EMERGENCE OF TEMPLATE-AND-SEQUENCE-DIRECTED (TSD) SYNTHESES: I. A BIO-GEOCHEMICAL MODEL

A biogeochemical model for the evolution of template-and-sequence-directed (TSD) syntheses of biological templates (proto-RNAs) and catalysts (peptides) is described. A fluctuating environment characterized by hydrating (cool) and dehydrating (warm) phases with cycles of consecutive organic reactions, as well as a constant supply of the polymeric building blocks is assumed. The scenario starts with the catalyzed formation of a primordial population of small random peptides, based on the relatively-ineffective mineral catalysts. The resulting peptides initiate a catalytic takeover process, during which the catalytic functions are gradually taken over by peptides. The evolution of TSD peptides is based on a combination of Lahavs (1991) co-evolution and Möller and Janssen's (1990) specific recognition sites hypotheses. During the emergence of TSD systems the fraction of TSD peptides and proto-RNA constituents rises from almost insignificance to dominance in a TSD Reactions Takeover. The TSD system is characterized by autocatalysis, positive feedback loops and a primordial genetic code. The model is the basis for a computer program (Part II of present series).     

Towards an evolutionary theory of the origin of life based on kinetics and thermodynamics

A sudden transition in a system from an inanimate state to the living state—defined on the basis of present day living organisms—would constitute a highly unlikely event hardly predictable from physical laws. From this uncontroversial idea, a self-consistent representation of the origin of life process is built up, which is based on the possibility of a series of intermediate stages. This approach requires a particular kind of stability for these stages—dynamic kinetic stability (DKS)—which is not usually observed in regular chemistry, and which is reflected in the persistence of entities capable of self-reproduction. The necessary connection of this kinetic behaviour with far-from-equilibrium thermodynamic conditions is emphasized and this leads to an evolutionary view for the origin of life in which multiplying entities must be associated with the dissipation of free energy. Any kind of entity involved in this process has to pay the energetic cost of irreversibility, but, by doing so, the contingent emergence of new functions is made feasible. The consequences of these views on the studies of processes by which life can emerge are inferred.     

Emergence of Template-and-Sequence-Directed (tsd) Syntheses: Ii. A Computer Simulation Model

The initiation of the bio-geochemical scenario described in Part I serves in the present work as the basis for computer modeling, where the central process of the simulation algorithm, i.e., peptide-catalyzed oligomeric growth, is based on mass action equations. The computer model starts with a minimal system in which catalyzed growth processes of proto-RNA templates and small peptides take place, starting from their building blocks. The emerging populations of random oligomers also include a very small fraction of proto-tRNAs and a small fraction of catalytic peptides. Using simplifying assumptions regarding catalyzed proto-RNA template-replication, as well as selectivity of certain molecules and processes, the proportion of proto-tRNA in the proto-RNA molecular population increases rapidly; it is followed by TSD peptide synthesis, based on an ad hoc genetic code and specific peptide catalysts allocated for this synthesis. Consequently, a feedback system is initiated in which TSD peptides involved in the relevant catalytic reactions of the TSD syntheses also start to accumulate. The initial sporadic formation of TSD peptides is thus replaced gradually by cycles of positive feedback and autocatalysis characterized by accumulation of catalytic peptides and Proto-tRNAs and TSD-Reaction-Takeover. The model system which can be considered a toy model can synthesize its templates and catalysts under a wide range of reaction parameters and initial concentrations, thus demonstrating a robustness which is essential for molecular evolution processes. The critical stage of the buildup of a molecular mechanism for the initiation of a minimal TSD reaction cycle has thus been described; because of the centrality of TSD reaction cycles in biology, it is assumed to be central also in the origin of life processes.     

