The ability to synthesize and propagate genetic information encoded within the framework of a xeno-nucleic acid (XNA) polymer would inform a wide range of topics from the origins of life to molecular medicine. However, the engineering of natural DNA polymerases to replicate artificial genetic polymers with backbone structures that are distinct from those found in nature is a challenging problem due to the strong evolutionary constraints that have long specify the use of DNA substrates. Here, I will discuss an interdisciplinary approach to polymerase engineering that combines chemical synthesis, droplet microfluidics, and X-ray crystallography to establish an integrated technology platform for expanding the functional properties of natural DNA polymerases. This talk will focus on the challenges and successes of polymerase evolution and provide examples where Darwinian evolution has been used to isolate functional XNAs. These results, which shows that XNAs have the ability to fold into structures with sophisticated chemical functions, provides evidence that certain XNAs could have served as an ancestral genetic system during an early stage of life on Earth. Given that some XNAs are refractory to nuclease digestion, this approach could also be used to develop a new generation of diagnostic and therapeutic agents with practical applications in biotechnology and molecular medicine.

Re-engineering DNA polymerases to recognize xeno-nucleic acids (XNAs)

256th National Meeting (2018)

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