Amino acid analogues provide multiple plausible pathways to prebiotic peptides.

Prebiotic peptide synthesis has consistently been a prominent topic within the field of the origin of life. While research predominantly centres on the 20 classical amino acids, the synthesis process encounters significant thermodynamic barriers. Consequently, amino acid analogues are being explored as potential building blocks for prebiotic peptide synthesis. This review delves into the pathway of polypeptide formation, identifying specific amino acid analogues that might have existed on early Earth, potentially participating in peptide synthesis and chemical evolution. Moreover, considering the complexity and variability of the environment on early Earth, we propose the plausibility of coevolution between amino acids and their analogues.

On the Re-Creation of Protoribosome Analogues in the Lab.

The evolution of the translation system is a fundamental issue in the quest for the origin of life. A feasible evolutionary scenario necessitates the autonomous emergence of a protoribosome capable of catalyzing the synthesis of the initial peptides. The peptidyl transferase center (PTC) region in the modern ribosomal large subunit is believed to retain a vestige of such a prebiotic non-coded protoribosome, which would have self-assembled from random RNA chains, catalyzed peptide bond formation between arbitrary amino acids, and produced short peptides. Recently, three research groups experimentally demonstrated that several distinct dimeric constructs of protoribosome analogues, derived predicated on the approximate 2-fold rotational symmetry inherent in the PTC region, possess the ability to spontaneously fold, dimerize, and catalyze the formation of peptide bonds and of short peptides. These dimers are examined, aiming at retrieving information concerned with the characteristics of a prebiotic protoribosome. The analysis suggests preconditions for the laboratory re-creation of credible protoribosome analogues, including the preference of a heterodimer protoribosome, contradicting the common belief in the precedence of homodimers. Additionally, it derives a dynamic process which possibly played a role in the spontaneous production of the first bio-catalyzed peptides in the prebiotic world.

Heat flows enrich prebiotic building blocks and enhance their reactivity.

The emergence of biopolymer building blocks is a crucial step during the origins of life1-6. However, all known formation pathways rely on rare pure feedstocks and demand successive purification and mixing steps to suppress unwanted side reactions and enable high product yields. Here we show that heat flows through thin, crack-like geo-compartments could have provided a widely available yet selective mechanism that separates more than 50 prebiotically relevant building blocks from complex mixtures of amino acids, nucleobases, nucleotides, polyphosphates and 2-aminoazoles. Using measured thermophoretic properties7,8, we numerically model and experimentally prove the advantageous effect of geological networks of interconnected cracks9,10 that purify the previously mixed compounds, boosting their concentration ratios by up to three orders of magnitude. The importance for prebiotic chemistry is shown by the dimerization of glycine11,12, in which the selective purification of trimetaphosphate (TMP)13,14 increased reaction yields by five orders of magnitude. The observed effect is robust under various crack sizes, pH values, solvents and temperatures. Our results demonstrate how geologically driven non-equilibria could have explored highly parallelized reaction conditions to foster prebiotic chemistry.

Stabilization of Prebiotic Vesicles by Peptides Depends on Sequence and Chirality: A Mechanism for Selection of Protocell-Associated Peptides.

Cells require oligonucleotides and polypeptides with specific, homochiral sequences to perform essential functions, but it is unclear how such oligomers were selected from random sequences at the origin of life. Cells were probably preceded by simple compartments such as fatty acid vesicles, and oligomers that increased the stability, growth, or division of vesicles could have thereby increased in frequency. We therefore tested whether prebiotic peptides alter the stability or growth of vesicles composed of a prebiotic fatty acid. We find that three of 15 dipeptides tested reduce salt-induced flocculation of vesicles. All three contain leucine, and increasing their length increases the efficacy. Also, leucine-leucine but not alanine-alanine increases the size of vesicles grown by multiple additions of micelles. In a molecular simulation, leucine-leucine docks to the membrane, with the side chains inserted into the hydrophobic core of the bilayer, while alanine-alanine fails to dock. Finally, the heterochiral forms of leucine-leucine, at a high concentration, rapidly shrink the vesicles and make them leakier and less stable to high pH than the homochiral forms do. Thus, prebiotic peptide-membrane interactions influence the flocculation, growth, size, leakiness, and pH stability of prebiotic vesicles, with differential effects due to sequence, length, and chirality. These differences could lead to a population of vesicles enriched for peptides with beneficial sequence and chirality, beginning selection for the functional oligomers that underpin life.

