XNA marks the spot

The new field of synthetic genetics has made significant advances during the past four years, both to create artificial and modified nucleic acids, and to investigate their structural and functional properties. This rapid progress promises to improve our understanding of the origins and fundamental basis of life, and to enhance the application of this knowledge in the search for new therapeutic drugs. So far, synthetic genetics has been confined largely to modifying the naturally occurring nucleic acids, DNA and RNA, in order to understand how molecules have evolved to store information, catalyse chemical reactions and replicate themselves; developments that might have been the precursors to life on Earth. In doing so, the field has coined the slightly misleading term ‘XNA’, to describe chemically modified nucleic acids. The name suggests that the only variable is the sugar, represented by the letter X, whereas in fact, modified nucleic acids can be synthesized from the two naturally occurring ones by modifying any of the three components: the nitrogencontaining nucleobases that pair with each other, or the sugars and phosphate groups that form the backbone of the molecule (Fig 1). Moreover, as Phil Holliger, a pioneer in the field from Cambridge University in the UK, explained: “in addition, different modifications—and the density with which these modifications are introduced—can greatly affect the resulting XNA properties.” Holliger’s team has focused on creating an artificial version of RNA capable of copying information from DNA to XNA and back again. The challenge was to develop two sets of polymerase, one that could copy a gene from a DNA molecule to one of the new XNA molecules, and the other to copy it back into DNA. Holliger and colleagues focused on modifying the sugar component— identifying six different sugars that could replace ribose or deoxyribose— to demonstrate, in a landmark publication, that it is possible to generate artificial genetic polymers capable of both heredity and evolution [1]. Holliger likened the process to a retrovirus such as human immuno deficiency virus (HIV), whichcopies repeatedly between RNA and DNA. “We are now exploring some of those novel backbones to demonstrate that they can serve not only as repositories of genetic information, but also as a source of functional molecules,” he said. Such molecules could be used as ligands or aptamers that bind to specific targets to block undesirable pathways in a therapeutic application, or as catalysts or XNA enzymes to accelerate or enable target processes.