Optogenetic Engineering of Cell Behaviors for Discovery and Therapy
The complexity of human cellular behavior presents both immense potential for biomedical innovation and substantial challenges for control. Our lab pioneers a unique approach to dissect and program these behaviors using cellular optogenetics–integrating hardware, software, and wetware to deliver precise, "virtual" signals to signaling pathways. This platform enables us to explore and engineer cellular memories, with the goal of uncovering cellular design principles that govern stress resilience and immune function. We engineered an optogenetically controlled Fc receptor (opto-FCR) expressed in macrophages and discovered that specific stimulation patterns dramatically increase phagocytosis, enhancing their ability to engulf cancer cells. Similar optogenetic programming of Protein Kinase R (opto-PKR) showed that specific temporal inputs at one time point enhance cellular resilience to stress in the future, providing a mechanistic explanation for a cellular memory and laying the groundwork for engineering adaptive cell states. These fundamental insights into how signaling pathways govern cell function provided the foundation for developing a high-throughput, all-optical screening platform to test the effects of small molecules on signaling pathway dynamics. This platform identified a novel class of "potentiators," compounds that selectively amplify critical stress-response pathways in already-threatened cells. These potentiators exhibit broad-spectrum antiviral activity, demonstrating efficacy against over 10 viruses in vitro and significantly reducing viral titers in an in vivo herpes model. Overall, this platform enables drug discovery in context, allowing us to find modulators of ongoing signaling dynamics rather than indiscriminate activators or inhibitors. These breakthroughs exemplify the power of programmable biology to bridge the gap between fundamental discovery and translation.