The emergence of a chemical system capable of self-replication and evolution is a critical event in the origin of life. RNA polymerase ribozymes can replicate RNA, but their large size and structural complexity impede self-replication and preclude their spontaneous emergence. Here we describe QT45: a 45-nucleotide polymerase ribozyme, discovered from random sequence pools, that catalyzes general RNA-templated RNA synthesis using trinucleotide triphosphate (triplet) substrates in mildly alkaline eutectic ice. QT45 can synthesize both its complementary strand using a random triplet pool at 94.1% per-nucleotide fidelity, and a copy of itself using defined substrates, both with yields of ~0.2% in 72 days. The discovery of polymerase activity in a small RNA motif suggests that polymerase ribozymes are more abundant in RNA sequence space than previously thought.
Paper is paywalled so can only go by the abstract. Its surprisingly small, high enough fidelity to copy itself faithfully, but also very slow and low yield (which I suppose shouldn’t be surprising given it’s length).
Will be interesting to see what comes of this going forward.
72 days seems very slow, and I thought that RNA reactions were usually very fast? Perhaps I’m not understanding the denominator for that 0.2%.
I get that the discovery of a short self-replicating sequence is big news no matter how fast or slow it is. Very cool!
Edit to answer my own question …
Here we describe QT45: a 45-nucleotide ribozyme, discovered from a random sequence pool, that catalyzes general RNA-templated RNA synthesis using trinucleotide triphosphate substrates.
I have the paper and have only skimmed it. (DM me for the PDF.) The quote you provide is not a rate. It’s a yield. So, over 72 days, the ribozyme increased its abundance by ~0.02%. That parameter is likely to be partially independent of rate and instead reflects efficiency, which will be influenced by all sorts of things (reactant/product concentrations etc). My very quick initial skim suggests that the reaction (like all chemical reactions) is influenced strongly by competitive inhibition (of a sort). But the authors do describe the reaction as “slow.” Here is a portion of the first paragraph of the Discussion:
Our study shows that the complex functions needed for RNA replication — intermolecular binding to the primer-template-substrate complex, regiospecific catalysis, and general template-dependent RNA synthesis — can all be performed
by an RNA motif of just 45 nucleotides. This advanced phenotype, encoded in a small motif, enables QT45 to achieve the two key reactions required for self-replication: the synthesis of its complementary strand and of itself. These syntheses are currently slow and low-yielding, with further improvements in synthetic efficiency and fidelity likely required to overcome chemical degradation and achieve self-sustained replication. However, the QT ribozyme has only undergone a total of 18 rounds of evolution from a random sequence pool, indicating a likely potential for further development.
Remember, this reaction basically takes place in a thick slurry of ice and salt water, below the freezing point of pure water (reaction conditions are -7 degrees C). Water activity is very low under these conditions.
I will say I don’t think the conditions required for this replication cycle to proceed is particularly prebiotically plausible, but I don’t think that’s the main point of this discovery. It’s that a surprisingly small RNA self-replicator is even possible. Even though it is slow, low-yield, and has some rather odd requirements for it’s replication cycle, the fact that such a small self-replicator even exists implies others are possible that can also function under more plausible conditions. Oh, and it’s surprisingly high replication fidelity for such a tiny ribozyme.
To my mind this is most important as a springboard to further research into self-replicating polymerase-like RNA ribozymes. It shows they are not just an imaginary construct or hypothetical entity. They’re real, and there’s bound to be many more of them out there yet to have been discovered.
And (if I read this part right) they only looked at 10^{12} random sequences, a very small fraction of sequences potentially available. The odds this is the best sequence possible are fantastically small.
