Chemists at University College London have unveiled a groundbreaking chemical pathway that brings us tantalizingly closer to understanding life’s origin, demonstrating how RNA — the molecule fundamental to genetics — could have chemically linked with amino acids under conditions plausible on the early Earth. This monumental discovery, published recently in Nature, addresses one of the most elusive questions in molecular biology: how the first proteins began to form before the advent of complex cellular machinery.
Proteins, the molecules that perform the vast majority of cellular functions, are polymers of amino acids, whose sequences determine their structure and properties. Yet, proteins alone cannot replicate; they depend on genetic instructions encoded in RNA to dictate their fabrication. Modern life synthesizes proteins through ribosomes, intricate molecular complexes that read messenger RNA sequences, sequentially connecting amino acids into functional proteins with high fidelity. Understanding how this RNA-guided protein synthesis arose prebiotically has perplexed scientists for decades.
Previous laboratory attempts to link amino acids directly to RNA relied on highly reactive intermediates that decomposed rapidly in water, an environment essential for life’s chemistry but hostile to such unstable molecules. These reactions also induced unwanted side processes, such as amino acids binding among themselves rather than to RNA, thereby complicating the quest to recreate primordial peptide synthesis. Overcoming these hurdles has been a major scientific challenge since the 1970s.
The UCL team drew inspiration from natural biochemistry, employing a subtler method that leverages thioesters—high-energy sulfur-containing compounds known to drive many metabolic reactions in contemporary cells. Thioesters have long been hypothesized as key players in early metabolism, given their reactivity and plausible abundance on the primitive Earth, forming a conceptual bridge between simple chemistry and emergent biological complexity. This approach avoided the pitfalls of highly reactive agents by allowing amino acids to be selectively activated in a water-rich environment at neutral pH.
Central to their method, amino acids were reacted with pantetheine, a sulfur-bearing molecule that the same research group previously demonstrated could form from prebiotically plausible precursors. This reaction creates amino acid thioesters capable of spontaneously binding to RNA strands without causing undesirable polymerizations or degrading under aqueous conditions. The resulting aminoacylated RNA molecules represent the first steps in protein synthesis, mimicking the modern process where amino acids are attached to RNA before peptide bond formation.
This breakthrough highlights a potential convergence of two dominant origin-of-life hypotheses: the RNA World, positing that self-replicating RNA molecules were precursors to life, and the Thioester World, which suggests thioesters served as primordial energy carriers facilitating early biochemical reactions. By uniting these theories, the study provides a cohesive chemical framework for how life’s central dogma—information encoded in nucleic acids guiding protein synthesis—may have emerged naturally from prebiotic chemistry.
The team employed advanced spectroscopic techniques to validate their findings, including multiple forms of nuclear magnetic resonance spectroscopy (NMR) which elucidated atomic arrangements within molecules, alongside mass spectrometry that confirmed molecular weights and structures. These state-of-the-art tools allowed researchers to observe and characterize reactions invisible under conventional optical microscopy, providing unprecedented insight into the molecular dance that could have seeded life.
While the study focused on chemical mechanisms, the investigators propose that these reactions likely occurred in pools or lakes on early Earth, where higher concentrations of reactants could accumulate. The vast, dilute ocean would presumably have been unfavorable due to low molecular encounters, while smaller aqueous environments could encourage the necessary interactions to drive this chemistry forward, offering a plausible geochemical stage for the emergence of life.
Furthermore, the study suggests a pathway toward the origin of the genetic code itself, the set of rules translating RNA sequences into amino acid chains. The ability of RNA sequences to selectively bind specific amino acids is fundamental to this code, and deciphering early molecular recognition patterns remains a key goal. This research lays the groundwork by chemically linking RNA and amino acids, a vital prerequisite for exploring how the code arose.
Lead author Dr. Jyoti Singh illustrated the magnitude of this achievement: envisioning simple molecular building blocks—composed of carbon, nitrogen, hydrogen, oxygen, and sulfur—assembling into self-replicating, functional systems analogous to molecular “LEGO pieces.” This discovery marks a significant stride toward realizing that vision, showing that primordial ‘activated’ amino acids and RNA could combine and grow into the peptides essential for life.
Importantly, the activated amino acids used are thioesters derived from Coenzyme A-related compounds, ubiquitous in all known life forms. This connection opens the possibility that the chemistry underpinning modern metabolism, genetic information storage, and protein synthesis share a deep evolutionary origin traceable to simple prebiotic reactions. By potentially linking metabolism with genetic and protein-building pathways, the findings illuminate how life’s universal molecular machinery may have arisen from straightforward chemical beginnings.
Despite the headline achievements, many questions remain, particularly how RNA sequences could develop selective affinities for particular amino acids to build increasingly complex proteins—forming the basis of biology’s exquisite specificity. Yet this work decisively advances beyond prior limitations, bringing clarity to a problem that has spanned multiple scientific generations and will surely catalyze future discoveries in origin-of-life research.
The UCL research was funded by prominent institutions, including the Engineering and Physical Sciences Research Council, the Simons Foundation, and the Royal Society, highlighting the scientific community’s recognition of the high potential impact of uncovering life’s fundamental chemical origins. As techniques grow more sophisticated and novel theories integrate, the chemical evolution from molecular chaos to biological order comes ever more sharply into focus.
The path from simple chemicals in primordial pools to the extraordinary complexity of life on Earth is becoming increasingly illuminated by studies like this. By chemically demonstrating a plausible prebiotic route to aminoacylated RNA, this research bridges the historical gap between chemistry and biology, transforming abstract hypotheses into tangible molecular systems that echo the dawn of life itself.
Subject of Research: Origin of life; prebiotic chemistry; RNA-amino acid linkage; protein synthesis emergence.
Article Title: Not provided explicitly.
News Publication Date: Not explicitly stated.
Web References: http://dx.doi.org/10.1038/s41586-025-09388-y
References: Published in Nature.
Image Credits: Frank Kovalchek
Keywords
Origins of life, Protein synthesis, Proteins, Peptides, Amino acids, Biochemistry, Life sciences, Nucleic acids, Metabolism, Chemistry, Physical sciences
