Edoardo Gianni

With Eugene Koonin, we propose a concept of “the selfish ribosome”, under which evolution of life is viewed as a ribosomal takeover, where the ribosome evolved to consume most of the cell’s resources, while other cellular componentry ensures the propagation of the ribosome. arxiv.org/abs/2602.23268

A portable orthogonal replication system enables continuous gene evolution near the biological speed limit https://www.biorxiv.org/content/10.64898/2026.02.20.706958v1

A small polymerase ribozyme that can synthesize itself and its complementary strand 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 ...

Great summaries of our paper www.science.org/doi/10.1126/... in Science: www.science.org/doi/epdf/10.... and New Scientist: www.newscientist.com/article/2515... and in the Science museum blog: blog.sciencemuseum.org.uk/in-the-begin...

Bridging the gap from chemistry to life: discovery of a tiny RNA that can copy itself | MRC Laboratory of Molecular Biology Led by Edoardo Gianni, Philipp Holliger’s group in the LMB’s PNAC Division have identified a small self-replicating catalytic RNA (ribozyme), providing new ...

Have a look at the Insight on Research story on our Science paper www.science.org/doi/10.1126/... on the @mrclmb.bsky.social website: mrclmb.ac.uk/news-events/... including a great little animation from LMB VisLab.

Thank you! :)

Thank you for the lovely & clear explanation of the work by @rogerhighfield.bsky.social @sciencemuseum.org.uk. Gives a bit of the behind-the-scenes of the research that led to this work!

In the beginning - Science Museum Blog A tiny self-copying molecule offers the clearest answer yet to the mystery of the origins of biology, reports Science Director Roger Highfield.

Scientists have found a little RNA molecule – small enough to potentially form spontaneously, yet sophisticated enough to copy itself – that cd explain how life on Earth arose. Thanks @edogia.bsky.social of the @philholliger.bsky.social lab! blog.sciencemuseum.org.uk/in-the-begin...

Thank you :) Feel free to email if you still can't access it and would like a copy of the accepted version! (email should be in the author info on the paper link)

Clearly we think templated information transfer is critical for darwinian evolution, and that's what we focus on, but it definitely had to be embedded in a more complex system! Would love to keep the conversation going on this in the future :)

Thanks for the kind words and for spelling out the OoL models so clearly! We tried to be careful in the phrasing of the paper specifically to move the conversation a bit away from the running dichotomy between replication vs. metabolism first

Thank you! :)

How did life arise from simple chemical building blocks?

New #LMBResearch led by @edogia.bsky.social in @philholliger.bsky.social group has identified a small self-replicating ribozyme that could be the answer.

Read more: mrclmb.ac.uk/news-events/...

New paper from my group in @science.org : "A small polymerase ribozyme that can synthesise itself and its complementary strand" www.science.org/doi/10.1126/...
Outstanding work by @edogia.bsky.social

And last, a short animation showing what the two reactions look like: first we have self-synthesis, i.e. the ribozyme making a new copy of itself (+ strand). Then we have the synthesis of the complementary strand, i.e. the ribozyme making a copy of the template encoding itself (- strand).
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Grateful to the unique environment and long-term support of the MRC-LMB (@mrclmb.bsky.social) & Holliger lab, and a big thank you to the rest of the team: Sam Kwok, @chrisjwan.bsky.social, Kevin Goeij, @bryceclifton.bsky.social, @escolizzi.bsky.social, James Attwater, @philholliger.bsky.social.
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The QT ribozyme is still very early on in its evolutionary history compared to the class I polymerase lineage. I am excited to see what the next steps will bring, and looking forward to using the QT to build more complex self-replicating chemical systems and study their evolution.
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This enabled QT45 to synthesize itself and its complementary strand! So far, we’ve carried out the two reactions separately, and we had to use a hexamer to help prevent the two strands from annealing. This is on the list of things to fix next to get to self-sustained replication cycles.
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Thankfully triplets help with both problems! Past work led by co-author James Attwater showed that triplets can unfold RNA structure (elifesciences...) and attenuate strand reannealing (www.nature.com/articles/s41...). We were able to apply these two methods to the problems of self-replication.
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Diagram explaining the "quirks" of RNA replication. The ribozyme has to exist in two states: folded as a catalyst, and unfolded as a template. The reverse complement of the ribozyme is needed as a template to make the ribozyme, but it can also hybridise to the ribozyme and inhibit it.

