Microstructuralism in the philosophy of chemistry is the thesis that chemical kinds can be individuated in terms of their microstructural properties (Hendry in Philos Sci 73:864–875, 2006 ). Elements provide paradigmatic examples, since the atomic number should suffice to individuate the kind. In theory, Microstructuralism should also characterise higher-level chemical kinds such as molecules, compounds, and macromolecules based on their constituent atomic properties. In this paper, several microstructural theses are distinguished. An analysis of macromolecules such as moonlighting proteins (...) suggests that all the forms of microstructuralism cannot accommodate them. (shrink)

Rival paradigms of genetics suggest different perceptions of human life and, correspondingly, of the task of medicine. In dialogue with two paradigmatic heuristics of genetics, I will show that bioethics needs to articulate a narrative that encourages a renewed understanding of the complexity of the phenomena of human life to which molecular medicine must be open. These considerations will be put to the test by discussing the ethical implications of the recent developments in stem cell research and in personal genetics.

Chondrocytes are specialised cells which produce and maintain the extracellular matrix of cartilage, a tissue that is resilient and pliant. In vivo, it has to withstand very high compressive loads, and that is explicable in terms of the physico‐chemical properties of cartilage‐specific macromolecules and with the movement of water and ions within the matrix. The functions of the cartilage‐specific collagens, aggrecan (a hydrophilic proteoglycan) and hyaluronan are discussed within this context. The structures of cartilage collagens and proteoglycans and their (...) genes are known and a number of informative mutations have been identified. In particular, collagen fibrillogenesis is a complex process which can be altered by mutations whose effects fit what is known about collagen molecular structural functions. In other instances, mutations have indicated new functions for particular molecular domains. As cartilage provides the template for the developing skeleton, mutations in genes for cartilage‐specific proteins often produce developmental abnormalities. The search for mutations amongst such genes in heritable disorders is being actively pursued by many groups, although mutation and phenotype are not always well correlated, probably because of compensatory mechanisms. The special nature of the chondrocyte is stressed in connection with its cell involvement in osteoarthritis, the most widespread disease of diarthrodial joints. (shrink)

Musks, the foundation of many perfumes, as well as other ingredients of perfumes, were critical objects of study for establishing theoretical concepts about large ring chemical compounds and polymerization in the 1920s and 1930s. Because fragrance chemistry has been underdeveloped in the historiography, doubtless partly because it has become associated with the feminine, this has been ignored in the historiography. This essay highlights the strategic importance of perfume research, looking in particular at the work of Leopold Ružičkač, 1939 Nobel laureate (...) in chemistry who had close ties to the fragrance industry, and Wallace Carothers at DuPont, whose well-known work on polymerization was intimately concerned with large ring compounds, including musk, and which indeed led to DuPont producing a synthetic musk in the 1930s. (shrink)

Biological macromolecules, considered as the items of the biochemical domain, are typically conceived under the ontological category of substantial individuals. In this paper, I will argue that the philosophical framework of process ontology, according to which the living world is not populated by individuals but by a dynamic hierarchy of processes, is more adequate to account for the structure and functioning of macromolecules. In particular, I will analyze its application to the phenomenon of cell signaling and to one (...) of its key concepts, cell receptors. Current knowledge in biochemistry allows us to conceive receptors as processual and dynamic entities, relationally stabilized and not separated from the biochemical phenomenon of which they are part. (shrink)

Transport of macromolecules from the nucleus to the cytoplasm is essential for nearly all cellular and developmental events, and when mis‐regulated, is associated with diseases, tumor formation/growth, and cancer progression. Nuclear Envelope (NE)‐budding is a newly appreciated nuclear export pathway for large macromolecular machineries, including those assembled to allow co‐regulation of functionally related components, that bypasses canonical nuclear export through nuclear pores. In this pathway, large macromolecular complexes are enveloped by the inner nuclear membrane, transverse the perinuclear space, and (...) then exit through the outer nuclear membrane to release its contents into the cytoplasm. NE‐budding is a conserved process and shares many features with nuclear egress mechanisms used by herpesviruses. Despite its biological importance and clinical relevance, little is yet known about the regulatory and structural machineries that allow NE‐budding to occur in any system. Here we summarize what is currently known or proposed for this intriguing nuclear export process. (shrink)

Although the analogy between macroscopic machines and biological molecular devices plays an important role in the conceptual framework of both neo-mechanistic accounts and nanotechnology, it has recently been claimed that certain complex molecular devices cannot be considered machines since they are subject to physicochemical forces that are different from those of macroscopic machines. However, the structural and physicochemical conditions that allow both macroscopic machines and microscopic devices to work and perform new functions, through a combination of elemental functional parts, have (...) not yet been examined. In order to fill this void, this paper has a threefold aim: first, to clarify the structural and organisational conditions of macroscopic machines and microscopic devices; second, to determine whether the machine-like analogy fits nanoscale devices; and third, to assess whether the machine-like analogy is appropriate for describing the behaviour of some biological macromolecules. Finally, the paper gives an account of ‘machine’ which, while acknowledging the physicochemical and organisational differences between man-made machines and biological microscopic devices, nevertheless identifies a common conceptual core that allows us to consider the latter ‘machines’. (shrink)

