Scientists on their quest to find the origin of life have stared into the primordial soup, trying to answer the ultimate chicken-and-egg question: Which came first, the genetic code or the proteins that build it? In modern biology, this is a distinct division of labor. DNA holds the blueprints, while proteins do the heavy lifting of catalyzing chemical reactions. But in the deep past, roughly 4 billion years ago, some scientists believe the first life spawned in an “RNA World.”
In this hypothetical era, RNA — DNA’s single-stranded molecular cousin — did it all. It stored genetic information and folded itself into complex shapes to act as a catalyst, or “ribozyme.”
The theory is elegant, but it has always suffered from a massive paradox. Until now, the only RNA molecules known to science capable of copying themselves were massive, complex beasts. They were so large that the odds of them appearing spontaneously in a puddle of prebiotic sludge were vanishingly small.
That has just changed.
Researchers at the MRC Laboratory of Molecular Biology in Cambridge have discovered a ribozyme that is shockingly small, yet capable of the fundamental steps of self-replication. They call it QT45 — short for “Quite Tiny 45.”
The Paradox of RNA Complexity
The RNA World hypothesis posits that life began when an RNA molecule emerged that could make copies of itself. This molecule would need to act as a polymerase, an enzyme that builds RNA strands.
Previous attempts to evolve these molecules in the lab resulted in ribozymes that were large and structurally complex. While impressive, these bulky molecules are difficult to auto-copy because their complex folded structures act as a barrier to the replication machinery. This creates a seemingly impossible contradiction: to work, the first replicator had to be big and complex, but being big and complex made it impossible to emerge spontaneously.
Philipp Holliger and Edoardo Gianniand from the MRC Laboratory of Molecular Biology in Cambridge decided to bet against the conventional wisdom. “This led us to think, well, maybe we’re wrong. Maybe something simple, something small, could carry out this process,” Holliger told New Scientist. “And so we went looking, and we found one.”
Fishing in a Trillion Sequences
To find a needle in a haystack, the team created a haystack of their own. They generated a random pool of roughly one trillion unique RNA sequences. Unlike previous experiments that started with long strands, they focused on short sequences of 20, 30, or 40 nucleotides. Through a process of in vitro evolution — where molecules are selected for their ability to perform a task, mutated, and selected again — they isolated a winner.
After 11 rounds of this molecular arms race, they identified three small, unrelated RNA motifs. The best of the bunch was a 45-nucleotide ribozyme. This molecule, QT45, is a fraction of the size of previous polymerase ribozymes.
Zachary Adam, a researcher at the University of Wisconsin-Madison who was not involved in the study, puts the scale of this achievement into perspective. “The number of 45-nucleotide-long RNA sequences alone is ‘unimaginably large’,” Adam points out in an interview with New Scientist. Finding one that works is a massive stroke of luck and persistence.
How QT45 Works: Ice and Triplets
QT45 doesn’t work exactly like the polymerase enzymes in your cells today. To function, it relies on two specific prebiotic hacks: sub-zero temperatures and “triplet” building blocks. The team found that the ribozyme works best in conditions similar to modern-day Iceland, with ice present alongside hydrothermal activity. The ice concentrates the RNA, while freeze-thaw cycles help drive the reaction.
Instead of adding one letter of the genetic code at a time, QT45 grabs them in chunks of three, known as trinucleotide triphosphates or “triplets.” Using triplets solves critical problems that plague shorter molecules. It enables the copying of highly structured RNA templates that would otherwise stall a copier, and it inhibits the strands from sticking back together too quickly, which typically stops replication dead in its tracks.
Using this method, QT45 proved to be surprisingly competent. It could even copy a “Hammerhead” ribozyme — another functional RNA — demonstrating that it can synthesize complex, biologically active sequences.
Closing the Loop: Self-Replication
The ultimate test for any candidate for the “first spark of life” is the ability to replicate itself. This involves two distinct steps: the ribozyme (the positive strand) must use itself as a template to build a complementary negative strand, and then use that negative strand to rebuild the original positive ribozyme. QT45 can do both, apparently.
“This is, for the first time, a piece of RNA that can make itself and its encoding strand, and those are the two constituent reactions of self-replication,” says Holliger.
However, there is a catch. Currently, the team hasn’t managed to get both reactions to happen in the same pot simultaneously. The ribozyme can synthesize its complementary strand from a mix of all 64 possible triplets, but to copy itself back from that strand, it currently requires a specific set of 13 triplets and a “hexamer” (a six-nucleotide chunk) to get the job done.
Gianni, the study’s lead author, is transparent about the current limitations. “We’re not quite at the point where it makes a lot more of itself. It makes a tiny, tiny amount that we can start detecting,” Gianni said in an interview with The Naked Scientists. “But it’s the first time we can even see that first touch of self-synthesis, of the ability of making itself happening in the laboratory.”
Evolution in the Ice?
One of the most intriguing aspects of QT45 is that it is not a perfect copy machine. When it synthesizes strands, it operates with an average fidelity of roughly 93%. We tend to think of errors as usually bad, but at the dawn of life, errors may have been essential because they are the fuel for evolution.
If the copying were 100% perfect, the molecule would never change. If it were too sloppy, the genetic information would be lost in noise. QT45 sits in a sweet spot where the error-ridden process produces variations. “The most exciting thing is, once the system begins to self-replicate, it should become self-optimising,” Holliger says. Natural selection kicks in, and the molecular engine upgrades itself.
Despite having the sequence, the researchers don’t yet know exactly what QT45 looks like in 3D space. “We’d love to have a look at the structure,” says Gianni. “We’ve tried predicting it with AI tools such as AlphaFold, and it gives a sense of the size and the shape, but it’s not quite producing the correct structure we think yet.”
Understanding the fold is the next frontier, as it could reveal how a mere 45 letters can fold up to create a catalytic pocket capable of knitting life together.
By showing that the machinery of life can be small, simple, and evolved from random noise, the team has made the transition from “dead” chemistry to “living” biology feel much less like a miracle, and more like an inevitability. “It’s been a long quest to get to the point where you can convince yourself that RNA has the capacity to make itself under the right conditions,” says Holliger. “I think this shows that it is possible.”