Life is complicated. While that does apply to ordering your daily caffeine fix at Starbucks, what we’re talking about here is darwinian, entropy-defying, self-replicating life. Just to store, read, and apply genetic information requires 3 different types of molecules: DNA, RNA, and proteins. That makes it tough to imagine how life could ooze into being in some primordial pool, even with recent discoveries that the basic building blocks are out there in the universe. Fortunately, scientists at The Scripps Research Institute in San Diego recently created a molecule that demonstrates how life could have begun.
Origins of Life: The RNA World Hypothesis
One popular solution to the origin of life conundrum is the RNA world hypothesis. In our world, RNA (mostly) just “reads” genetic information, transferring it from DNA storage to the protein machines that do the work of life. But RNA can also store information, and a few RNAs (so-called ribozymes) can take the place of proteins as enzymes that catalyze reactions. So maybe in the beginning, life was a much simpler system with RNA doing everything.
Primordial Soup: High in RNA? Haldane’s Primordial Soup courtesy of InvaderXan under the CC BY-SA 3.0 license.
The Problem of Replicating RNA in an RNA World
The key element for this theory to work is that RNA needs to be able to replicate, and while technically it can, there are a couple of sticking points. For one, spontaneous replication with the usual RNA is too slow. More importantly, RNA has two mirror-image forms (chiralities), and neither form can replicate with the other around; right-handed nucleotides terminate left-handed RNA chains, and vice versa. Current life only makes and uses one chirality, but the recipe for prebiotic soup probably included both. This means there would have to be a ribozyme that could both speed up the replication and avoid inhibition by the opposite chirality.
Evolving a Cross Chiral RNA Polymerase Ribozyme
Scientists have already evolved such ribozymes that can catalyze chirality-specific RNA replication, which solve chiral inhibition by only incorporating correct-handed monomers. These ribozymes, however, have another problem: the replicators tend to stick to the template they’re trying to copy, making them too sequence-specific. To get around this, the Scripps scientists wondered if they could make a ribozyme from one chirality of RNA that would replicate the other form, since the two types don’t base-pair with each other, which would resolve this sticky issue.
Using a clever directed evolution set-up, the scientists mixed random right-handed RNA sequences with left-handed template RNA and selected for the best molecules. They also gave the aspiring ribo-replicators training wheels, by creating RNA pieces that were already on the template ready to be joined, or ligated. After several rounds of evolution, a ribozyme rose to the top of the pack that could efficiently ligate two pieces of opposite-chirality RNA. Not only that, but it could also add on new bases along the template, as a true RNA replicator would have to do. When the scientists made the ribozyme’s left-handed mirror image, it worked just like the original, except now copying right-handed templates. In their final test, the new right-handed ribozyme was able to make its own left-handed form, and in principle this left-handed form would be able reproduce the original right-handed form, finally realizing a self-reproducing RNA system.
Proof of Principle for the RNA World Hypothesis
This is a new ribozyme, of course; it’s not the discovery of some ancient fossil from the primordial soup. The ribozyme is also not perfect (yet, but the authors are still working on it). Currently, it’s better at adding bases after C or G than after A or U, for example. However, it does show how replication could work in a chirally-diverse RNA world, and it also demonstrates the power of well-designed directed evolution. There’s even a nice moral to be metaphorized from the story: Ironically, the solution to inhibition by the opposite chirality wasn’t to exclude the other form, it was to work with it.
You can find a perfect copy of the paper at Nature, November 2014.
To read more about the evolving RNA world hypothesis, see “The origins of the RNA World” (2012) and “The antiquity of RNA-based evolution” (2002)