Chemists at University College London (UCL) and the Medical Research Council Laboratory of Molecular Biology (MRC LMB) have unveiled a groundbreaking mechanism that sheds light on one of the most enduring mysteries in science: how RNA, the primordial molecule of life, could have replicated itself on early Earth. This replication process is fundamental to the origin of life, setting the stage for the evolution of complex biological systems. The team’s findings, published in Nature Chemistry, introduce a plausible chemical pathway that circumvents long-standing experimental challenges, potentially rewriting our understanding of life’s emergence billions of years ago.
The RNA world hypothesis posits that RNA molecules were the first to carry genetic information and catalyze biochemical reactions before the evolution of DNA and proteins. However, replicating RNA strands in laboratory conditions that mirror those of the prebiotic Earth has remained a formidable challenge. This difficulty largely arises because RNA strands tend to form double helices, in which complementary strands zip tightly together. These helices are extremely stable, acting like molecular Velcro that fastens the strands and inhibits the necessary separation required for replication, leaving no opportunity for copying.
Addressing this issue, the researchers developed an innovative approach using triplet RNA building blocks, or trinucleotides, which are composed of three nucleotides linked together rather than the canonical single nucleotides standard in biology today. Employing these triplets in aqueous solutions, combined with cycles of acidic pH adjustments and heat, the team was able to induce the separation of RNA duplexes effectively. The acid and heat conditions transiently disrupted the double helix, unwinding the paired strands in a manner that is chemically plausible given geothermal and diurnal cycles on the Hadean Earth.
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Following this separation, the scientists neutralized and rapidly froze the solution. In the microscopic liquid pockets or veins between forming ice crystals, they observed that the triplet building blocks coated the exposed single RNA strands. This coating prevented the RNA strands from re-annealing or zipping back together, preserving them in a configuration accessible for templated replication. As the solution was thawed, the triplets aligned themselves along the template strands and facilitated the formation of new complementary RNA strands, completing a cycle of replication without enzymatic assistance.
The cyclical process of thawing and freezing, alongside repeated shifts in pH and temperature, created an environmental scenario that plausibly mimics natural conditions on early Earth, such as those found in shallow ponds or geothermal lakes. These dynamic physicochemical changes can drive non-enzymatic RNA replication by enabling strand separation and template-directed assembly in a continuous loop. Importantly, the RNA strands produced through this mechanism were sufficiently long to exert biological functions, highlighting the potential significance of this pathway in prebiotic evolution.
Dr. Philipp Holliger, who led the study at MRC LMB, emphasized the centrality of information transfer in life’s definition. He explained that life is distinguished from mere chemistry by its ability to encode, preserve, and propagate information through molecular memory in genetic polymers like RNA. For life to arise, this informational substrate must be reliably copied across generations. The new findings demonstrate a chemical system that can achieve this fundamental step under simple, plausible conditions.
Echoing this perspective, lead author Dr. James Attwater remarked on the elusive nature of the primordial replicator. Although all contemporary organisms descend from a Last Universal Common Ancestor (LUCA), which is genetically complex, the first self-replicating molecules remain concealed in deep evolutionary history. This research reinvigorates the RNA world hypothesis by providing a feasible molecular mechanism devoid of complex enzymatic machinery necessary for modern replication, an aspect vital for pre-life chemistry.
The requirement for a simple, non-enzymatic method to replicate RNA challenged the team to explore alternatives to the stringent base-pairing systems seen in extant biology. Trinucleotides, which are absent in living organisms today, emerged as ideal candidates because they can bind in a more stable yet reversible manner, promoting efficient template copying while circumventing the kinetic trapping of RNA strands. Such molecular building blocks may well represent ancestral biochemical tools utilized by early life, which has since evolved beyond them.
Another pivotal finding was the environmental specificity of this replication process. The team discovered that replicating RNA under these conditions was not viable in freezing saltwater. Salt interferes with ice formation dynamics and prevents the concentration of RNA building blocks that freezing is supposed to achieve, thereby blocking the replication mechanism. This suggests that freshwater environments in geothermal settings would have been more conducive to the chemistry of early life’s replication processes.
Similarly, although evaporation in warm conditions can concentrate RNA, the instability of RNA molecules at elevated temperatures limits their longevity and functional capacity in such settings, according to the researchers. This underscores the delicate balance of physical parameters—temperature, solute concentration, and pH—that early Earth environments must have maintained to permit RNA’s survival and replication.
The origin of life is now thought to have been orchestrated not by RNA alone but by an interplay of various molecular constituents. Peptides (short amino acid polymers), enzymes, and lipid-based compartments likely co-evolved, each contributing vital roles such as catalysis, structural scaffolding, and protection from harsh environmental fluctuations. The current study contributes a crucial piece of this complex puzzle by elucidating how the first RNA-based replication cycles could have arisen in isolation.
Building on decades of foundational research in prebiotic chemistry, teams led by researchers such as Dr. John Sutherland and Professor Matthew Powner have demonstrated plausible synthetic pathways for essential biomolecules including nucleotides, amino acids, peptides, simple lipids, and vitamin precursors under early Earth-like conditions. The present study complements these advances by showing how RNA polymers constructed from such building blocks could replicate, thereby initiating biological information flow.
In sum, this innovative study outlines a chemically credible and experimentally validated path for the non-enzymatic replication of RNA on prebiotic Earth. By harnessing triplet RNA building blocks and environmental cycling of temperature and acidity, the research reconciles a critical gap between pure chemistry and biology, offering profound insights into the molecular dawn of life. Such breakthroughs bring us closer to unraveling one of humanity’s oldest questions: how did life begin?
Subject of Research: RNA self-replication under prebiotic Earth conditions
Article Title: A plausible chemical route for RNA replication on early Earth enabled by triplet building blocks and environmental cycling
Web References: 10.1038/s41557-025-01830-y
Image Credits: Philipp Holliger, MRC Laboratory of Molecular Biology
Keywords: Origins of life, RNA replication, prebiotic chemistry, evolutionary biology, trinucleotides, molecular biology, early Earth chemistry, non-enzymatic replication, geothermal environments, laboratory simulation
Tags: biochemical reactions and RNAevolution of complex biological systemsexperimental challenges in RNA replicationimplications for life’s emergenceNature Chemistry publicationorigin of life researchprebiotic Earth conditionsprimordial molecules of lifeRNA self-replication mechanismRNA world hypothesistriplet RNA building blocksUCL and MRC LMB collaboration