Synthesis at the Interface of Virology and Mammalian Genetic Code Expansion

How a virus efficiently invade its host cell and masterfully engineers its properties provides valuable lessons and resources for the emerging discipline of synthetic biology, which seeks to create engineered biological systems with novel functions. Recently, the toolbox of synthetic biology has also been enriched by the genetic code expansion technology, which has provided access to a large assortment of unnatural amino acids with novel chemical functionalities that can be site-specifically incorporated into proteins in living cells. The synergistic interplay of these two disciplines holds much promise to advance their individual progress, while creating new paradigms for synthetic biology. Our group has applied the genetic code expansion technology to generate mammalian viruses site-specifically incorporating a variety of unnatural amino acids, and used them to create engineer engineered viral vectors with novel properties. We have also used virus-based tools to overcome some of the long-standing fundamental limitations of the mammalian genetic code expansion technology. For example, we have developed a novel baculovirus-based vector that is able to deliver all of the genetic components required to facilitate efficient site-specific incorporation of UAAs of varied structures and properties into practically any target protein in a wide range of mammalian cells and tissues. Furthermore, we have developed a mammalian cell-based directed evolution platform to address the innate inefficiencies of the engineered genetic components at the core of this technology.