Ageing causes progressive decline in metabolic, behavioural, and physiological functions, leading to a reduced health span. The extracellular matrix (ECM) is the three‐dimensional network of macromolecules that provides our tissues with structure and biomechanical resilience. Imbalance between damage and repair/regeneration causes the ECM to undergo structural deterioration with age, contributing to age‐associated pathology. The ECM ‘Ageing Across the Life Course’ interdisciplinary research network (ECMage) was established to bring together researchers in the United Kingdom, and internationally, working on the emerging (...) field of ECM ageing. Here we report on a consultation at a joint meeting of ECMage and the Medical Research Council / Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing, held in January 2023, in which delegates analysed the key questions and research opportunities in the field of ECM ageing. We examine fundamental biological questions, enabling technologies, systems of study and emerging in vitro and in silico models, alongside consideration of the broader challenges facing the field. (shrink)

The theory of chemical symbiosis suggests that biological systems started with the collaboration of two polymeric molecules existing in early Earth: nucleic acids and peptides. Chemical symbiosis emerged when RNA-like nucleic acid polymers happened to fold into 3D structures capable to bind amino acids together, forming a proto peptidyl-transferase center. This folding catalyzed the formation of quasi-random small peptides, some of them capable to bind this ribozyme structure back and starting to form an initial layer that would produce the larger (...) subunit of the ribosome by accretion. TCS suggests that there is no chicken-and-egg problem into the emergence of biological systems as RNAs and peptides were of equal importance to the origin of life. Life has initially emerged when these two macromolecules started to interact in molecular symbiosis. Further, we suggest that life evolved into progenotes and cells due to the emergence of new layers of symbiosis. Mutualism is the strongest force in biology, capable to create novelties by emergent principles; on which the whole is bigger than the sum of the parts. TCS aims to apply the Margulian view of biology into the origins of life field. (shrink)

Different chemical species are often cited as paradigm examples of structurally delimited natural kinds. While classificatory monism may thus seem plausible for simple molecules, it looks less attractive for complex biological macromolecules. I focus on the case of proteins that are most plausibly individuated by their functions. Is there a single, objective count of proteins? I argue that the vagaries of function individuation infect protein classification. We should be pluralists about macromolecular classification.

In the advertising discourse of human genetic database projects, of genetic ancestry tracing companies, and in popular books on anthropological genetics, what I refer to as the anthropological gene and genome appear as documents of human history, by far surpassing the written record and oral history in scope and accuracy as archives of our past. How did macromolecules become "documents of human evolutionary history"? Historically, molecular anthropology, a term introduced by Emile Zuckerkandl in 1962 to characterize the study of (...) primate phylogeny and human evolution on the molecular level, asserted its claim to the privilege of interpretation regarding hominoid, hominid, and human phylogeny and evolution vis-à-vis other historical sciences such as evolutionary biology, physical anthropology, and paleoanthropology. This process will be discussed on the basis of three key conferences on primate classification and evolution that brought together exponents of the respective fields and that were held in approximately ten-years intervals between the early 1960s and the 1980s. I show how the anthropological gene and genome gained their status as the most fundamental, clean, and direct records of historical information, and how the prioritizing of these epistemic objects was part of a complex involving the objectivity of numbers, logic, and mathematics, the objectivity of machines and instruments, and the objectivity seen to reside in the epistemic objects themselves. (shrink)

One of the foundational problems of biochemistry concerns the conceptualisation of the relationship between the composition, structure and function of macromolecules like proteins. Part of the recent philosophical literature displays a reductionist bias, that is, the endorsement of a form of microstructuralism mirroring an out-dated biochemical conceptualisation. We shall argue that such microstructuralist approaches are ultimately committed to a potentialist form of micro-predeterminism whereby the macrostructure and function of proteins is accounted for solely in terms of the intrinsic properties (...) and potentialities of the components of the primary structure as if they were self-contained or essentially immutable entities. We shall instead suggest that a conceptualisation of the relationship between proteins’ composition, structure and function consistent with contemporary biochemical practice should account also for the causal role of the cellular, organismal and environmental relations in protein development. The analysis of the folding process we propose suggests that microstructure-laden reductionist approaches are ontologically indefensible. Rather than a potentialist form of micro-predeterminism, our analysis ultimately supports a relational-construction-based view of protein development and potentialities formation, which requires an indispensable analysis of the dynamical interplay between the micro-level of the parts and the macro-level of the relational structures of their systems. (shrink)