What is Life? Defining Life in the Context of Emergent Complexity

Erwin Schrödinger defined life not only as a “self-reproducing” aperiodic crystal of DNA coding for proteins but within the context of living entities increasing their order by dissipating matter/energy gradients to maintain themselves away from equilibirium. Since then most definitions of life have focused on the former. But living cells do more than replicate their DNA. Cells also have membrane barriers across which metabolites must move, via which energy transduction as well as information processing occurs, and within which metabolic transformation occurs. An approach of complex systems dynamics, including nonequilibrium thermodynamics, may provide a more robust approach for defining life than a “naked replicator” at the origin of life. The crucial issue becomes the process of emergence of life from pre-biotic chemistry, concomitant with the emergence of function, information, and semiosis. Living entities can be viewed as bounded, informed autocatalytic cycles feeding off matter/energy gradients, exhibiting agency, capable of growth, reproduction, and evolution. Understanding how life might have emerged should sharpen our definition of what life is.     

The living state and cancer

Most inanimate systems are build of closed-shell molecules in which electrons lack excitability and mobility. These electrons can be rendered reactive and mobile by taking out some of them, desaturating the system electronically. Single electrons can be taken out of molecules by transfer to an external acceptor, creating two radicals that form a biradical having no net charge. The living state is such an electronically desaturated state. The universal electron acceptor of the biosphere is oxygen. Before light and O2 appeared, a weak electron acceptor could occur through linkage of two C=O groups to glyoxal and addition of a methyl group. The resulting methylglyoxal, being a weak acceptor, could lead to only a low degree of desaturation and thus to formation of only the simple life forms extant during this dark and anaerobic period--the alpha period. During the subsequent aerobic beta period, more highly differentiated life forms could develop because of occurrence of O2, a strong electron acceptor leading to a greater degree of desaturation. When dividing, however, beta-type cells return partially to the proliferative alpha state. The process of electron (charge) transfer, described here in two models, depends on the dielectric constant of the medium and the relative concentration of SH and methylglyoxal. Structure-building proteins that perform the main biological functions carry with them this chemical mechanism of their desaturation. Central to the mechanism is the NH2 of lysine that attaches a methylglyoxal. Through folding of the side chain, the CO groups of resulting Schiff bases can come in touch with the NH's of the peptide chain and accept electrons from it, desaturating it. Ascorbic acid is the catalyst of this charge transfer, which brings protein into the living state. Purified protein is inanimate matter. Manganese and oxygen form part of the chemical mechanism of desaturation, and the charge transfer reactions studied were found to be autocatalytic. It follows from the above observations that a cancer cell is a cell trapped in the alpha state.     

Hyperthermophily and the origin and earliest evolution of life

The possibility of a high-temperature origin of life has gained support based on indirect evidence of a hot, early Earth and on the basal position of hyperthermophilic organisms in rRNA-based phylogenies. However, although the availability of more than 80 completely sequenced cellular genomes has led to the identification of hyperthermophilic-specific traits, such as a trend towards smaller genomes, reduced protein-encoding gene sizes, and glutamic-acid-rich simple sequences, none of these characteristics are in themselves an indication of primitiveness. There is no geological evidence for the physical setting in which life arose, but current models suggest that the Earth's surface cooled down rapidly. Moreover, at 100 °C the half-lives of several organic compounds, including ribose, nucleobases, and amino acids, which are generally thought to have been essential for the emergence of the first living systems, are too short to allow for their accumulation in the prebiotic environment. Accordingly, if hyperthermophily is not truly primordial, then heat-loving lifestyles may be relics of a secondary adaptation that evolved after the origin of life, and before or soon after separation of the major lineages.     

Millennial musings on molecular motors

In a universe that is dominated by increasing entropy, living organisms are a curious anomaly. The organization that distinguishes living organisms from their inanimate surroundings relies upon their ability to execute vectorial processes, such as directed movements and the assembly of macromolecules and organelle systems. Many of these phenomena are executed by molecular motors that harness chemical potential energy to perform mechanical work and unidirectional motion. This article explores how these remarkable protein machines might have evolved and what roles they could play in biological and medical research in the coming decades.     

Millennial musings on molecular motors

In a universe that is dominated by increasing entropy, living organisms are a curious anomaly. The organization that distinguishes living organisms from their inanimate surroundings relies upon their ability to execute vectorial processes, such as directed movements and the assembly of macromolecules and organelle systems. Many of these phenomena are executed by molecular motors that harness chemical potential energy to perform mechanical work and unidirectional motion. This article explores how these remarkable protein machines might have evolved and what roles they could play in biological and medical research in the coming decades.     

