Photochemical Genomics: Controlling Genes with Light
In order to obtain a fundamental understanding of the mechanisms involved in the regulation of biological processes and their disease manifestations though genetic misregulation, more precise methods for the external manipulation of gene function need to be developed. Towards this goal, light represents an ideal control element for gene regulation, as it can be controlled with high spatiotemporal resolution, while inducing minimal secondary perturbations in the organism under study. Recently, my lab accomplished the modulation of DNA and protein activity through photochemical means. Here, we describe conceptually novel, generally applicable tools for the reversible regulation of gene function using light. These photochemical gene switches are created in a modular fashion, since they are composed of two components: photoresponsive small organic molecules and RNA aptamers engineered to bind selectively to these molecules. These aptamers are then fused to genetically relevant mRNAs in vivo, to provide control over the activity of single genes and synthetic gene networks with unprecedented spatial (single cell level) and temporal (minute timescale) resolution. We already made substantial progress towards the development of such gene switches by synthesizing an array of photoswitchable molecules and successfully evolving an RNA aptamer for a light-responsive molecule. By combining both components we recently achieved light control over the RNA binding event in vitro. With these results in hand we are quickly striving to employ this system for in vivo studies of highly regulated gene expression. The proposed methodology will have a significant impact on the life sciences and beyond, and ultimately provide an initial step towards Photochemical Genomics as a new research area. Achieving precise photochemical control over single gene switches and synthetic gene networks will enable investigators to address a broad array of fundamental questions in Genetics, Developmental Biology, Medicine, and Physiology.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.