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A paper by Philipp Holliger’s group in the MRC Laboratory of Molecular Biology’s Protein and Nucleic Acid Chemistry (PNAC) Division, Cambridge, UK, announces the discovery of a self-replicating small RNA molecule that can also synthesise its complementary strand. It was published yesterday in Science Advances.
This effectively resolves one of the few remaining major questions in explanations of abiogenesis: the origin of a simple self-catalysing replicator. Such a molecule must have existed at the very beginning of life’s emergence, and for decades RNA has been the leading candidate, because it can function both as an enzyme and as an information store — capable of copying that information repeatedly, provided there is a supply of nucleotides from which to build itself.
The question of where such a replicator first arose — in Darwin’s “warm little pond”, at a deep-ocean hydrothermal vent, or on wave-splashed rocks providing a steady supply of raw materials — is secondary to the more fundamental question of what could have initiated self-replication in the first place. Once replication began, occasional copying errors would inevitably generate variation, giving natural selection something to act upon. From that point, it is difficult to avoid the conclusion that progressively more efficient replicators would emerge, eventually dominating and monopolising the available resources.
Although various RNA molecules are known that can also act as catalysts (ribozymes), most are far too large to self-catalyse, or plausibly to have arisen spontaneously under prebiotic conditions. This newly discovered RNA molecule, at a mere 45 nucleotides long, neatly plugs that gap.
Creationists will no doubt reach for their usual “astronomical improbability” trope, but it only works by assuming the wrong problem. It treats abiogenesis as if one exact, predetermined sequence had to assemble by perfectly random chance in a single step. Real chemistry is biased, real environments concentrate and cycle materials, and—most importantly—the target was never one unique sequence but any of a potentially vast number of small RNAs with even modest replicative activity.
Once replication begins, copying errors generate variation and natural selection can take over, amplifying the better replicators. In short: the relevant question is not the odds of one bullseye in 445, but how quickly chemistry can stumble into a broad foothold and let Darwinian processes do what they inevitably do.
The ‘RNA World’ Hypothesis — Life Before DNA and Proteins. One of the central problems in understanding abiogenesis is the familiar chicken-and-egg dilemma of modern biology: today, life requires DNA to store information and proteins to catalyse the chemical reactions of metabolism and replication. But DNA cannot replicate without proteins, and proteins cannot be made without instructions stored in DNA. So how could the first self-sustaining system ever have begun?The discovery, and its significance for the study of abiogenesis, is the subject of a news item from the MRC Laboratory of Molecular Biology.
The leading solution is the RNA world hypothesis, first proposed in the 1960s and developed in detail during the 1980s. It suggests that before life evolved the division of labour we see today, early life may have relied on RNA alone.
RNA is uniquely suited to this role because it can do two crucial jobs at once:
- Store genetic information, like DNA.
- Act as a catalyst, like a protein enzyme.
Catalytic RNAs are known as ribozymes, and they are not speculative: they exist in living cells today. In fact, one of the most important molecular machines in biology — the ribosome, which builds proteins — is itself fundamentally a ribozyme. Proteins assist, but the core chemistry is carried out by RNA.
In an RNA world, the earliest “life” may have consisted of little more than small RNA molecules capable of copying themselves, competing for nucleotides, and occasionally producing copying errors. Those errors would generate variation, allowing natural selection to begin operating long before the first true cells existed.
Over time, evolution could then have favoured systems in which:
- RNA began to recruit amino acids as helpers, eventually giving rise to proteins.
- More stable DNA replaced RNA as the long-term genetic archive.
- Lipid membranes enclosed replicators into protocells, allowing cooperation and metabolic complexity.
Thus, the RNA world hypothesis provides a plausible bridge between prebiotic chemistry and the first Darwinian evolution — a stage of life where heredity and catalysis were united in a single molecule.
Discoveries of ever smaller self-replicating ribozymes, such as the newly reported 45-nucleotide RNA, strengthen this hypothesis by showing that the gap between chemistry and biology may be far narrower than once assumed.
Bridging the gap from chemistry to life: discovery of a tiny RNA that can copy itself
A newly discovered small catalytic RNA (ribozyme) suggests how simple molecules could have self-replicated to kickstart life
How life arose from simple chemical building blocks remains one of science’s greatest unanswered questions. Early life would have required a way to store and transmit genetic information without the complex molecular machinery used by modern organisms. RNA has long been proposed as a central player in this process because it can act both as a catalyst and as an instructive template for replication. This dual function of RNA potentially enables both heredity and replication within a single molecule, a prerequisite for the evolution of more complex forms. According to the “RNA World” hypothesis, such RNA molecules may have formed spontaneously in a primordial soup, eventually acquiring the ability to self-replicate and evolve. However, most known catalytic RNAs, or ribozymes, discovered so far are too large and too complex to either replicate themselves or to plausibly arise spontaneously. A recent study from Philipp Holliger’s group in the LMB’s PNAC Division addresses this problem by identifying a new small polymerase ribozyme that may overcome these fundamental limitations.