Oncogene activation leads to cellular transformation by deregulation of biological processes such as proliferation and metabolism. Paradoxically, this can also sensitize cells to nutrient deprivation, potentially representing an Achilles' heel in early stage tumors. The mechanisms underlying this phenotype include loss of energetic and redox homeostasis as a result of metabolic reprogramming, favoring synthesis of macromolecules. Moreover, an emerging mechanism involving the deregulation of mRNA translation elongation through inhibition of eukaryotic elongation factor 2 kinase (eEF2K) is presented. The potential (...) consequences of eEF2K deregulation leading to cell death under nutrient depletion are discussed. Finally, the relevance of eEF2K as a master regulator of the response to nutrient deprivation in vivo, and its potential exploitation for therapeutic targeting of cancers, are elaborated. Overall, a better understanding of the adaptive mechanisms allowing tumors to circumvent oncogene‐induced hypersensitivity to nutrient deprivation is a promising avenue for uncovering novel therapeutic targets in cancers. (shrink)

We propose a signaling pathway in which cell‐extracellular matrix (ECM) adhesion components PINCH‐1 and kindlin‐2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH‐1 expression via integrin signaling, which suppresses dynamin‐related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin‐2 translocation into mitochondria and interaction with Δ1‐pyrroline‐5‐carboxylate (P5C) reductase 1 (PYCR1). Kindlin‐2 interaction with PYCR1 protects the latter from proteolytic degradation, (...) leading to elevated PYCR1 level. Additionally, PINCH‐1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. (shrink)

The Oparin hypothesis from 1936 was a milestone in the origin of life research, making a model that was at least in part empirically testable, and changing the course of life studies from a long tradition of metaphysics to a scientific domain of investigation. His hypothesis is based on the idea of the prebiotic synthesis of macromolecules as a fundamental step on the road to first life. Although the Oparin hypothesis brought fresh ideas and concepts, in its description of (...) the steps in the hypothesized transition from the inorganic to the organic world in detail, today some premises are considered unconfirmed, uncertain, or even rejected. With high respect to its metatheoretical reach and scientific impact on prebiotic chemistry, pushing the origin of first life research into an empirical context, from a contemporary viewpoint, its contribution is highly limited in the area of history of science and history of philosophy (of science). Keywords: biology, history of science, Oparin, origin of life, philosophy of science. (shrink)

Computational approaches in systems biology have become a powerful tool for understanding the fundamental mechanisms of cellular metabolism and regulation. However, the interplay between the regulatory and the metabolic system is still poorly understood. In particular, there is a need for formal mathematical frameworks that allow analyzing metabolism together with dynamic enzyme resources and regulatory events. Here, we introduce a metabolic-regulatory network model that allows integrating metabolism with transcriptional regulation, macromolecule production and enzyme resources. Using this model, we show that (...) the dynamic interplay between these different cellular processes can be formalized by a hybrid automaton, combining continuous dynamics and discrete control. (shrink)

The notion of the value of information is discussed. The value one attributes to information is determined by the result of its reception by an open nonequilibrium system. Qualitative reasoning shows that the concept of value of information makes sense only in nonequilibrium situations, and is directly connected with the nonredundancy of information. In biology it is the value and not the amount of information that is important. The value of information is especially high if there are instabilities in the (...) system; these are connected with the notions of purpose and of freedom of will. The notion of selective value, introduced by Eigen in the theory of the prebiological evolution of macromolecules, is discussed. The amount of information in various codons is calculated and the conventional definition of its value is given based on the determination of the danger of the replacement of one amino acid by another with a different value of hydrophobicity. It is shown that the relative probability of transversion is considerably lower than that of transition. As most nonsense mutations are transversions, the genetic code provides decreased probability for the most dangerous mutations. It is shown that the information of the codonUGG(Trp) is highest in both amount and value. (shrink)

Altered cellular metabolism is an emerging hallmark of cancer. Accumulating recent evidence links long non‐coding RNAs (lncRNAs), a still poorly understood class of non‐coding RNAs, to cancer metabolism. Here we review the emerging findings on the functions of lncRNAs in cancer metabolism, with particular emphasis on how lncRNAs regulate glucose and glutamine metabolism in cancer cells, discuss how lncRNAs regulate various aspects of cancer metabolism through their cross‐talk with other macromolecules, explore the mechanistic conceptual framework of lncRNAs in reprogramming (...) metabolism in cancers, and highlight the challenges in this field. A more in‐depth understanding of lncRNAs in cancer metabolism may enable the development of novel and effective therapeutic strategies targeting cancer metabolism. (shrink)