A Prebiotic Precursor to Life's Phosphate Transfer System with an ATP Analog and Histidyl Peptide Organocatalysts.

Biochemistry is dependent upon enzyme catalysts accelerating key reactions. At the origin of life, prebiotic chemistry must have incorporated catalytic reactions. While this would have yielded much needed amplification of certain reaction products, it would come at the possible cost of rapidly depleting the high energy molecules that acted as chemical fuels. Biochemistry solves this problem by combining kinetically stable and thermodynamically activated molecules (e.g., ATP) with enzyme catalysts. Here, we demonstrate a prebiotic phosphate transfer system involving an ATP analog (imidazole phosphate) and histidyl peptides, which function as organocatalytic enzyme analogs. We demonstrate that histidyl peptides catalyze phosphorylations via a phosphorylated histidyl intermediate. We integrate these histidyl-catalyzed phosphorylations into a complete prebiotic scenario whereby inorganic phosphate is incorporated into organic compounds though physicochemical wet-dry cycles. Our work demonstrates a plausible system for the catalyzed production of phosphorylated compounds on the early Earth and how organocatalytic peptides, as enzyme precursors, could have played an important role in this.

Primitive purine biosynthesis connects ancient geochemistry to modern metabolism.

An unresolved question in the origin and evolution of life is whether a continuous path from geochemical precursors to the majority of molecules in the biosphere can be reconstructed from modern-day biochemistry. Here we identified a feasible path by simulating the evolution of biosphere-scale metabolism, using only known biochemical reactions and models of primitive coenzymes. We find that purine synthesis constitutes a bottleneck for metabolic expansion, which can be alleviated by non-autocatalytic phosphoryl coupling agents. Early phases of the expansion are enriched with enzymes that are metal dependent and structurally symmetric, supporting models of early biochemical evolution. This expansion trajectory suggests distinct hypotheses regarding the tempo, mode and timing of metabolic pathway evolution, including a late appearance of methane metabolisms and oxygenic photosynthesis consistent with the geochemical record. The concordance between biological and geological analyses suggests that this trajectory provides a plausible evolutionary history for the vast majority of core biochemistry.

Prebiotically plausible chemoselective pantetheine synthesis in water.

Coenzyme A (CoA) is essential to all life on Earth, and its functional subunit, pantetheine, is important in many origin-of-life scenarios, but how pantetheine emerged on the early Earth remains a mystery. Earlier attempts to selectively synthesize pantetheine failed, leading to suggestions that "simpler" thiols must have preceded pantetheine at the origin of life. In this work, we report high-yielding and selective prebiotic syntheses of pantetheine in water. Chemoselective multicomponent aldol, iminolactone, and aminonitrile reactions delivered spontaneous differentiation of pantoic acid and proteinogenic amino acid syntheses, as well as the dihydroxyl, gem-dimethyl, and ß-alanine-amide moieties of pantetheine in dilute water. Our results are consistent with a role for canonical pantetheine at the outset of life on Earth.

New origin of life theory may explain biomolecular handedness.

Experiments suggest chemical reaction rates explain how proteins came to be built from left-handed building blocks.

Symmetry breaking and chiral amplification in prebiotic ligation reactions.

