Research

Biology is driven by molecular machines capable of sophisticated function. Our work takes an interdisciplinary approach to engineer existing biological machinery to generate variants endowed with new useful functional capabilities – such as tools to tease apart complex biological riddles, or biologics to precisely target human diseases. Our research combines elements from chemistry, biochemistry, molecular and cellular biology, and virology. We are pursuing several interdependent projects:

Expanding the genetic code of mammalian cells: The ability to site-specifically incorporate unnatural amino acids into specific sites in the mammalian proteome promises powerful new ways to probe and engineer the biology of these cells. We seek to expand the scope of this technology by 1) Enhancing the structural diversity of the genetically encoded unnatural amino acids through the development of new engineered aminoacyl-tRNA synthetase/tRNA pairs to drive genetic code expansion in mammalian cells. 2) Understanding and addressing the factors that limit the performance of this technology in the context of the mammalian translation system. 3) Simultaneous incorporation of multiple different unnatural amino acids within one polypeptide to spur new powerful applications.

Post-translational modification (PTM) of human proteins: Advances in unbiased mass-spectrometry-based proteomics have unveiled many novel post-translational modifications within the human proteome, and expanded the catalog of sites harboring known PTMs. However, the functional roles associated with the majority of these PTMs remain poorly understood. At the core of this knowledge gap lies our current inability to generate target proteins in a homogeneous state of modification, and ask how its properties are affected in response to these PTMs. We are developing genetically encoded tools to overcome this limitation and better understand the role of protein post-translational modification in human biology.

Viruses: Viruses have developed highly sophisticated strategies to invade and reprogram human cells to facilitate their own replication. We seek to both understand and engineer the molecular processes associated with viral entry using unique chemical functionalities precisely incorporated into the virus capsid. We are also interested in taking advantage of the ability of viruses to evolve in the context of mammalian cells to perform directed evolution of new biological functions in these cells.