(548g) Chemogenetic Control of Organisms Using Redesigned Proteins

Our long-term goal is to create programmable organisms in which we are able to dynamically control metabolism, phenotype, and function so that user-defined functions can be turned on and off at will; this capacity would be essential for (i.) agriculture, where farmers could manage crop production in response to real-time environmental data; (ii.) therapeutic interventions like CAR-T or phage therapy where the biological agent would need to be contained after successful treatment; and (iii.) industrial microbiology where fermentation parameters could be precisely controlled.

To help realize this long-term vision, I will discuss the engineering and design of proteins that sense and respond to relevant, user-defined chemical ligands. Plant hormone receptors represent an attractive platform for engineering these biosensors because their chemically induced dimerization architectures naturally decouple small molecule sensing and sensor actuation. We show the use of a palette of exogenous chemicals can control plant function, including protein subcellular localization, activation of genome editing, and remote measurable phenotypic changes. We will also discuss efforts in other application areas. A particular focus of this talk will be on advanced protein engineering and design strategies needed to accomplish this vision, including on-chip oligo synthesis for mutagenesis, computationally-aided design, new surface display platforms, deep sequencing, and application of machine learning to tune biosensor affinity and specificity.