The single chirality of biological molecules is a signature of life. Yet, rationalizing how single chirality emerged remains a challenging goal1. Research has commonly focused on initial symmetry breaking and subsequent enantioenrichment of monomer building blocks-sugars and amino acids-that compose the genetic polymers RNA and DNA as well as peptides. If these building blocks are only partially enantioenriched, however, stalling of chain growth may occur, whimsically termed in the case of nucleic acids as "the problem of original syn"2. Here, in studying a new prebiotically plausible route to proteinogenic peptides3-5, we discovered that the reaction favours heterochiral ligation (that is, the ligation of L monomers with D monomers). Although this finding seems problematic for the prebiotic emergence of homochiral L-peptides, we demonstrate, paradoxically, that this heterochiral preference provides a mechanism for enantioenrichment in homochiral chains. Symmetry breaking, chiral amplification and chirality transfer processes occur for all reactants and products in multicomponent competitive reactions even when only one of the molecules in the complex mixture exhibits an imbalance in enantiomer concentrations (non-racemic). Solubility considerations rationalize further chemical purification and enhanced chiral amplification. Experimental data and kinetic modelling support this prebiotically plausible mechanism for the emergence of homochiral biological polymers.

Oldest thylakoids in fossil cells directly evidence oxygenic photosynthesis.

Today oxygenic photosynthesis is unique to cyanobacteria and their plastid relatives within eukaryotes. Although its origin before the Great Oxidation Event is still debated1-4, the accumulation of O2 profoundly modified the redox chemistry of the Earth and the evolution of the biosphere, including complex life. Understanding the diversification of cyanobacteria is thus crucial to grasping the coevolution of our planet and life, but their early fossil record remains ambiguous5. Extant cyanobacteria include the thylakoid-less Gloeobacter-like group and the remainder of cyanobacteria that acquired thylakoid membranes6,7. The timing of this divergence is indirectly estimated at between 2.7 and 2.0 billion years ago (Ga) based on molecular clocks and phylogenies8-11 and inferred from the earliest undisputed fossil record of Eoentophysalis belcherensis, a 2.018-1.854 Ga pleurocapsalean cyanobacterium preserved in silicified stromatolites12,13. Here we report the oldest direct evidence of thylakoid membranes in a parallel-to-contorted arrangement within the enigmatic cylindrical microfossils Navifusa majensis from the McDermott Formation, Tawallah Group, Australia (1.78-1.73 Ga), and in a parietal arrangement in specimens from the Grassy Bay Formation, Shaler Supergroup, Canada (1.01-0.9 Ga). This discovery extends their fossil record by at least 1.2 Ga and provides a minimum age for the divergence of thylakoid-bearing cyanobacteria at roughly 1.75 Ga. It allows the unambiguous identification of early oxygenic photosynthesizers and a new redox proxy for probing early Earth ecosystems, highlighting the importance of examining the ultrastructure of fossil cells to decipher their palaeobiology and early evolution.

Small-molecule autocatalysis drives compartment growth, competition and reproduction.

Sustained autocatalysis coupled to compartment growth and division is a key step in the origin of life, but an experimental demonstration of this phenomenon in an artificial system has previously proven elusive. We show that autocatalytic reactions within compartments-when autocatalysis, and reactant and solvent exchange outpace product exchange-drive osmosis and diffusion, resulting in compartment growth. We demonstrate, using the formose reaction compartmentalized in aqueous droplets in an emulsion, that compartment volume can more than double. Competition for a common reactant (formaldehyde) causes variation in droplet growth rate based on the composition of the surrounding droplets. These growth rate variations are partially transmitted after selective division of the largest droplets by shearing, which converts growth-rate differences into differences in droplet frequency. This shows how a combination of properties of living systems (growth, division, variation, competition, rudimentary heredity and selection) can arise from simple physical-chemical processes and may have paved the way for the emergence of evolution by natural selection.

Early-life origin of prostate cancer through deregulation of miR-206 networks in maternally malnourished offspring rats.