Recently a number of complex electrophysiological responses to neurotransmitters have been observed that cannot be described as simple excitation or inhibition. These responses are often characterized as modulatory, although there is no consensus on what defines modulation. Morphological studies reveal certain neurotransmitters stored in what might be release sites without synaptic contact. There is no direct evidence for nonsynaptic release from CNS sites, although such release does occur in the periphery and in invertebrates. Nonsynaptic release might provide a basis for (...) diffuse one-cell-to-many communication, but it might also simply be a means of sending the transmitter to a broader area of a single neuron than occurs in typical synapses. Several kinds of macromolecules have been found to be transported in a retrograde direction – and in some cases transsynaptically. There have been suggestions that some neurons may release more than one type of transmitter. Particularly intriguing is the possibility of release of substances that modulate actions of a primary transmitter. Taken together this range of evidence suggests that neurons may use a variety of forms of molecular communication in addition to traditionally described synaptic transmission.Several authors have suggested modes of communication distinct from classical synaptic transmission and have classified released substances using terms such as neurohumor, neurohormone, neuroregulator, and modulator. These suggestions have the heuristic value of drawing together diverse kinds of data, but it remains to be established that the pieces fit together in that fashion – for example, that complex electrophysiological effects are associated with substances released nonsynaptically. In order to reduce confusion, a flexible, generic approach to nomenclature for substances released from neurons and for hypothetical modes of communication is recommended. Some behavioral implications of nonconventional transmission are considered. (shrink)

Intermediary metabolism molecules are orchestrated into logical pathways stemming from history (L-amino acids, D-sugars) and dynamic constraints (hydrolysis of pyrophosphate or amide groups is the driving force of anabolism). Beside essential metabolites, numerous variants derive from programmed or accidental changes. Broken down, variants enter standard pathways, producing further variants. Macromolecule modification alters enzyme reactions specificity. Metabolism conform thermodynamic laws, precluding strict accuracy. Hence, for each regular pathway, a wealth of variants inputs and produces metabolites that are similar to but not (...) the exact replicas of core metabolites. As corollary, a shadow, paralogous metabolism, is associated to standard metabolism. We focus on a logic of paralogous metabolism based on diversion of the core metabolic mimics into pathways where they are modified to minimize their input in the core pathways where they create havoc. We propose that a significant proportion of paralogues of well-characterized enzymes have evolved as the natural way to cope with paralogous metabolites. A second type of denouement uses a process where protecting/deprotecting unwanted metabolites - conceptually similar to the procedure used in the laboratory of an organic chemist - is used to enter a completely new catabolic pathway. (shrink)

Scientific models are often said to be more or less general depending on how many cases they cover. In this paper we argue that the cardinality of cases is insufficient as a metric of generality, and we present a novel account based on measure theory. This account overcomes several problems with the cardinality approach, and additionally provides some insight into the nature of assessments of generality. Specifically, measure theory affords a natural and quantitative way of describing local spaces of possibility. (...) The generality of models can be understood as the measure of possibilities to which the models apply. In order to illustrate our view, we consider the example of structural genomics, the ongoing project of building three-dimensional models of biological macromolecules like proteins. Using measure theory, we interpret the practice of homology modeling, where such models are understood to apply widely but imperfectly to the space of possible proteins. (shrink)

Following Kripke and Putnam, the received view of chemical kinds has been a microstructuralist one. To be a microstructuralist about chemical kinds is to think that membership in said kinds is conferred by microstructural properties. Recently, the received microstructuralist view has been elaborated and defended, but it has also been attacked on the basis of complexities, both chemical and ontological. Here, I look at which complexities really challenge the microstructuralist view; at how the view itself might be made more complicated (...) in order to accommodate such challenges; and finally, at what this increasingly complicated picture implies for our standard assessment of chemical kindhood—primarily, for the widespread assumption that chemical kinds in general are more neat and tidy than those messy biological ones. _1_ The Received View _2_ A Taxonomy of Chemical Kinds _3_ Atomic Number _4_ H2O, H3O+, OH−, and More _5_ Complicating the Microstructuralist Picture _6_ Concrete and Other Mixtures _7_ Macromolecules, Especially Proteins _8_ Abandoning Sameness of Elemental Composition _9_ Not So Different after All. (shrink)

The genetic code has been regarded as arbitrary in the sense that the codon-amino acid assignments could be different than they actually are. This general idea has been spelled out differently by previous, often rather implicit accounts of arbitrariness. They have drawn on the frozen accident theory, on evolutionary contingency, on alternative causal pathways, and on the absence of direct stereochemical interactions between codons and amino acids. It has also been suggested that the arbitrariness of the genetic code justifies attributing (...) semantic information to macromolecules, notably to DNA. I argue that these accounts of arbitrariness are unsatisfactory. I propose that the code is arbitrary in the sense of Jacques Monod's concept of chemical arbitrariness: the genetic code is arbitrary in that any codon requires certain chemical and structural properties to specify a particular amino acid, but these properties are not required in virtue of a principle of chemistry. This notion of arbitrariness is compatible with several recent hypotheses about code evolution. I maintain that the code's chemical arbitrariness is neither sufficient nor necessary for attributing semantic information to nucleic acids. (shrink)

