Our laboratory integrates chemistry and evolution to program and illuminate biology. We conduct research in three major areas. The first aims to precisely manipulate information flow in mammalian cells through the use of synthetic regulatory elements (SREs), proteins, and nucleic acids that modify genes and gene products with tailor-made specificities. Achieving this ambitious goal requires addressing two long-standing challenges in the molecular life sciences: (1) the development of a system for the continuous directed evolution of proteins and nucleic acids, and (2) the development of a general platform for the delivery of macromolecules into mammalian cells in vitro and in vivo.
Over the past several years we have developed new solutions to both of these key challenges. In the second research area, we continue to pioneer the development and application of DNA-templated synthesis (DTS), resulting in the discovery of new small-molecule inhibitors of therapeutically relevant proteins and three new chemical reactions over the past five years. The third area of research seeks to discover cellular nucleic acids with novel structures and functions. This research resulted in the discovery of cofactor-linked RNAs, geranylated RNAs, and a new DNA nucleotide, as well as metabolite-binding and unusually chemically reactive naturally occurring nucleic acids.
We have developed DNA-templated synthesis, a method that uses DNA sequences to program chemical synthesis in a way that enables synthetic molecules, and applied this method to discover novel inhibitors of kinases and proteases relevant to human disease. We have also developed and applied phage-assisted continuous evolution (PACE), a method to rapidly and continuously evolve proteins in the laboratory without human intervention.