The Developmental Origins of Health and Disease (DOHaD) concept has provided the framework to assess how early life experiences can shape health and disease throughout the life course. While maternal malnutrition has been proposed as a risk factor for the developmental programming of prostate cancer (PCa), the molecular mechanisms remain poorly understood. Using RNA-seq data, we demonstrated deregulation of miR-206-Plasminogen (PLG) network in the ventral prostate (VP) of young maternally malnourished offspring. RT-qPCR confirmed the deregulation of the miR-206-PLG network in the VP of young and old offspring rats. Considering the key role of estrogenic signaling pathways in prostate carcinogenesis, in vitro miRNA mimic studies also revealed a negative correlation between miR-206 and estrogen receptor α (ESR1) expression in PNT2 cells. Together, we demonstrate that early life estrogenization associated with the deregulation of miR-206 networks can contribute to the developmental origins of PCa in maternally malnourished offspring. Understanding the molecular mechanisms by which early life malnutrition affects offspring health can encourage the adoption of a governmental policy for the prevention of non-communicable chronic diseases related to the DOHaD concept.

The protometabolic nature of prebiotic chemistry.

The field of prebiotic chemistry has been dedicated over decades to finding abiotic routes towards the molecular components of life. There is nowadays a handful of prebiotically plausible scenarios that enable the laboratory synthesis of most amino acids, fatty acids, simple sugars, nucleotides and core metabolites of extant living organisms. The major bottleneck then seems to be the self-organization of those building blocks into systems that can self-sustain. The purpose of this tutorial review is having a close look, guided by experimental research, into the main synthetic pathways of prebiotic chemistry, suggesting how they could be wired through common intermediates and catalytic cycles, as well as how recursively changing conditions could help them engage in self-organized and dissipative networks/assemblies (i.e., systems that consume chemical or physical energy from their environment to maintain their internal organization in a dynamic steady state out of equilibrium). In the article we also pay attention to the implications of this view for the emergence of homochirality. The revealed connectivity between those prebiotic routes should constitute the basis for a robust research program towards the bottom-up implementation of protometabolic systems, taken as a central part of the origins-of-life problem. In addition, this approach should foster further exploration of control mechanisms to tame the combinatorial explosion that typically occurs in mixtures of various reactive precursors, thus regulating the functional integration of their respective chemistries into self-sustaining protocellular assemblies.

The ecology-evolution continuum and the origin of life.

Prior research on evolutionary mechanisms during the origin of life has mainly assumed the existence of populations of discrete entities with information encoded in genetic polymers. Recent theoretical advances in autocatalytic chemical ecology establish a broader evolutionary framework that allows for adaptive complexification prior to the emergence of bounded individuals or genetic encoding. This framework establishes the formal equivalence of cells, ecosystems and certain localized chemical reaction systems as autocatalytic chemical ecosystems (ACEs): food-driven (open) systems that can grow due to the action of autocatalytic cycles (ACs). When ACEs are organized in meta-ecosystems, whether they be populations of cells or sets of chemically similar environmental patches, evolution, defined as change in AC frequency over time, can occur. In cases where ACs are enriched because they enhance ACE persistence or dispersal ability, evolution is adaptive and can build complexity. In particular, adaptive evolution can explain the emergence of self-bounded units (e.g. protocells) and genetic inheritance mechanisms. Recognizing the continuity between ecological and evolutionary change through the lens of autocatalytic chemical ecology suggests that the origin of life should be seen as a general and predictable outcome of driven chemical ecosystems rather than a phenomenon requiring specific, rare conditions.

The Origin and Early Evolution of Life: Homochirality Emergence in Prebiotic Environments.

Homochirality is one of the signatures of life. Numerous geological and prebiotic chemistry studies have proved that disordered soups containing small organic molecules, gases, liquids, and minerals (such as those containing phosphorous) yielded racemic mixtures of building blocks for biomolecule assembly. Polymers obtained from these bricks should have been enantiopure with functional properties similar to modern biomolecules or heterochiral with some functions such as catalyzing a chemical transformation unspecifically. Up until now, no clues have been found as to how symmetry breaking occurred. In this review, we highlight the principal achievements regarding the emergence of homochirality during the prebiotic synthesis of building blocks. Furthermore, we tried to focus on approaches based on prebiotic systems chemistry (bottom-up) and laboratory scales to simulate plausible prebiotic messy environments for the emergence of life. We aim with this review to assemble, even partially, the puzzle pieces of the origin of life regarding the relevant phenomenon of homochiral symmetry breaking.

