Alphabet soup

Why are we here? It’s a question that’s puzzled philosophers and scientists for centuries. “Every human society has its story of how everything began,” says William Martin, who studies evolution at the University of Düsseldorf. “Scientists do, too. It’s a fundamental human need. We want to know where we belong in the bigger picture.”

One of the biggest unknowns is how the first self-replicating molecules formed. Most scientists think that RNA was the earliest macromolecule that could be acted upon by evolutionary processes, but how did it arise? “How could you create information without any previous information?” asks Ernesto di Mauro of the Università La Sapienza di Roma, who spends his days investigating this very question. “The easiest things [to ask] are the most difficult to solve,” he says. It is the paradox of the chicken and the egg: before polymerases and ribosomes existed, how were nucleic acid...

That is precisely the puzzle di Mauro has tried to solve, taking his inspiration from William of Ockham (of Occam’s razor fame): “The solution is simple: you have to use the easiest, the cheapest, the most available procedure you can find.” He lives by this motto, running a small lab—just him and his graduate student Giovanni Costanzo.

It started over 15 years ago, when Di Mauro and a colleague were looking at a DNA sequencing gel. By accident—or serendipity—there was too much formamide in the gel, and rather than simply denaturing, the individual DNA bases degraded. Di Mauro saw the reaction as more than a simple degradation of DNA, rather a phase of a dynamic equilibrium, and went on to show that in the presence of inorganic catalysts (such as calcium carbonate), heating formamide would produce purine molecules.

Before polymerases and ribosomes existed, how were nucleic acid and proteins made?

Indeed, formamide is the reaction product of hydrogen cyanide (HCN) and water—coincidentally two of the most abundant inorganic molecules in interstellar space. Di Mauro figures that formamide was present on the early Earth, and went on to show that simple metal oxides and silicates found in rocks could catalyze the condensation of the five nucleosides found in DNA and RNA today, all from formamide (Topics in Current Chemistry, 2005).

What’s more, formamide also catalyzes the addition of phosphorus to nucleosides just by heating nucleosides to about 50°C. “I was surprised,” admits di Mauro. Before long chains of nucleic acid bases can form, though, another problem has to be overcome: polymerization is a condensation reaction—a molecule of water is released when two nucleosides join up. But the reaction takes place in water—Darwin’s “warm little pond,” in fact—making the reaction all but energetically impossible, since the reaction cannot release an extra molecule of water into an already saturated milieu.

However, di Mauro, thinking back to his sequencing gel, found that when nucleosides are cooked long enough in the presence of water and formamide, they eventually became stable, neither being made nor breaking down: instead, they form cyclic structures. These cyclic bases were the key to solving the polymerization paradox—how chains of nucleosides might form in water after all.

According to Mike Yarus, who studies the origins of translation at the University of Colorado at Boulder, one of the major problems with early-life research is that no one knows how to activate nucleotides so that they will polymerize. “[It] inexplicably never gets mentioned.” Experimenters have previously used metal ions and other catalysts without success, but di Mauro and Costanzo simply took the cyclic nucleoside monophosphates in water and warmed them up. “Shoop-de-whoop!” says Bill Martin. “Big polymers. Look Ma, no enzymes!” Simply in the presence of heat, the cyclic bases formed RNA chains in water alone. The reaction to the results of the experiment in di Mauro’s own “warm little pond” of a lab was quite muted. He was delighted, but Costanzo was very cool on seeing the RNA chains, over 100 nucleotides long. “‘How nice,’” Di Mauro recalls her saying. The reaction from Nature, where he first submitted the paper, was also a little quiet. It was rejected overnight, without review. It was eventually published in the Journal of Biological Chemistry (284:33206–16, 2009).

But the paper has created a stir in the scientific community, and Yarus and Martin, both F1000 members, have flagged it as one of F1000’s Hidden Jewels. “These things are [polymerizing] right in front of our eyes. That’s pretty exciting, actually,” says Martin. “The origin of life is unfalsifiable conjecture…What this finding does, it makes one of the more difficult transitions more imaginable.” “The appearance of a new kind of chemical activation…is big news,” agrees Yarus. “This might give us a leg up on going right back …to the first Darwinian creatures that ever existed on Earth.”

The Hidden Jewel describes a recent paper from a less obvious journal, selected by the Faculty.

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