PROJECT SUMMARY/ABSTRACT Technological advances in molecular biology have led to the development of a variety of innovative tools to control gene expression. Those tools are crucial for both interrogating complex biological questions and developing the next generation of therapeutics. Yet, there are two main challenges that remain to be resolved. One is remote controlling of transcription on demand with the utmost temporal and spatial resolution. The other is to avoid crosstalk with existing signaling pathways. In this study, we propose to develop a new genetic tool based on synthetic biology to better control gene expression within cells. This novel tool is based on rewiring cellular networks and converting energy into biological action. We intend to harness the power of electromagnetism and biophotonics to control gene expression. Our goal is to devise multiplex gene arrangements, fusion proteins and transcription factors, that can be controlled remotely by electromagnetic fields (EMF). This unique, artificial cellular machinery will use biophotonic principles for activation of specific transcription factors and subsequently switch on gene transcription with the utmost precision. In the first Aim we will develop and evolve a genetically encoded biomagnetic switch that can convert EMF to photons. In parallel, in the second Aim we will develop an orthogonal transcription machinery that interacts with the biomagnetic switch and controls transcription without interacting with any endogenous signaling pathway. Finally, in the third Aim we will test the synthetic circuit in vivo, in a relevant animal model. This magneto-photonic circuit will by-pass the limitations of current chemical, optical, and magnetic approaches by allowing genetically targeted, non-invasive remote control of gene expression in a highly precise and physiologically relevant temporal manner. We anticipate that upon completion of the proposed research we will create an innovative tool that will be immensely beneficial for basic research, drug development and developing the next generation of synthetic biology-based therapeutics.