Assembly theory explains and quantifies selection and evolution.

Scientists have grappled with reconciling biological evolution1,2 with the immutable laws of the Universe defined by physics. These laws underpin life's origin, evolution and the development of human culture and technology, yet they do not predict the emergence of these phenomena. Evolutionary theory explains why some things exist and others do not through the lens of selection. To comprehend how diverse, open-ended forms can emerge from physics without an inherent design blueprint, a new approach to understanding and quantifying selection is necessary3-5. We present assembly theory (AT) as a framework that does not alter the laws of physics, but redefines the concept of an 'object' on which these laws act. AT conceptualizes objects not as point particles, but as entities defined by their possible formation histories. This allows objects to show evidence of selection, within well-defined boundaries of individuals or selected units. We introduce a measure called assembly (A), capturing the degree of causation required to produce a given ensemble of objects. This approach enables us to incorporate novelty generation and selection into the physics of complex objects. It explains how these objects can be characterized through a forward dynamical process considering their assembly. By reimagining the concept of matter within assembly spaces, AT provides a powerful interface between physics and biology. It discloses a new aspect of physics emerging at the chemical scale, whereby history and causal contingency influence what exists.

Quantifying Catalysis at the Origin of Life.

The construction of hypothetical environments to produce organic molecules such as metabolic intermediates or amino acids is the subject of ongoing research into the emergence of life. Experiments specifically focused on an anabolic approach typically rely on a mineral catalyst to facilitate the supply of organics that may have produced prebiotic building blocks for life. Alternatively to a true catalytic system, a mineral could be sacrificially oxidized in the production of organics, necessitating the emergent 'life' to turn to virgin materials for each iteration of metabolic processes. The aim of this perspective is to view the current 'metabolism-first' literature through the lens of materials chemistry to evaluate the need for higher catalytic activity and materials analyses. While many elegant studies have detailed the production of chemical building blocks under geologically plausible and biologically relevant conditions, few appear to do so with sub-stoichiometric amounts of metals or minerals. Moving toward sub-stoichiometric metals with rigorous materials analyses is necessary to demonstrate the viability of an elusive cornerstone of the 'metabolism-first' hypotheses: catalysis. We emphasize that future work should aim to demonstrate decreased catalyst loading, increased productivity, and/or rigorous materials analyses for evidence of true catalysis.

Replaying the evolution of multicellularity.

The first organisms on Earth were presumably unicellular. At one point, evolution shaped these individual cells into multicellular organisms, which was a significant transition in the history of life on Earth. To investigate how this change happened, Bozdag et al. re-ran evolution in the lab and observed how single-celled yeast forms large multicellular aggregates.

From autocatalysis to survival of the fittest in self-reproducing lipid systems.

Studying autocatalysis - in which molecules catalyse their own formation - might help to explain the emergence of chemical systems that exhibit traits normally associated with biology. When coupled to other processes, autocatalysis can lead to complex systems-level behaviour in apparently simple mixtures. Lipids are an important class of chemicals that appear simple in isolation, but collectively show complex supramolecular and mesoscale dynamics. Here we discuss autocatalytic lipids as a source of extraordinary behaviour such as primitive chemical evolution, chemotaxis, temporally controllable materials and even as supramolecular catalysts for continuous synthesis. We survey the literature since the first examples of lipid autocatalysis and highlight state-of-the-art synthetic systems that emulate life, displaying behaviour such as metabolism and homeostasis, with special consideration for generating structural complexity and out-of-equilibrium models of life. Autocatalytic lipid systems have enormous potential for building complexity from simple components, and connections between physical effects and molecular reactivity are only just beginning to be discovered.