2019 Birch Lecture - Nobel Laureate Professor Frances Arnold - California Institute of Technology

Not satisfied with nature’s vast catalyst repertoire, I want to create new protein catalysts and expand the space of genetically encoded enzyme functions. We use the most powerful biological design process, evolution, to optimize existing enzymes and invent new ones, thereby circumventing our profound ignorance of how sequence encodes function. Using mechanistic understanding and mimicking nature’s evolutionary design processes, we have generated whole new enzyme families that catalyze chemical reactions not previously known in biology. Recent successes include engineering heme proteins for selective carbene insertion to form C-Si and C-B bonds, and alkyne cyclopropanation to make highly strained carbocycles, all in living cells. To create these new enzymes, we use synthetic reagents to drive generation of new reactive intermediates and directed evolution to optimize the emerging functions. Extending the capabilities and uncovering the mechanisms of these newly-evolved enzymes derived from natural iron-heme proteins provides a basis for discovering biocatalysts for increasingly challenging reactions. These capabilities increase the scope of molecules and materials we can build using synthetic biology and move us closer to a sustainable world where chemical synthesis can be fully programmed in DNA.