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A Synthetic Alternative

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DNA and RNA are needed to store and process genetic information, and so far, no similar molecules found in nature have been shown to be capable of those tasks. Researchers led by Philipp Holliger at the MRC Laboratory of Molecular Biology in the UK took nature's designs and built on them, creating six synthetic polymers called xenonucleic acids — XNAs — that can store genetic information and evolve like DNA and RNA, but are hardier and more malleable than their natural counterparts. Genome Technology's Christie Rizk spoke with Holliger about the study, which was recently published in Science.

Genome Technology: Where did the idea come from to do this study?

Philipp Holliger: In general, if you look at the famous central dogma diagram, which summarizes the flow of information in biological systems, you see genetic information goes from DNA to RNA and then into proteins. As it turns out, you could reverse the information flow between DNA and RNA through the action of reverse transcript-ases and, to some limited degree, telomerase. This naturally led to questions of if there were any other types of polymers that we could conceive of — simple chemical alternatives, simple genetic polymers — which could also exchange information with the natural system. To do this, you needed to construct a polymerase which could move genetic information from DNA into such a polymer — we call it XNA — and then a reverse transcriptase to move the genetic information back from the XNA into DNA.

GT: What is the structure of the XNAs?

PH: We chose, rather opportunistically, a type of backbone which was known to retain the ability to form helices and base pairs to hybridize to DNA and RNA. What we brought to the table was the ability to polymerize these chemistries on a DNA template and then reverse-transcribe them back into DNA. In at least one case, we've shown that we can evolve them into complex structures and functions, such as binding to a given molecular target with high affinity and specificity. We have retained standard Watson-Crick base pairing, and we really just altered the backbone. ... They're really like a different script, like cuneiform or hieroglyphics as opposed to standard letters. They say the same thing, but in a different medium.

GT: How do the XNAs differ from DNA and RNA?

PH: We've replaced the canonical ribofuranose sugar — ribose and deoxyribose — with different ring structures, like six-membered rings or interlocked rings, and this changes the helical parameters and the physical chemical properties of these new materials. So they're much more chemically inert, and — certainly in the case of the ones we used for aptamer selection — completely impervious to degradation by natural nucleases like DNAses or RNAses. So with a view to using these as future therapeutics, they're going to persist much longer in the body and they'll also be able to withstand a range of chemical insults which damage DNA.

GT: What else are they capable of?

PH: You could think of doing pretty much anything you could do with DNA or RNA. Or there's a whole field which seeks to build nano-structures and devices from DNA and … presumably you could build similar structure using XNAs. What we'd like to do is continue on the aptamer research and, really, we see those XNAs we described so far not as an end, but as a beginning.

GT: What are some of the implications of this work?

PH: The fact that you can implement these essential functions of DNA and RNA in a sort of different backbone tells us, I think, that there is nothing unique about DNA and RNA, but really that these functionalities are probably emergent properties which occur in a wide range of polymers that can encode information. So nature's choice of DNA and RNA as genetic material has not been driven by — not entirely, at least — a functional imperative, but more likely reflects an opportunistic choice at the origin of life.

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