenic systems [29,85,86]. Current methods for toggling gene expression in mammalian cells employ drug-mediated transactivator localization, such as allosteric modulation of DNA-binding protein domains [29,85,87], blue light-responsive CRY proteins [88], and chemically induced dimerization (CID) systems [89][90][91], or RNA interference to deplete the regulator [86]. To our knowledge, no systems currently exist where the transactivation module's activity (i.e., MYB-CBP binding) is modulated by a small molecule drug.…”

Components from the human c-myb transcriptional regulation system reactivate epigenetically repressed transgenes

“…The ability to quickly toggle between enhanced and repressed states is a fundamental feature of engineered transgenic systems (29,88,89) . Current methods for toggling gene expression in mammalian cells employ drug-mediated transactivator localization, such as allosteric modulation of DNA-binding protein domains (29,88,90) , blue light-responsive CRY proteins (91) , and chemically induced dimerization (CID) systems (92)(93)(94) , or RNA interference to deplete the regulator (89) . To our knowledge, no systems currently exist where the transactivation module's activity (i.e., MYB-CBP binding) is modulated by a small molecule drug.…”