Previously discovered large RNA polymerase ribozyme structure (grey, based on pdb: 8T2P) vs. newly discovered small RNA polymerase ribozyme QT45 (blue, AlphaFold3 prediction).
RNA self-replication is defined as the ability of an RNA molecule to copy both itself and the information encoded in its complementary strand, i.e. its template. Over the past 25 years, ribozymes that can copy RNA (polymerase ribozymes) have been identified but they are generally large and structurally complex, making self-replication reactions difficult. Because no shorter ribozymes with this activity have been found, it has been widely assumed that it is only large and complex RNAs that can catalyse RNA copying reactions. This assumption leads to a paradox regarding the origin of the first self-replicating RNA: it would need to be large and complex enough to catalyse its own replication, yet that very size and complexity hinder self-replication and make its spontaneous origin highly unlikely. As such, if this catalytic activity can be found in smaller, simpler RNA molecules, this paradox could be resolved, with important implications for the earliest steps in the origin of life.
Led by Investigator Scientist Edoardo Gianni, the group applied in vitro selection to renew the search for active ribozymes in pools of short, random RNA sequences. The process was repeated several times to enrich the active sequences. In the end, they identified three small, unrelated RNA sequences that exhibited polymerase ribozyme activity. These RNAs underwent further laboratory-based evolution to improve their catalytic activity, resulting in an unexpectedly small ribozyme of 45 nucleotides with robust RNA polymerase activity, named “Quite Tiny 45” (QT45).
To further characterise QT45, the group evaluated its capacity to copy a range of RNA sequences distinct from its own, thereby assessing its generality across multiple RNA templates. QT45 demonstrated the ability to copy RNA templates of increased length and structural complexity. Notably, it successfully copied another ribozyme known as the Hammerhead ribozyme. To date, such a complex synthesis has been reported only for large and complex ribozymes. Furthermore, QT45 was shown to be able to use a range of different RNA substrates for its copying reaction. This observed promiscuity in the substrates and RNA templates copied by QT45 indicates that RNA replication can likely occur within a chemically diverse prebiotic environment.
Once the generality of QT45 was established, the group investigated its ability to synthesise both itself and its complementary strand. The synthesis of itself uses the ribozyme’s complementary strand as the template, whereby the synthesis of the complementary strand uses the ribozyme itself as the template – exploiting the dual function of RNA acting as both a template strand and as a catalyst. The experiments confirmed that QT45 could carry out both syntheses in two separate reactions, individually completing the two steps of a self-replication cycle.
Animation of the QT45 ribozyme copying itself and its complementary strand.
Ultimately, identification of this small ribozyme has shown that catalytic RNAs with polymerase function can be much simpler and are likely much more abundant than previously anticipated. This lends support to the spontaneous emergence and self-replication of RNA at the dawn of life.
Publication:
For creationists, this is yet another uncomfortable example of reality refusing to conform to their preferred Bronze Age mythology. Abiogenesis is so often misrepresented by its opponents as an absurd fairy tale in which a fully-formed modern cell supposedly “just happened” to assemble itself by blind luck. But that caricature bears no resemblance to what science actually proposes. The real question has always been how chemistry could give rise to the first simple self-replicating systems — and each discovery like this one shrinks that gap still further.
What makes the finding so significant is not that one particular RNA molecule had to appear in a single miraculous stroke, but that the threshold for Darwinian evolution may be far lower than creationists would like. Once even a crude replicator exists, variation is inevitable, selection becomes unavoidable, and improvement becomes a matter of time. The emergence of life ceases to be a one-shot lottery and becomes instead an incremental evolutionary process, driven by chemistry and natural selection acting over immense spans of time.
And that is the deeper problem for Intelligent Design advocates. Their arguments depend on portraying life as something that cannot possibly arise without external guidance — yet again and again, the mechanisms they insist must be impossible turn out to be entirely plausible, even expected, once we abandon teleological thinking and look instead at what nature actually does. Far from requiring a supernatural hand placing each nucleotide with deliberate intent, the evidence increasingly points towards life as an emergent consequence of ordinary chemistry given enough opportunity.
Science, as always, advances by closing the gaps with evidence, while creationism survives only by retreating into them.
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