A strand of RNA that can almost replicate itself may be the key to the origin of life

According to the RNA world hypothesis, life began when RNA molecules evolved the ability to make multiple copies of themselves. Now we’ve discovered an RNA molecule that’s almost capable of doing just that—it can do key steps, but not all at once.

“It’s been a long search to get to the point where you can convince yourself that RNA has the ability to form under the right conditions. I think this shows that it’s possible,” he says. Philip Holliger at the MRC Laboratory of Molecular Biology in Cambridge, UK.

In living cells, proteins perform key tasks, such as catalyzing chemical reactions, and the recipes for making them are stored in double-stranded DNA molecules. RNA is a chemical relative of DNA that usually exists as single strands.

It’s not as good at storing information as DNA because it’s less stable, but it can do something DNA can’t: fold itself up to form protein-like enzymes that can catalyze chemical reactions. Because RNA can both store information and act as a catalyst, it was proposed as early as the 1960s that life may have begun with RNA molecules capable of catalyzing their own creation.

But finding such molecules turned out to be really difficult. Researchers have long assumed that self-replicating RNAs must be relatively large and complex, but it has turned out to be very difficult to evolve large RNAs to replicate.

What’s more, while it has been shown that relatively short RNA molecules can form spontaneously under the right conditions, large molecules are highly unlikely to do so.

“That led us to think, well, maybe we’re wrong. Maybe something simple, something small could do this process,” says Holliger. “So we went looking and we found.

RNAs are made up of building blocks called nucleotides. The team started by generating a trillion random sequences that were either 20, 30 or 40 nucleotides long. Of these, they selected three that could perform reactions such as joining nucleotides together. The three were spliced ​​together and went through several cycles of evolution—randomly changing or mutating parts of the sequence and selecting better variants.

The resulting molecule, called QT45, is only 45 nucleotides long. In alkaline water just above freezing, it can use single-stranded RNA as a template to make complementary strands by joining together short strands of two or three nucleotides, including creating a sequence complementary to its own. “It’s quite slow and unprofitable at the moment, but that’s no surprise,” says Holliger.

QT45 can also make multiple copies of itself from these complementary strands. “This is the first time a piece of RNA can make itself and its coding strand, and those are the two fundamental reactions of self-replication,” says Holliger. But so far, the team has not been able to get both reactions to take place in the same container. The plan now is to develop the molecule further and experiment with conditions such as freeze-thaw cycles to see if both reactions could occur at once.

“The most interesting part is that once the system starts replicating itself, it should optimize itself,” says Holliger. This is because the error process will create many variations, some of which may perform better, produce more of themselves, and so on.

“The new results from the Holliger lab are exceptional and represent a significant advance that moves things even closer to fully self-replicating RNA,” he says Sabina Müller at the University of Greifswald in Germany.

“Perhaps the most significant aspect of this finding is the discovery of a medium-sized RNA oligomer sequence with these self-synthesizing capabilities,” he says. Zachariah Adam at the University of Wisconsin-Madison.

The sheer number of 45 nucleotide RNA sequences is “unimaginably large,” Adam points out, so the team did well to find QT45 from a starting point of just a trillion random sequences.

On the early Earth, QT45-like molecules could replicate themselves in an environment somewhat similar to present-day Iceland, Holliger says, with ice present but also hydrothermal activity that drives freeze-thaw cycles and creates pH gradients. He thinks some separation would be needed to isolate the key components, but there are many ways this could happen, from pockets of melting water in ice to cell-like vesicles that spontaneously form from fatty acids.

topics:

• chemistry /
• origin of life