Studying the origin of life is a real challenge. Any actual evidence of the specific chemicals involved has long since been destroyed, leaving researchers with a big gap to bridge between the chemistry of the early earth and the molecules that appear to be fundamental to life itself. Recent years have seen a number of discoveries about DNA's close chemical relative, RNA, that suggest it played a key role in early protolife, leading to a proposal that life started out in an RNA world. One of the problems with this concept, however, was the fact that chemists hadn't come up with a way to synthesize the basic building blocks of RNA using the chemicals that were likely to be present in the early earth. Now, by taking a systems chemistry approach, a team of researchers at the University of Manchester have neatly cleared that hurdle.

On the biology side of things, support for an RNA world has built steadily in the last couple of decades, as discoveries have shown that RNA, in addition to carrying genetic information, can catalyze a variety of chemical reactions and undergo a form of chemical evolution when placed under a selective pressure. Remnants of the RNA world also appear to be central to modern life. Key molecules such as ATP and NADH are derivatives of RNA components, and RNA appears to catalyze a key step in the production of proteins.

But, so far, chemistry had come up a bit short. An RNA molecule is basically a polymer of individual units comprised of a ring-shaped base molecule, a sugar, and a phosphate. Chemists had figured out different ways that simple organic chemicals that were likely to be present in the early earth could form the base and sugar (phosphates are abundant). But, so far, they'd failed to chemically link them together in a functional unit.

The new research, published in Nature, suggests the problem may have been the reductionist approach itself. In short, scientists had been taking a bit of a "we'll deal with that later" approach to the problem, synthesizing the individual components separately before trying to figure out how they could link up. Instead, the researchers found that, by having the phosphate present in the reactions from the start, they could build up a three-ringed structure that would then react with the phosphate. That reaction would split open one of the rings, with the remaining two linked rings forming the cytosine base and sugar, all hooked up to a reactive phosphate that could undergo polymerization into RNA.

To get there, the researchers took the simple organic chemicals that had been used to make a sugar and base in separate reactions: cyanamide, cyanoacetylene, glycolaldehyde, and glyceraldehyde. They then used a systems chemistry approach, exploring all the reactions that the chemicals could undergo. They came up with a simple, four-step synthesis that went through the three-ringed intermediate molecule. The key question was whether any of the reactions would actually take place under realistic conditions.

Building up a two-ringed intermediate had already been described in the literature, but the reaction only ran under very basic conditions, which would have destroyed one of the other reaction compounds. It turned out that adding phosphate at this step allowed it to catalyze the reaction at neutral pH, providing an 80 percent yield of a two-ringed chemical. The next step, a reaction with cyanoacetylene to form the final intermediate, would typically turn the reaction solution acidic, altering the products. Instead, the phosphate buffered the solution, keeping it near a neutral pH and fostering the production of the three-ringed compound. The phosphate also reacted with a reaction byproduct, ensuring that a reverse-reaction couldn't take place.

Finally, with a little bit of heat, the phosphate would react with the three ringed structure, forming a mature RNA base, and linking the phosphate in a reactive state that's suitable for polymerization into an RNA molecule. Although this is specific for the cytosine base, exposing it to UV converted some of it to uridine, the other base of this sort.

All in all, most of these reactions seem pretty reasonable. They do require some different temperatures, but temperature gradients aren't uncommon in nature. The big stumbling block seems to be the fact that the authors kept one of the chemicals out of the reaction mix until the third step of the synthesis. I'm curious to see what kind of yields they might get if they put all the reactants together at once. There are also two other nucleotides that need to be synthesized, so the chemists' job isn't done yet.

Still, it's difficult not to be extremely impressed by the work. Not only have the authors managed to devise a very straightforward synthesis process, but they've vastly simplified the conditions necessary for getting the reactions to take place. And it's not just me who's impressed; Jack Szostak, who conducts origin of life research, wrote that the work "will stand for years as one of the great advances in prebiotic chemistry," in an accompanying perspective.

Nature, 2009. DOI: 10.1038/nature08013