Lysosomes are the site of degradation of obsolete intracellular material during autophagy and of extracellular macromolecules following endocytosis and phagocytosis. The membrane of lysosomes and late endosomes is enriched in highly glycosylated transmembrane proteins of largely unknown function. Significant progress has been made in recent years towards elucidating the pathways by which these lysosomal membrane proteins are delivered to late endosomes and lysosomes. While some lysosomal membrane proteins follow the constitutive secretory pathway and reach lysosomes indirectly via the cell (...) surface and endocytosis, others exit the trans‐Golgi network in clathrin‐coated vesicles for direct delivery to endosomes and lysosomes. Sorting from the Golgi or the plasma membrane into the endosomal system is mediated by signals encoded by the short cytosolic domain of these proteins. This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysosomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins. (shrink)

Reductionists in biology claim that all biological events can be explained in terms of genes and macromolecules alone, while antireductionists argue that some biological events must be explained at a higher level. The literature, however, does not distinguish between different kinds of molecular explanation. The goal of this article is to identify and analyze three such kinds. The analysis of molecular explanations herein carries an important philosophical implication; in shunning crude reductionism and extreme versions of holism, we can combine (...) the insights of thoughtful reductionists with sophisticated antireductionism. When this is done, the question of explanatory reductionism becomes less substantial than often supposed. (shrink)

Over the past decade, research has revealed biomolecular condensates' relevance in diverse cellular functions. Through a phase separation process, they concentrate macromolecules in subcompartments shaping the cellular organization and physiology. In the nucleus, biomolecular condensates assemble relevant biomolecules that orchestrate gene expression. We here hypothesize that chromatin condensates can also modulate the nongenetic functions of the genome, including the nuclear mechanical properties. The importance of chromatin condensates is supported by the genetic evidence indicating that mutations in their members are (...) causative of a group of rare Mendelian diseases named chromatinopathies (CPs). Despite a broad spectrum of clinical features and the perturbations of the epigenetic machinery characterizing the CPs, recent findings highlighted negligible changes in gene expression. These data argue in favor of possible noncanonical functions of chromatin condensates in regulating the genome's spatial organization and, consequently, the nuclear mechanics. In this review, we discuss how condensates may impact nuclear mechanical properties, thus affecting the cellular response to mechanical cues and, eventually, cell fate and identity.Chromatin condensates organize macromolecules in the nucleus orchestrating the transcription regulation and mutations in their members are responsible for rare diseases named chromatinopathies. We argue that chromatin condensates, in concert with the nuclear lamina, may also govern the nuclear mechanical properties affecting the cellular response to external cues. (shrink)

Annoncé à grand fracas, le décryptage do génome humain devait nous révéler le secret ultime de la vie et ouvrir la voie à de nouvelles thérapies miracles. Espoirs déçus : à l'ère de la post-génomique, les secrets du vivant sont maintenant recherchés dans les théories de la complexité, dans la convergence des efforts des biologistes, des physiciens et des mathématiciens. Comment comprendre la signification de cette succession rapide d'objectifs apparemment différents, de cette alternance d'espoirs et de désillusions? Dans ce livre (...) novateur, Michel Morange propose une clé pour rendre compte de ces difficultés, et de beaucoup d'autres analogues touchant toutes les branches de la biologie. Les annonces sensationnelles reflètent l'espoir toujours déçu qu'une explication unique pourrait suffire. Or les faits biologiques - comme ceux relevant de bien d'autres disciplines scientifiques -ne peuvent être expliqués par un principe d'intelligibilité unique. Exemples à l'appui et de façon très pédagogique, Michel Morange montre pourquoi des explications différentes doivent être articulées pour décrire le fonctionnement des macromolécules aussi bien que l'évolution humaine ou le développement des cancers. Admettre une idée aussi simple n'est pas évident, car tout scientifique a été formé à privilégier un principe d'intelligibilité particulier. L'articulation entre explications différentes est pourtant indispensable pour le progrès des connaissances ; elle est aussi une exigence éthique ; elle est requise pour que la science conserve sa place dans nos sociétés. (shrink)

The term biology is of Greek origin meaning the study of life. On the other hand, chemistry is the science of matter, which deals with matter and its properties, structure, composition, behavior, reactions, interactions and the changes it undergoes. The theory of abiogenesis maintains that chemistry made a transition to biology in a primordial soup. To keep the naturalistic ‘inanimate molecules to human life’ evolution ideology intact, scientists must assemble billions of links to bridge the gap between the inanimate chemicals (...) that existed in the primordial soup and anatomically modern humans. Even though the proponents of a natural origin of life expressed much optimism for providing their theories, presently there is a detailed compilation of information seriously questioning this doctrine. This reductionistic ideology has always failed to answer two simple questions: (1) What is the minimum number of parts that are essential for a living organism to survive? (2) By what mechanism do these parts get assembled together? Evolutionists say a series of prebiotic processes and developments guide networks of dynamically linked small molecules and amphiphiles to form biological macromolecules, membraneous compartments, and finally primitive cells. However, none of these proposed pathways to life appears to be credible. The continuous advancement in various fields of science are not only providing major challenges to reductionistic ideology but are supplying increasing evidence for a systemic concept of life as an organic whole. Several leading researchers in the field of ‘origin of life’ are continually concluding that there are major scientific problems attached with all existing naturalistic ‘origin of life’ hypothesis. Only by taking into account all biological activities collectively as a system can a satisfactory elucidation of the living state be realized. In this present paper an attempt has been made to present a few significant challenges to the theory of abiogenesis based on the peer reviewed scientific literature. Subsequently, a non-reductionistic concept of life as a system is proposed as an alternative for resolving some of the problems inherent in origin of life research. (shrink)

