RNA strand 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 developed the ability to make multiple copies of themselves. Now we have discovered an RNA molecule that is almost capable of this – it can carry out the key steps involved, just not all at once.

“It has been a long quest to get to the point where you can convince yourself that RNA has the capacity to make itself under the right conditions. I think this shows that it is possible,” says Philipp 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 cousin 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 up to form protein-like enzymes that can catalyze chemical reactions. Because RNA can both store information and act as a catalyst, it was suggested as early as the 1960s that life may have begun with RNA molecules capable of catalyzing their own formation.

But finding such molecules has proven very difficult. Scientists had long assumed that self-replicating RNAs must be relatively large and complex, but it turns out to be very difficult to unfold large RNAs to replicate them.

Also, while it has been shown that relatively short RNA molecules can form spontaneously under the right conditions, it is highly unlikely that large molecules have.

“This made us think, well, maybe we’re wrong. Maybe something simple, something small, can perform this process,” says Holliger. “And so we went hunting, and we found one.”

RNA is made of building blocks called nucleotides. The team started by generating a trillion random sequences that were 20, 30 or 40 nucleotides long. From these, they picked out three that could carry out reactions such as connecting nucleotides. The three were merged and put through several rounds of evolution – randomly changing, or mutating, parts of the sequence and selecting the better performers.

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 linking together short strands of two or three nucleotides, including making a sequence complementary to its own. “It’s currently quite slow and low yielding, but that’s not a surprise,” says Holliger.

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

“The most exciting thing is that when the system starts replicating itself, it should become self-optimizing,” says Holliger. That’s because the flawed process will produce many variations, some of which may work better, produce more of itself, and so on.

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

“Perhaps the most important aspect of this finding is the discovery of a moderately sized RNA oligomer sequence with these self-synthesizing capabilities,” says Zachary Adam of the University of Wisconsin-Madison.

The number of 45-nucleotide RNA sequences alone is “unbelievably 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, molecules similar to QT45 could have been able to replicate themselves in an environment a bit like today’s Iceland, Holliger says, with ice present but also hydrothermal activity to drive freeze-thaw cycles and create pH gradients. Some kind of division will be necessary to isolate the key components, he believes, but there are many ways this can happen, from pockets of meltwater in ice to cell-like vesicles that form spontaneously from fatty acids.