Engineering of Far-Red Light-Controlled Optogenetic Devices for Biomedical Applications

Synthetic biology-inspired gene- and cell-based therapies are recognized as central pillars of next-generation medicine. However, the controllability remains a critical issue for clinical applications. Optogenetics is opening up exciting new opportunities for precision-guided medicine by illumination with light as a trigger signal to achieve spatiotemporal control of cellular activities. Optogenetics-based technology promises the capability to achieve traceless, remotely controlled precision dosing of an enormous range of therapeutic outputs. In this talk, I will introduce a far-red light (FRL)-controlled transgene expression device that was created for diabetes therapy. Using a multidisciplinary design principle coupling electrical engineering, software development, and synthetic biology, we have engineered a technological infrastructure enabling the smartphone-assisted semiautomatic treatment of diabetes in mice. By combining electronic device-generated digital signals with optogenetically engineered cells, this study provides a step toward translating cell-based therapies into the clinic. Furthermore, the FRL-controlled transgene expression device was further combined with CRISPR-Cas9/dCas9 tool to obtain a FRL-Cas9 device for controllable gene editing and a FRL-activated CRISPR-dCas9 effector (FACE) system for epigenome remodeling. The FRL-Cas9 device enables gene editing both in mammalian cells and animals controlled by FRL illumination. The FACE system enables transcriptional activation of user-defined endogenous genes under FRL illumination with high induction efficiency (~500-fold), and demonstrated to mediate targeted epigenetic modulation in mammalian cells and animals. Optogenetic devices developed in this work expanded the optogenetic toolkit for the development of therapeutic interventions and precise genome engineering in many areas of basic and translational research, which may in turn boost the clinical progress of optogenetics-based precision medicines.