From its first proposal, the Central Dogma had a graphical form, complete with arrows of different types, and this form quickly became its standard presentation. In different scientific contexts, arrows have different meanings and in this particular case the arrows indicated the flow of information among different macromolecules. A deeper analysis illustrates that the arrows also imply a causal statement, directly connected to the causal role of genetic information. The author suggests a distinction between two different kinds of causal (...) links, defined as 'physical causality' and 'biological determination', both implied in the production of biological specificity. (shrink)

The molecular aspects of the microtubule system is a research area that has developed very rapidly during the past decade. Research on the assembly mechanisms and chemistry of tubulin and the molecular biology of microtubules have advanced our understanding of microtubule formation and its regulation. The emerging view of tubulin is of a macromolecule containing spatially discrete sequences that constitute functionally different domains with respect to self‐association, interactions with microtubule associated proteins (MAPs) and specific ligands. Recent studies point to the (...) role of the carboxyl‐terminal moiety of tubulin subunits in regulating its assembly into microtubules. These investigations combined with further studies on the spatial relationships between tubulin domains should provide new insights into the detailed structural basis of microtubule assembly. (shrink)

Exposure of man to chemical agents can occur intentionally, as in the treatment of disease, or inadvertently because the environment contains a wide range of synthetic or naturally occurring chemicals. The alkylating agents are a diverse group of compounds (Fig. 1) and comprise a good example of such xenobiotics, since much is known about their occurrence, and their biological effects include carcinogenicity, mutagenicity, toxicity and teratogenicity.Exposure to potentially carcinogenic alkylating agents such as nitrosamines may occur occupationally, from cigarette smoke, from (...) certain foodstuffs and even endogenously through the ingestion of the appropriate precursor chemicals.1 At the other extreme, the cytotoxic effects of agents such as the chloroethylating nitrosamides or mustards have been exploited in the design of certain antitumour drugs.2 The effectiveness of antitumour agents and the other, mostly adverse, biological effects of alkylating agents have been ascribed to their ability to damage cellular macromolecules, in particular DNA. This review concentrates on investigations carried out over the past two years on the role of DNA damage in carcinogenesis, but we shall see how recent advances in this area of research have also led to a better understanding of the mechanisms of the cytotoxic effects of alkylating antitumour agents. (shrink)

Despite their seemingly endless diversity, proteins adopt a limited number of structural forms. It has been estimated that 80% of proteins will be found to adopt one of only about 400 folds, most of which are already known. These folds are largely formed by a limited ‘vocabulary’ of recurring supersecondary structure elements, often by repetition of the same element and, increasingly, elements similar in both structure and sequence are discovered. This suggests that modern proteins evolved by fusion and recombination from (...) a more ancient peptide world and that many of the core folds observed today may contain homologous building blocks. The peptides forming these building blocks would not in themselves have had the ability to fold, but would have emerged as cofactors supporting RNA‐based replication and catalysis (the ‘RNA world’). Their association into larger structures and eventual fusion into polypeptide chains would have allowed them to become independent of their RNA scaffold, leading to the evolution of a novel type of macromolecule: the folded protein. BioEssays 25:837–846, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

An important function of scientific diagrams is to identify causal relationships. This commonly relies on contrasts that highlight the effects of specific difference-makers. However, causal contrast diagrams are not an obvious and easy to recognize category because they appear in many guises. In this paper, four case studies are presented to examine how causal contrast diagrams appear in a wide range of scientific reports, from experimental to observational and even purely theoretical studies. It is shown that causal contrasts can be (...) expressed in starkly different formats, including photographs of complexly visualized macromolecules as well as line graphs, bar graphs, or plots of state spaces. Despite surface differences, however, there is a measure of conceptual unity among such diagrams. In empirical studies they generally serve not only to infer and communicate specific causal claims, but also as evidence for them. The key data of some studies is given nowhere except in the diagrams. Many diagrams show multiple causal contrasts in order to demonstrate both that an effect exists and that the effect is specific -- that is, to narrowly circumscribe the phenomenon to be explained. In a large range of scientific reports, causal contrast diagrams reflect the core epistemic claims of the researchers. (shrink)

