Polymerase engineering: towards the encoded synthesis of unnatural biopolymers

DNA is not only a repository of genetic information for life, it is also a unique polymer with remarkable properties: it associates according to well-defined rules, it can be assembled into diverse nanostructures of defined geometry, it can be evolved to bind ligands and catalyse chemical reactions and it can serve as a supramolecular scaffold to arrange chemical groups in space. However, its chemical makeup is rather uniform and the physicochemical properties of the four canonical bases only span a narrow range. Much wider chemical diversity is accessible through solid-phase synthesis but oligomers are limited to <100 nucleotides and variations in chemistry can usually not be replicated and thus are not amenable to evolution. Recent advances in nucleic acid chemistry and polymerase engineering promise to bring the synthesis, replication and ultimately evolution of nucleic acid polymers with greatly expanded chemical diversity within our reach.