Millennial musings on molecular motors

In a universe that is dominated by increasing entropy, living organisms are a curious anomaly. The organization that distinguishes living organisms from their inanimate surroundings relies upon their ability to execute vectorial processes, such as directed movements and the assembly of macromolecules and organelle systems. Many of these phenomena are executed by molecular motors that harness chemical potential energy to perform mechanical work and unidirectional motion. This article explores how these remarkable protein machines might have evolved and what roles they could play in biological and medical research in the coming decades.     

Bioenergetics of early life: Coupling of reaction networks and compartments may have sparked the first life forms

Living cells are powered by intricate networks of chemical reactions of thousands of molecules. Understanding how living systems emerged through the assembly of chemical processes is one of the biggest challenges in science. Subject Categories: Biotechnology & Synthetic Biology, Evolution & Ecology, Metabolism

How can chemistry turn into biology? How can living cells be built from molecules? These are fundamental questions in biology and, despite much research efforts, remain unanswered. Yet, the past two decades have seen considerable advances in our knowledge of how and which (bio)physical and (bio)chemical processes could have driven the emergence of the first living cells. These achievements have led not only to a better understanding of the molecular origins of life, but also spurred significant developments in synthetic biology, biophysics and supramolecular chemistry. Although the exact events that sparked life on Earth will quite likely remain a mystery, at least partially, exploring the chemical origins of life offers clues about our primordial past and could contribute to shaping our future.

Although the exact events that sparked life on Earth will quite likely remain a mystery […] exploring the chemical origins of life offers clues about our primordial past and could contribute to shaping our future.

     

Modelling periodic oscillation of biological systems with multiple timescale networks

In this paper, we aim to develop a new methodology to model and design periodic oscillators of biological networks, in particular gene regulatory networks with multiple genes, proteins and time delays, by using multiple timescale networks (MTN). Fast reactions constitute a positive feedback-loop network (PFN), while slow reactions consist of a cyclic feedback-loop network (CFN), in MTN. Multiple timescales are exploited to simplify models according to singular perturbation theory. We show that a MTN has no stable equilibrium but stable periodic orbits when certain conditions are satisfied. Specifically, we first prove the basic properties of MTNs with only one PFN, and then generalise the result to MTNs with multiple PFNs. Finally, we design a biologically plausible gene regulatory network by the cI and Lac genes, to demonstrate the theoretical results. Since there is less restriction on the network structure of a MTN, it can be expected to apply to a wide variety of areas on the modelling, analysing and designing of biological systems.     

Viruses: are they living entities?

The essence (living or nonliving entities) of viruses has today become an aporia, i.e. a difficulty inherent in reasoning because they shared four fundamental characteristics with livings (multiplication, genetic information, mutation and evolution) without having the capacity to have an independent life. For much time, however, they were considered minuscule pathogenetic micro-organisms in observance of Koch and Pasteur's 'germ theory' albeit no microbiologist could show their existence except their filterability and pathogenetic action. Only some voices based on experimental results raised against this dogmatic view, in particular those of Beijerinck, Baur and Mrowka, without dipping effectively into the dominant theory. The discovery relative to their nucleoprotein nature made between 1934 and 1936 (Schlesinger as for the phage, and Bawden and co-operators as for Tobacco mosaic virus; TMV), together with the first demonstrations of their structures thanks to electron microscopy (from 1939 onwards) started on casting a new light on their true identity, which could be more clearly identified when, from 1955 onwards, phage and TMV proved to be decisive factors to understand the strategies of replication of the genetic material. Following the new knowledge, the theoretical view relative to viruses changed rather radically and the current view looks on these pathogenetic agents as nonliving aggregates of macromolecules provided with biological properties. There is, however, a current of thought, made explicitly by Lwoff that places viruses as compromise between living and non living and, perhaps, as primitive forms of life which have had great importance for the evolution of cellular life. At any rate, viruses are peculiar entities whose importance cannot be unacknowledged.     

An Answer to Schrödinger’s What Is Life?

