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December 3, 2014

XNAs Artificially Evolved to Create XNAzymes

  • XNAs, synthetic genetic polymers with alternative backbone chemistries not found in nature, are capable of forming XNAzymes, forming an all-artificial parallel to the more familiar—but not necessarily inevitable—DNA-based system for generating DNAzymes and ribozymes. XNAs have been known to store genetic information and evolve through natural selection. And now, thanks to work carried out by scientists at the Medical Research Council (MRC) Laboratory of Molecular Biology, XNAs are also known to support catalytic processes—another essential life-sustaining capability.

    The MRC group’s findings appeared December 1 in Nature, in an article entitled, “Catalysts from synthetic genetic polymers.” The article describes how the scientists generated XNAzymes that are capable of catalyzing simple reactions such as cutting and joining RNA strands in a test tube. One of the XNAzymes can even join XNA strands together, which represents one of the first steps to creating a living system.

    The XNAzymes were created directly from random XNA oligomer pools via four different chemistries: arabino nucleic acids (ANA); 2′-fluoroarabino nucleic acids (FANA); hexitol nucleic acids (HNA); and cyclohexene nucleic acids (CeNA). Essentially, XNAs of these four types were synthesized from DNA templates and replicated by means of specially engineered mutant polymerases. These polymerases had been developed previously, as described in a 2012 Science article. They introduced errors and thereby produced novel XNA sequences.

    Through 13 to 17 rounds of selection, XNA sequences capable of catalysis were recovered and amplified. Over time, through this exercise of guided evolution, the XNA pools gradually yielded “fitter”—that is, faster—enzymes.

    “These results extend catalysis beyond biopolymers and establish technologies for the discovery of catalysts in a wide range of polymer scaffolds not found in nature,” wrote the authors of the Nature article. “Evolution of catalysis independent of any natural polymer has implications for the definition of chemical boundary conditions for the emergence of life on Earth and elsewhere in the Universe.”

    “Until recently, it was thought that DNA and RNA were the only molecules that could store genetic information and, together with proteins, the only biomolecules able to form enzymes,” said Philipp Holliger, Ph.D., a program leader at the MRC Laboratory of Molecular Biology and the senior author of the Nature paper. “Our work suggests that, in principle, there are a number of possible alternatives to nature's molecules that will support the catalytic processes required for life. Life’s ‘choice’ of RNA and DNA may just be an accident of prehistoric chemistry.

    “The creation of synthetic DNA, and now enzymes, from building blocks that don’t exist in nature also raises the possibility that if there is life on other planets it may have sprung up from an entirely different set of molecules," added Alex Taylor, Ph.D., the first author of the Nature paper. "[This work] widens the possible number of planets that might be able to host life.”

    At a more practical level, the scientists noted that XNAzymes, which are much more stable than naturally occurring enzymes, could be particularly useful in developing new therapies for a range of diseases, including cancers and viral infections, which exploit the body’s natural processes to take hold in the body.

    “Our XNAs are chemically extremely robust and, because they do not occur in nature, they are not recognised by the body’s natural degrading enzymes,” explained Dr. Holliger. “This might make them an attractive candidate for long-lasting treatments that can disrupt disease-related RNAs.”

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