So, we have a small ribozyme with a complex function. But can it make itself?
RNA-based self-replication is full of quirks that we had to deal with, where the ribozyme is also a template, and the reverse complement (also a template - I know, confusing) sticks to the ribozyme and inhibits it.
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Secondary structure diagram of the hammerhead ribozyme synthesized by QT45, also showing the location of the substrate cleaved by the hammerhead, and the primers used for the synthesis.

To confirm that QT45 could synthesize complex sequences, we showed that it can make another ribozyme (the hammerhead ribozyme). This is a key functionality in any RNA world scenario, previously only observed in the large class I polymerases.
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To better understand this new ribozyme, we mapped its fitness landscape by characterising over 130k mutants. The map shows a functionally dense small core held together by a stem that is more tolerant to mutations. A big shoutout to Samantha Kwok for generating this treasure trove of a dataset!
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Diagrams comparing the behaviour of a ribozyme acting in cis versus the one of a ribozyme acting in trans. Both extend a primer opposite a template using trinucleotide triphosphate substrates, but the in cis requires base pairing and a linker to connect it to the template to work. In trans works fully via tertiary interactions.

QT45 shows general RNA polymerase activity using trinucleotide building blocks, aka triplets (+ a touch with di-/mononucleotides) and works fully via tertiary interactions. We describe this as acting “in trans” rather than “in cis”, this is critical if you need to be able to copy any sequence.
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Secondary structure diagram of the QT45 RNA polymerase ribozyme. It looks roughly like a hairpin RNA (a bulge held together by a stem), with extra tertiary interactions.

We took a leap of faith and started a search for shorter polymerases in random RNA sequence pools. We found three ribozymes, but one really stood out of the pack for its activity and variety of sequences it could copy. We named it “QT45”, as it is Quite Tiny and only 45 nucleotides long.
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For 30+ years we and others have been evolving RNA polymerase ribozymes with the goal of building a self-replicating RNA-based system. These ribozymes are long and complex, which we thought was necessary for their function, but also prevented us from getting self-synthesis to work in the lab.
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First of all, why RNA?

RNA was first proposed in the late 60s as a solution to the chicken and egg problem of what came first between DNA, RNA, and proteins. If RNA could drive its own replication, then potentially a single polymer could have kickstarted the process of heredity and evolution.
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A small polymerase ribozyme that can synthesize itself and its complementary strand 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 ...

How could a simple self-replicating system emerge at the origins of life? RNA polymerase ribozymes can replicate RNA, but existing ones are so large that their self-replication seems impossible. Could they be smaller?

Excited to share our latest work in @science.org on a new small polymerase.
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it's coming it's coming!

Hi Erik! May I also be added to the Science feed please? Below is my google scholar :) scholar.google.com/citations?us...

RosettaFold 3 is here! 🧬🚀

AtomWorks (the foundational data pipeline powering it) is perhaps the really most exciting part of this release!

Congratulations @simonmathis.bsky.social and team!!! ❤️

bioRxiv preprint: www.biorxiv.org/content/10.1...

Trinucleotide substrates under pH–freeze–thaw cycles enable open-ended exponential RNA replication by a polymerase ribozyme Nature Chemistry - Models of abiotic RNA replication suffer from inherent product inhibition arising from the high stability of RNA duplexes. Now, it has been shown that RNA trinucleotide...

New paper from my group rdcu.be/eoaRr "Trinucleotide substrates under pH–freeze–thaw cycles enable open-ended exponential RNA replication by a polymerase ribozyme" in Nature Chemistry — great collaboration with attwaterlab.uk.