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A variety of catalytic RNA molecules, or ribozymes, have been identified in nature and engineered in the laboratory; DNA-based versions of these ribozymes, however, consistently lack catalytic activity. Some people are surprised by this, says Gerald Joyce of The Scripps Research Institute, in part because it is easy to overlook the importance of the biochemical differences that distinguish ribonucleotides from deoxyribonucleotides. “But by the time they're functional molecules,” he says, “by the time it's an RNA or DNA that folds into a particular shape and carries out an enzymatic function, all of the little differences between RNA and DNA make all the difference in the world.”

This bears directly on one leading theory of the earliest stages of life, which posits a 'pre-RNA world' in which an RNA precursor mediated the earliest biological functions. At some point in time, pre-RNA gave way to RNA, but somehow these functional properties also transferred over to the more sophisticated macromolecule. This led Joyce to ask, “if you start with one kind of informational macromolecule that has a function, let's say RNA in this case, can you evolve it over to another informational macromolecule that retains the function or reacquires the function?”

To answer this, Joyce's group used R3C—an engineered RNA ligase ribozyme—as the starting point, synthesized its (inactive) DNA counterpart and then subjected it to multiple rounds of test-tube evolution, each time selecting for DNAs with the ability to ligate two RNA substrate molecules. After ten rounds, they isolated clone 10-18, a deoxyribozyme with approximately one-half the catalytic rate of the template ribozyme.

Clone 10-18 seems to retain the same general catalytic mechanism, although the ligation bond it forms is chemically different than that formed by R3C. Nonetheless, says Joyce, “it's the first time that anybody's ever taken function 'over the falls', from one macromolecule to another through an evolutionary transition.” As such, this work marks a milestone in understanding the earliest stages of prebiotic evolution. This work has practical benefits as well, according to Joyce: “If you have an RNA enzyme that's interesting, but you wish it was more rock-hard like DNA... you could take the RNA and evolve it into being a DNA enzyme. So one way to harden an RNA enzyme is by 'DNA-izing' it.”