That semiosis is specific to the living world is the cornerstone of biosemiotics. For checking an information-theoretic interpretation of this statement already proposed at the 2009 Biosemiotics Gathering in Prague, it is first attempted here to answer a question asked by Kupiec and Sonigo in Ni Dieu ni Gène (2000) on what differentiates living objects and those resulting from a geophysical process. Similar questions were asked by Schr?dinger in his essay What Is Life? where the emphasis was laid on the relationship of the atomic scale of the genes and the macroscopic scale of living beings. This essay was published in 1944, before information was introduced as a scientific entity, at a time when DNA was not yet identified as the vector of heredity. We undertake answering some of these questions, arguing that the living world is made of organisms, i.e., of assemblies possessing in a genome the information needed for their replication and their maintenance while the inanimate world only contains aggregates. In short, a biological process keeps its order through the use of information. For defining order, it is proposed that an orderly object can be produced by a construction (e.g., the copy of a template) using available data within some given context. In other words, replicating an orderly object does not bring new information into its context. Order in this meaning appears as specific to the living world, at variance with the inanimate world which is basically disorderly. A better understanding of what separates the living world from the inanimate world results: the use of information is the distinguishing feature which defines their border. Any living thing contains a symbolic information, referred to as its genome, inscribed into DNA molecules. This genome can indeed be copied but, its support being embedded in the physical world, it incurs disturbances which result in symbol errors. Keeping its order thus needs endowing any genome with error correction ability: it must belong to a redundant code, i.e., a set of sequences separated by some minimum distance. The larger its minimum distance, the more immune to errors are the elements of a code. Then genomes become as distinct as to ensure order. Identity and specificity result. Although conservative according to the above definition of order, the living world actually exhibits an extreme diversity which even tends to increase as evolution proceeds. In sharp contrast, homogeneity and monotony are observed in the inanimate world, assumed however non-conservative. In order to solve this paradox and justify the proposed definition of order, it is argued that the error-correcting means which ensure the conservation of genomes fail with some low, but non-zero, probability. Although very infrequent, regeneration errors result in genomes largely different from the initial ones; and the correction mechanisms conserve the mutated genomes just as the original ones. The operation of life changes scales, since the regeneration errors which originate in atomic events have observable consequences at the macroscopic scale.     

The Cell and Protoplasm as Container,Object, and Substance, 1835–1861

This article revisits the development of the protoplasm concept as it originally arose from critiques of the cell theory, and examines how the term “protoplasm” transformed from a botanical term of art in the 1840s to the so-called “living substance” and “the physical basis of life” two decades later. I show that there were two major shifts in biological materialism that needed to occur before protoplasm theory could be elevated to have equal status with cell theory in the nineteenth century. First, I argue that biologists had to accept that life could inhere in matter alone, regardless of form. Second, I argue that in the 1840s, ideas of what formless, biological matter was capable of dramatically changed: going from a “coagulation paradigm” (Pickstone, 1973) that had existed since Theophrastus, to a more robust conception of matter that was itself capable of movement and self-maintenance. In addition to revisiting Schleiden and Schwann’s original writings on cell theory, this article looks especially closely at Hugo von Mohl’s definition of the protoplasm concept in 1846, how it differed from his primordial utricle theory of cell structure two years earlier. This article draws on Lakoff and Johnson’s theory of “ontological metaphors” to show that the cell, primordial utricle, and protoplasm can be understood as material container, object, and substance, and that these overlapping distinctions help explain the chaotic and confusing early history of cell theory.     

The Evolutionary Origin of Biological Function and Complexity

The identification of dynamic kinetic stability (DKS) as a stability kind that governs the evolutionary process for both chemical and biological replicators, opens up new avenues for uncovering the chemical basis of biological phenomena. In this paper, we utilize the DKS concept to explore the chemical roots of two of biology’s central concepts—function and complexity. It is found that the selection rule in the world of persistent replicating systems—from DKS less stable to DKS more stable—is the operational law whose very existence leads to the creation of function from of a world initially devoid of function. The origin of biological complexity is found to be directly related to the origin of function through an underlying connection between the two phenomena. Thus the emergence of both function and complexity during abiogenesis, and their growing expression during biological evolution, are found to be governed by the same single driving force, the drive toward greater DKS. It is reaffirmed that the essence of biological phenomena can be best revealed by uncovering biology’s chemical roots, by elucidating the physicochemical principles that governed the process by which life on earth emerged from inanimate matter.     