The network concept is increasingly used for the description of complex systems. Here, we summarize key aspects of the evolvability and robustness of the hierarchical network set of macromolecules, cells, organisms and ecosystems. Listing the costs and benefits of cooperation as a necessary behaviour to build this network hierarchy, we outline the major hypothesis of the paper: the emergence of hierarchical complexity needs cooperation leading to the ageing (i.e. gradual deterioration) of the constituent networks. A stable environment develops cooperation (...) leading to over‐optimization, and forming an ‘always‐old’ network, which accumulates damage, and dies in an apoptosis‐like process. A rapidly changing environment develops competition forming a ‘forever‐young’ network, which may suffer an occasional over‐perturbation exhausting system resources, and causing death in a necrosis‐like process. Giving a number of examples we demonstrate how cooperation evokes the gradual accumulation of damage typical to ageing. Finally, we show how various forms of cooperation and consequent ageing emerge as key elements in all major steps of evolution from the formation of protocells to the establishment of the globalized, modern human society. (shrink)

In 1957, Francis Crick outlined a startling vision of life in which the great diversity of forms and shapes of macromolecules was encoded in the one-dimensional sequence of nucleic acids. This paper situates Crick's new vision in the debates of the 1950s about protein synthesis and gene action. After exploring the reception of Crick's ideas, it shows how they differed radically from a different model of protein synthesis which enjoyed wide currency in that decade. In this alternative model, advocated (...) by Linus Pauling and other luminaries, three-dimensional templates directed the folding of proteins. Even though it was always considered somewhat speculative, this theory was supported by a number of empirical results originating in different experimental systems. It was eventually replaced by a model in which the forms and shapes of macromolecules resulted solely from their amino acid sequence, dramatically simplifying the problem of protein synthesis which Crick was attempting to solve in 1957. (shrink)

According to process ontology in the philosophy of biology, the living world is better understood as processes rather than as substantial individuals. Within this perspective, an organism does not consist of a hierarchy of structures like a machine, but rather a dynamic hierarchy of processes, dynamically maintained and stabilized at different time scales. With this respect, two processual approaches on enzymes by Stein (Hyle Int J Philos Chem 10(4):5–22, 2004, Process Stud 34:62–80, 2005, Found Chem 8:3–29, 2006) and by Guttinger (...) (Everything Flows: Towards a Processual Philosophy of Biology, Oxford University Press, Oxford, 2018) allows to think of macromolecules as relational and processual entities. In this work, I propose to extend their arguments to another case study within the biochemical domain, which is the case of ligand receptors and receptor-mediated biosignaling. The aim of this work is to analyze the case of G Protein-Coupled Receptors and biosignaling under the consideration of a processual ontology. I will defend that the processual ontology framework is adequate for the biochemical domain and that it allows accounting for the current biochemical knowledge related to the case study. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Teleology in Natural Theology and Theology of Nature:Classical Theism, Science-Oriented Panentheism, and Process TheismMariusz Tabaczek, O.P.IntroductionThe world is full of teleological dimensions. When we search for them, we can easily see that virtually any of the main aspects of our world can be taken as a particular case of teleology. Although this holds especially for living beings, the physicochemical world also exhibits many directional features that acquire a special (...) meaning when seen as necessary conditions for the existence of living beings. Directionality indicates the existence of tendencies toward goals, which is the hallmark of natural teleology.... It is not difficult to find examples of directionality and cooperativity. If we begin with the most elementary components of the world, we find out that subatomic particles and the four basic interactions behave according to well-known specific patterns and collaborate to build up successive levels of organization—atoms, molecules, macromolecules, and the bigger inorganic and organic beings. The entire construction of our world is the result of the deployment of tendencies that collaborate to make up unitary systems.1If Mariano Artigas is right in his assertion—and many seem to agree that he is2—it seems reasonable to ask about the ways in which the notion of [End Page 1179] teleology may inspire theology, especially in the context of the ongoing dialogue between science and theology. We may think about at least two possible answers to this question, in reference to two related, yet distinctive strategies pursued in theological reflection, (1) the approach of natural theology and (2) the approach of theology of nature. What brings them together is their close attention to nature and our attempts to understand it. Avoiding theological and spiritual escapism and dismissive detachment from nature and natural phenomena, both natural theology and theology of nature point toward their ultimate grounding in God. While doing so, both approaches strive to remain free from the errors of panpsychism, vitalism, and pantheism, thus enabling nature to be natural, available to a thorough and meaningful analysis and description at the level of the research pursued by natural sciences and philosophy of nature and of science. What differentiates these theological approaches are their starting and ending points.Natural theology departs from the observation of natural phenomena. In a search for their ultimate explanation, in reference to philosophy of nature and metaphysics, it arrives at the theological conclusion that only the existence of God offers a satisfying and conclusive answer to the human search for understanding and meaning of the reality that surrounds us. Consequently, one may say that natural phenomena, or at least some of their most fundamental aspects such as teleology, can be used as a basis for arguing in favor of the existence of God.The advantage of such an approach—notes Ian Barbour—is that "it starts from scientific data on which we might expect agreement despite cultural and religious differences."3 However, taken alone, it may reduce the notion of God to the God of philosophers, the unmoved mover, [End Page 1180] or even a deistic Creator, remote and not engaged in his relation to the created reality. Moreover, although we know many examples of people who actually did go through a conversion and discovered the existence of God following the path of natural theology, one might ask whether at least some of the arguments developed within it do not presuppose God's existence as rhetorical exercises for the expression of religious faith, compromising thus its principal commitment.In contrast to natural theology, theology of nature begins with a firm belief in God, based on historical revelation—codified in the Scriptures and reflected upon within theological Tradition—and religious experience (personal and communal). It applies this perspective as an explanatory tool, providing a definitive answer to the questions of origin and ultimate fulfillment of natural phenomena observed in the universe. Hence, while it would be rather strange to claim that the existence of God proves the existence of the natural world—which is better known to us (quoad nos) than the principles of theology—we may still argue that, from the point of view of theology of nature, our knowledge... (shrink)

