QT45 ribozyme enables self-replicating RNA

Edoardo Gianni and colleagues at the MRC Laboratory of Molecular Biology reported on February 13 that they had identified a 45-nucleotide RNA polymerase ribozyme, QT45, that can synthesize both itself and its complementary strand. The study was published in *Science* after appearing as a bioRxiv preprint in October 2024. (ukri.org) The authors said the work addresses a long-standing obstacle in origin-of-life research: previously known RNA-copying ribozymes were generally larger than 150 nucleotides and too complex to plausibly copy themselves. (zenodo.org) The paper describes laboratory experiments using activated trinucleotide building blocks rather than protein enzymes. (ukri.org) The authors reported that QT45 can copy its complementary strand from a random pool of trinucleotide substrates and can copy itself using a defined set of 13 trinucleotides and one hexamer. A Zenodo dataset released on February 9 said both reactions produced yields of about 0.2% over 72 days under mildly alkaline eutectic ice conditions. ### Why are researchers focused on a 45-nucleotide RNA? The number 45 is central because earlier polymerase ribozymes were much larger. The *Science* summary says known RNA polymerase ribozymes were generally more than 150 nucleotides long, a size that raised the synthetic burden and the accuracy needed to avoid mutational decay. (ukri.org) QT45, by contrast, emerged from a renewed search in pools of short random RNA sequences. Philipp Holliger’s group said the small size matters for both chemistry and origin-of-life models. The MRC Laboratory of Molecular Biology said QT45 is easier to copy than earlier ribozymes and could more plausibly have arisen spontaneously than larger, structurally complex RNA catalysts. (zenodo.org) Edoardo Gianni said in the institute’s release that the finding made spontaneous emergence of self-replicating RNA “much more likely.” ### What did QT45 actually do in the experiments? The experiments showed two separate steps that together define a self-replication cycle. The authors reported that QT45 synthesized its complementary strand using a random pool of all 64 possible trinucleotides, then synthesized a copy of itself using a defined substrate mixture. (science.org) The preprint and associated dataset describe those as the two key reactions needed for self-replication. The Zenodo record gives the most specific performance figures available in the source material. It says QT45 synthesized its complementary strand at 94.1% per-nucleotide fidelity, and that both the complementary-strand and self-strand reactions had yields of about 0.2% in 72 days. (ukri.org) The *Science* summary also says QT45 copied a range of RNA templates, including tightly folded sequences and templates encoding a hammerhead endonuclease ribozyme. ### How was QT45 found? The researchers said QT45 was discovered through in vitro selection from pools of short, random RNA sequences. The *Science* summary says the team identified three ribozymes with RNA polymerase activity and then used directed evolution and engineering to improve their activity, yielding QT45. (zenodo.org) The MRC Laboratory of Molecular Biology said the process involved repeated rounds of selection to enrich active sequences. A high-throughput mutation screen was then used to map QT45’s fitness landscape. The *Science* summary says that screen revealed a densely functional, small catalytic core, a result the authors linked to the ribozyme’s compact architecture. (zenodo.org) ### What does the paper say this changes for origin-of-life work? The authors frame the result as a laboratory model for a central RNA-world question. The *Science* summary says the emergence of a system capable of self-replication and evolution is a critical event in the origin of life, and the paper argues that finding polymerase activity in a much smaller RNA motif reduces the gap between catalytic function and plausible spontaneous emergence. (science.org) UK Research and Innovation, which highlighted the work in a February 13 release, said earlier RNA strands could copy other RNA but were too long and complex to copy themselves. The agency said QT45 changes that picture by showing a short RNA polymerase ribozyme can carry out both syntheses needed for self-replication, though so far in separate reactions. (science.org) ### What comes next for the team? The next milestone is a combined replication cycle rather than two separate reactions. The MRC Laboratory of Molecular Biology said the team is now trying to join the two experimentally demonstrated steps to “kickstart a self-replication cycle.” The data and code associated with the paper were posted to Zenodo on February 9, 2026, alongside sequencing files and analysis scripts tied to the published results. (science.org) (ukri.org)