Unnatural Bases: The genetic basis of all life on the planet is comprised of deoxyribonucleic acid (DNA) with four nitrogenous nucleotide bases, abbreviated to A, G, C, and T. But there are variations on this theme, and Pinheiro et al. (p. 341 ; see the Perspective by Joyce ) describe the directed evolution of unnatural nucleic acid–like genetic polymers. Variant enzymes were developed that efficiently transcribed DNA to anhydrohexitol (HNA), cyclohexenyl (CeNA), locked (LNA), and threofuranosyl (TNA) nuceic acid analogs. Further variant enzymes were developed to reverse-transcribe these analogs back to DNA. Thus, man-made nucleic acid analogs can be designed and selected that have the potential to operate in a way analogous to the natural process of heredity and evolution.

A novel class of nucleic acid analogues, termed LNA (locked nucleic acids), is introduced. Following the Watson–Crick base pairing rules, LNA forms duplexes with complementary DNA and RNA with remarkably increased thermal stabilities and generally improved selectivities.