According to process ontology in the philosophy of biology, the living world is better understood as processes rather than as substantial individuals. Within this perspective, an organism does not consist of a hierarchy of structures like a machine, but rather a dynamic hierarchy of processes, dynamically maintained and stabilized at different time scales. With this respect, two processual approaches on enzymes by Stein (Hyle Int J Philos Chem 10(4):5–22, 2004, Process Stud 34:62–80, 2005, Found Chem 8:3–29, 2006) and by Guttinger (...) (Everything Flows: Towards a Processual Philosophy of Biology, Oxford University Press, Oxford, 2018) allows to think of macromolecules as relational and processual entities. In this work, I propose to extend their arguments to another case study within the biochemical domain, which is the case of ligand receptors and receptor-mediated biosignaling. The aim of this work is to analyze the case of G Protein-Coupled Receptors and biosignaling under the consideration of a processual ontology. I will defend that the processual ontology framework is adequate for the biochemical domain and that it allows accounting for the current biochemical knowledge related to the case study. (shrink)

New discoveries and theories are crucial for the development of science, but they are often initially resisted by the scientific community. This paper analyses resistance to scientific discoveries that supplement previous research results or conclusions with new phenomena, such as long chains in macromolecules, Alfvén waves, parity nonconservation in weak interactions and quasicrystals. Construal-level theory is used to explain that the probability of new discoveries may be underestimated because of psychological distance. Thus, the insufficiently examined scope of an accepted (...) theory may lead to overstating the suitable scope and underestimating the probability of its undiscovered counter-examples. Therefore, psychological activity can result in people instinctively resisting new discoveries. Direct evidence can help people judge the validity of a hypothesis with rational thinking. The effects of authorities and textbooks on the resistance to discoveries are also discussed. From the results of our analysis, suggestions are provided to reduce resistance to real discoveries, which will benefit the development of science. (shrink)

I argue here that Goethe's "delicate empiricism" is not an alternative approach to science, but an approach that scientists use consistently, though they usually do not label it as such. I further contend that Goethe's views are relevant to today's science, specifically to work on the structure of macromolecules such as proteins. Using the work of Agnes Arber, a botanist and philosopher of science, I will show how her writings help to relate Goethe's work to present-day issues of cognition (...) and perception. (shrink)

Cryo‐electron microscopy allows the visualization of macromolecules in their native state. Combined with techniques of three‐dimensional reconstruction, cryo‐EM images of single molecules can be used to study macromolecular interactions. The ribosome, a large RNA–protein complex with multiple binding interactions, is an excellent test case illustrating the power of these new techniques. Conformational changes during the binding of tRNA and protein factors to the ribosome can now be studied without the interference of crystal packing. Now that the first X‐ray structures (...) of ribosomal subunits have become available, conformational changes observed by cryo‐EM in different functional states can be traced back to internal rearrangements of the underlying structural framework. Electron microscopy, X‐ray crystallography, and modeling should be used together in the endeavor to understand the functioning of the translational machinery. BioEssays 23:725–732, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

This paper analyzes the necessity and operation of conceptual macromolecule inside Edgar Morin’s school of thought due to the significant connection of his epistemological proposal and the language transformation with which the knowledge of reality is expressed in complex thought. This paper is organized as follows. First, we pointed the essential link between conceptualizer/observer subject and the macro-conceptualization. Second, we interpret the system or complex basic unity expounded in Method I based on complexity principles. Finally, it may be concluded that (...) the linguistic resources used by this paradigm are in accordance with the new ways to understand complexity. (shrink)

The invention in 1986 of scanning force microscopy (SFM) provided a new and powerful tool for the investigation of biological structures. SFM yields a three‐dimensional view at nanometer resolution of the surface topography associated with biological objects. The potential for imaging either macromolecules or biomolecules and cells under native (physiological) conditions is currently being exploited to obtain functional information at the molecular level. In addition, the forces involved in individual bimolecular interactions are being assessed under static and dynamic conditions. (...) In this report we focus on the imaging capability of the SFM. The rather broad spectrum of applications represented is intended to orient the prospective user of biological SFM. (shrink)