Research

Overview

Our research focuses on expansion of the genetic code to incorporate unnatural amino acids into proteins; these new amino acids are designed and harnessed to understand protein and cellular function and to develop biotherapeutics.

We expand the genetic code to incorporate unnatural amino acids (Uaas) into proteins in various cells and organisms, and harness their designed properties to investigate protein and cellular functions in vivo and to develop new biotherapeutics.

• Expansion of the genetic code:
  We have developed new methods enabling the efficient incorporation of Uaas in yeast, mammalian cells, primary neurons, stem cells, C. elegans, and embryonic mouse. We keep exploring new directions for expanding the genetic code.
• Biospecific chemistry via latent bioreactive Uaa:
  Interactions among biomacromolecules, which are primarily noncovalent, form the foundation of biology. We introduced the concept of “proximity-enabled bioreactivity”, which allows specific covalent bonds to form between biomacromolecules in vivo. By genetically encoding a new class of latent bioreactive Uaas into proteins, we have enabled these proteins to selectively crosslink with other proteins, RNAs, and carbohydrates. This transition from noncovalent to covalent interactions is driving advancements in fundamental biological research, biotherapeutics, and synthetic biology. 
• RF1 is nonessential:
  Contradictory to the paradigm that release factor one (RF1) is essential in bacteria, we discovered that RF1 can be unconditionally knocked out in E. coli. RF1-deletion strains afford a previously unavailable model for studying code evolution and a unique host for exploiting Uaas to evolve new biological functions.
• Imprints of the genetic code:
  The establishment of the genetic code remains elusive nearly five decades after the code was elucidated. We discovered imprints of the genetic code in the ribosome, providing biological evidence to support the stereochemical theory. A two-stage transition model for code origin was proposed.
• Ion channels:
  We design Uaas to probe the channel mechanisms of inactivation and membrane-voltage sensing.
• GPCR:
  GPCRs are the targets of almost half of today’s pharmaceuticals. Using photo-responsive and bioreactive Uaas, we mapped the ligand-receptor interaction for a class B GPCR directly in live mammalian cells, providing insights on ligand binding and activation.

Image credit: Elisabeth Fall