Did Life Begin in an RNA World?

A discovery about RNA in the late 1980s seemed to break the deadlock. Researchers found that, in addition to helping to convert genetic information into proteins, some RNAs can act as catalysts that enable chemical reactions. These were christened ribozymes, in reference to the protein catalysts called enzymes. The existence of ribozymes suggested that RNA can both carry genetic sequence information and act as a catalyst, thereby doing the jobs of both DNA and proteins. That makes it plausible that in its very earliest days, life — or the complex chemistry that preceded it — was all about RNA. According to this picture, championed by the physicist-turned-biologist Walter Gilbert, life began as an RNA world.

Imagine then that, somewhere on the prebiotic Earth, individual nucleotide molecules appeared and joined together spontaneously and randomly in chains. By chance one momentous day, one of these nucleotide chains acquired the right sequence to act as a ribozyme with the ability to help other RNAs form. Such a prebiotic ribozyme could even act as an autocatalyst, able to replicate itself. In 1996, this theory got a boost when researchers created a ribozyme that could indeed stitch individual nucleotides together to form RNA. This raised the prospect of RNA that could replicate.

Because such replication would be vulnerable to the random noise of the molecular world, errors would happen. Some replicated RNA would have a slightly different sequence from its parent. With such mutations, Darwinian evolution becomes possible: Natural selection would favor mutant replicators that make copies at a faster rate.

These primitive, evolving molecular systems wouldn’t be “alive” in themselves. It’s easy to imagine, however, how some RNA molecules could evolve into forms that catalyzed metabolic processes or made other complex biomolecules — and from there the path to the first truly living protocells comes into view.

The “RNA world,” as the idea was dubbed, sounds good in theory. But there are problems with the hypothesis. In 2019, the RNA biologist Gerald Joyce of the Salk Institute and his colleagues were exploring a method for making new ribozymes in the lab. They started by creating synthetic ribozymes that could make other RNAs. Then they scrambled the ribozymes’ sequences a bit to let them evolve artificially. Although they eventually found a ribozyme capable of synthesizing the RNA from which it had “evolved,” Joyce and colleagues found that the mutations introduced in each round of evolution tended to kill off the catalytic behavior. Very few mutants in each successive generation retained the ability to construct other RNA molecules at all. All told, the experiments suggest that self-sustaining RNA evolution appears to be hard.

What’s more, all of Joyce’s ribozymes were big, comprising perhaps several hundred or so linked nucleotides. However, current experiments have only yielded spontaneous assembly of RNAs that are relatively tiny — about 10 to 15 nucleotides long. It’s big jump to go from random assembly of small, fragmentary RNAs to an RNA world in which large molecules can form, much less replicate and evolve. The chance of functional molecules like these assembling at random and then sustaining themselves in some primordial pool seems minuscule.

But RNA-world true believers have some reason to maintain hope. Recent work from the biologist Philipp Holliger at the MRC Laboratory of Molecular Biology in the United Kingdom and his colleagues has shown that self-replicating RNAs don’t have to be as big as Joyce’s ribozymes. In their own RNA artificial evolution experiments, Holliger’s team looked for catalytic activity in small RNAs (between 20 and 40 nucleotides in length), allowing for small changes in length in each cycle of mutation. They found a 45-nucleotide molecule that they christened QT45 (“quite tiny”) that could seize another RNA strand and copy it. “In principle it can copy any sequence,” Holliger said. And getting a 45-nucleotide molecule spontaneously “does not seem an unreasonable ask,” he added. In fact, the researchers say, the catalytic activity might be sustained even if QT45 is split into two fragments, since the parts should remain able to do their jobs.

The researchers also found two other comparably small RNAs with similar activity within a starting pool of around 10 trillion different molecules. Given that this many molecules includes just a hundred-billionth of all the possible RNA sequences of this length, that’s actually a pretty good hit rate, Holliger said. It suggests that this sort of self-copying ability in small RNAs might be common enough that such molecules could have appeared quite readily among random RNAs in some kind of primordial soup.

That “could” is doing a lot of work. It’s not known whether there was a niche for an RNA world, either geographically or temporally, on the early Earth. Holliger and colleagues have shown that rounds of RNA replication leading to exponential growth can be driven by cyclic changes in acidity coupled with cycles of freezing and thawing of the solution — a plausible scenario at the icy poles of the young Earth. But any potential habitat would have to have been life-friendly for long enough for a spark of life to catch.

Perhaps most importantly, it’s not clear that an RNA world would be truly alive. Life isn’t just about self-replicating carriers of genetic information — it takes more ingredients, in particular the existence of some form of metabolism to harvest energy from the environment and use it to make useful molecules. However life started, it probably needed more than just a string of nucleotides.