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Synthetic heredity molecules emulate DNA

XNAs might find uses in drugs, studies of life’s origins

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2:07pm, April 19, 2012
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By swapping out the sugar molecules that put the D in DNA, scientists have created new hereditary molecules that can undergo Darwinian evolution.

Making the six new molecules, collectively called XNAs, is a major technological advance that could lead to all sorts of new drugs, sensors and diagnostic devices. The research, reported in the April 20 Science, could also provide clues to how life evolved on Earth.

“What makes DNA and RNA so cool is they are the genetic molecules, they are the basis for propagating information through generations,” says biochemist Gerald Joyce of the Scripps Research Institute in La Jolla, Calif. “Well, we now have eight genetic molecules: RNA, DNA and these six.”

While just creating the XNAs (for xenonucleic acids) represents a feat in itself, the molecules can’t do the entire evolution thing on their own: DNA still lends a hand at the replication stage. But the work is a step towards an alternative kind of life and as such is “a wonderful achievement,” says Joyce, author of a commentary on the work in the same issue of Science.

“We only know this one example of life — it’s what’s been on Earth for 4 billion years,” he says. “Maybe we’ll find evidence of some kind of life on Europa [a moon of Jupiter] or fossilized life on Mars. Or maybe we’ll just make it. That’s my bet.”

The researchers, led by Philipp Holliger of the MRC Laboratory of Molecular Biology in Cambridge, England, did make completely new genetic molecules. In the backbone of every DNA molecule there are repeating units of deoxyribose sugar, in the RNA backbone it’s ribose sugar. Instead of those sugars, the various XNAs have different molecules in their backbones: a five-carbon sugar called arabinose in ANA, the ringed structure anhydrohexitol in HNA, and threose, a four-carbon sugar in TNA. The scientists also created XNA molecules called FANA (2´-fluoroarabinose), CeNA (cyclohexene) and LNA (“locked” ribose analog). 

In a second bioengineering feat, the researchers created special enzymes for the XNAs so that they could evolve. This requires enzymes that can “read” the order of molecular components in a strand of XNA and use that information to build a complementary strand of DNA. Working with an enzyme from a sulfur-loving microbe, the team selected for versions that could “read” each of the XNAs. The researchers also made enzymes that could do the reverse: read DNA and use that information to build XNA.

Because the XNAs can’t copy themselves without help from DNA, it’s not truly synthetic life, says Joyce. But the molecules do undergo good old-fashioned evolution. With HNA, for example, the researchers created a random population of HNA molecules, then exposed them to a bunch of target molecules (such as proteins or RNA) for the HNA to attach to. Most of the HNAs didn’t do diddly-squat, but a fraction were slightly better at connecting to the target molecules.

So then the scientists selected the handful of HNAs that showed some affinity for the targets and replicated those with the help of DNA. After several generations of such HNA selecting and copying, the researchers had a group of HNAs that were pretty good at attaching to their targets.

“Thus, heredity and evolution, two hallmarks of life, are not limited to DNA and RNA but are likely to be emergent properties of polymers capable of information storage,” the researchers write.

Because ordinary enzymes that snip and degrade things in the body shouldn’t recognize the XNAs, the molecules should be very stable — in fact some are just more stable to begin with due to their chemistry, says coauthor Vitor Pinheiro, also from the MRC Laboratory. After incubating HNA in an extremely acidic solution for an hour, for example, the molecule was fine. “DNA just would have been shredded,” says Pinheiro.

This stability suggests the XNAs have great potential as biotechnology and materials science tools. RNA and DNA are used in vaccines and drugs, for example, but often have to be modified to be more durable. And because the XNA molecules can evolve, researchers can select for traits they want in a particular XNA and then direct its evolution.

Steven Benner of the Foundation for Applied Molecular Evolution in Gainesville, Fla., says the work is not only relevant to biotechnology here on Earth, but also “for the possible forms that life might take throughout the cosmos.”

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