On the Emergence of Living Systems

If the problem of the origin of life is conceptualized as a process of emergence of biochemistry from proto-biochemistry, which in turn emerged from the organic chemistry and geochemistry of primitive earth, then the resources of the new sciences of complex systems dynamics can provide a more robust conceptual framework within which to explore the possible pathways of chemical complexification leading to living systems and biosemiosis. In such a view the emergence of life, and concomitantly of natural selection and biosemiosis, is the result of deep natural laws (the outlines of which we are only beginning to perceive) and reflects a degree of holism in those systems that led to life. Further, such an approach may lead to the development of a more general theory of biology and of natural organization, one informed by semiotic concepts.     

Beating the acetyl coenzyme A-pathway to the origin of life

Attempts to draft plausible scenarios for the origin of life have in the past mainly built upon palaeogeochemical boundary conditions while, as detailed in a companion article in this issue, frequently neglecting to comply with fundamental thermodynamic laws. Even if demands from both palaeogeochemistry and thermodynamics are respected, then a plethora of strongly differing models are still conceivable. Although we have no guarantee that life at its origin necessarily resembled biology in extant organisms, we consider that the only empirical way to deduce how life may have emerged is by taking the stance of assuming continuity of biology from its inception to the present day. Building upon this conviction, we have assessed extant types of energy and carbon metabolism for their appropriateness to conditions probably pertaining in those settings of the Hadean planet that fulfil the thermodynamic requirements for life to come into being. Wood–Ljungdahl (WL) pathways leading to acetyl CoA formation are excellent candidates for such primordial metabolism. Based on a review of our present understanding of the biochemistry and biophysics of acetogenic, methanogenic and methanotrophic pathways and on a phylogenetic analysis of involved enzymes, we propose that a variant of modern methanotrophy is more likely than traditional WL systems to date back to the origin of life. The proposed model furthermore better fits basic thermodynamic demands and palaeogeochemical conditions suggested by recent results from extant alkaline hydrothermal seeps.     

Functional cell permeable motifs within medically relevant proteins

Increasing experimental evidence indicates that short polybasic peptides are able to translocate across the membrane of living cells. However, these peptides, often derived from viruses and insects, may induce unspecific effects that could mask the action of their cargoes. Here, we show that a panel of lysine and/or arginine-rich peptides, derived from human proteins involved in cell signalling pathways leading to inflammation, possess the intrinsic ability to cross intact cellular membranes. These peptides are also capable of carrying a biologically active cargo. One of these peptides, encompassing the cell permeable sequence of the Toll-receptor 4 (TLR4) adaptor protein (TIRAP) and modified to carry a dominant-negative domain of the same TIRAP protein, selectively inhibited the production of pro-inflammatory cytokines upon LPS challenge, in in vitro, ex vivo and in vivo experiments. Docking studies indicated that this inhibition might be mediated by the disruption of the recruitment of downstream effector molecules. These results show for the first time the potential of using for therapy cell permeable peptides derived from human proteins involved in disease.     

A high-quality catalog of the Drosophila melanogaster proteome

Understanding how proteins and their complex interaction networks convert the genomic information into a dynamic living organism is a fundamental challenge in biological sciences. As an important step towards understanding the systems biology of a complex eukaryote, we cataloged 63% of the predicted Drosophila melanogaster proteome by detecting 9,124 proteins from 498,000 redundant and 72,281 distinct peptide identifications. This unprecedented high proteome coverage for a complex eukaryote was achieved by combining sample diversity, multidimensional biochemical fractionation and analysis-driven experimentation feedback loops, whereby data collection is guided by statistical analysis of prior data. We show that high-quality proteomics data provide crucial information to amend genome annotation and to confirm many predicted gene models. We also present experimentally identified proteotypic peptides matching approximately 50% of D. melanogaster gene models. This library of proteotypic peptides should enable fast, targeted and quantitative proteomic studies to elucidate the systems biology of this model organism.