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)

The aim of this book is to show how supramolecular complexity of cell organization can dramatically alter the functions of individual macromolecules within a cell. The emergence of new functions which appear as a consequence of supramolecular complexity, is explained in terms of physical chemistry. The book is interdisciplinary, at the border between cell biochemistry, physics and physical chemistry. This interdisciplinarity does not result in the use of physical techniques but from the use of physical concepts to study (...) class='Hi'>biological problems. In the domain of complexity studies, most works are purely theoretical or based on computer simulation. The present book is partly theoretical, partly experimental and theory is always based on experimental results. Moreover, the book encompasses in a unified manner the dynamic aspects of many different biological fields ranging from dynamics to pattern emergence in a young embryo. The volume puts emphasis on dynamic physical studies of biological events. It also develops, in a unified perspective, this new interdisciplinary approach of various important problems of cell biology and chemistry, ranging from enzyme dynamics to pattern formation during embryo development, thus paving the way to what may become a central issue of future biology. (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)

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)

The gap between Science and the Humanities becomes tangible when they both attempt to address the same problem. One such case is relationship between Life and biological molecules. Traditionally, molecular biology has attempted to explain biological processes in terms of physicochemical characteristics of individual macromolecules. The new science of systems biology largely ignores the molecular characteristics of specific molecules and endeavors to analyze biological processes through the relationship between thousands of molecules. On the face of it, (...) the difference between the molecular and the systems approach to biological research corresponds to the tension between the reductionist and the emergentist view in the philosophy of biology. However, a closer analysis reveals that experimental science and philosophy are concerned with different aspects of the problem and therefore search for different solutions. A main reason for this is the difference in their respective concepts of “question” and “answer”, which is essentially unbridgeable. (shrink)

The recent development of single molecule detection techniques has opened new horizons for the study of individual macromolecules under physiological conditions. Conformational subpopulations, internal dynamics and activity of single biomolecules, parameters that have so far been hidden in large ensemble averages, are now being unveiled. Herein, we review a particular attractive solution‐based single molecule technique, fluorescence correlation spectroscopy (FCS). This time‐averaging fluctuation analysis which is usually performed in Confocal setups combines maximum sensitivity with high statistical confidence. FCS has proven (...) to be a very versatile and powerful tool for detection and temporal investigation of biomolecules at ultralow concentrations on surfaces, in solution, and in living cells. The introduction of dual‐color cross‐correlation and two‐photon excitation in FCS experiments is currently increasing the number of promising applications of FCS to biological research. BioEssays 24:758–764, 2002. © 2002 Wiley Periodicals, Inc. (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)

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 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.

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)

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)

Although negative stain electron microscopy is a wonderfully simple way of directly visualizing protein complexes and other biological macromolecules, the images are not really comparable to those of objects seen in everyday life. The failure to appreciate this has recently led to an incorrect interpretation of RecA‐family filament structures.

What is biological complexity? How many sorts exist? Are there levels of complexity? How are they related to one another? How is complexity related to the emergence of new phenotypes? To try to get to grips with these questions, we consider the archetype of a complex biological system, Escherichia coli. We take the position that E. coli has been selected to survive adverse conditions and to grow in favourable ones and that many other complex systems undergo similar selection. (...) We invoke the concept of hyperstructures which constitute a level of organisation intermediate between macromolecules and cells. We also invoke a new concept, competitive coherence, to describe how phenotypes are created by a competition between maintaining a consistent story over time and creating a response that is coherent with respect to both internal and external conditions. We suggest how these concepts lead to parameters suitable for describing the rich form of complexity termed hypercomplexity and we propose a relationship between competitive coherence and emergence. (shrink)

Recent successes of systems biology clarified that biological functionality is multilevel. We point out that this fact makes it necessary to revise popular views about macromolecular functions and distinguish between local, physico-chemical and global, biological functions. Our analysis shows that physico-chemical functions are merely tools of biological functionality. This result sheds new light on the origin of cellular life, indicating that in evolutionary history, assignment of biological functions to cellular ingredients plays a crucial role. In this (...) wider picture, even if aggregation of chance mutations of replicator molecules and spontaneously self-assembled proteins led to the formation of a system identical with a living cell in all physical respects but devoid of biological functions, it would remain an inanimate physical system, a pseudo-cell or a zombie-cell but not a viable cell. In the origin of life scenarios, a fundamental circularity arises, since if cells are the minimal units of life, it is apparent that assignments of cellular functions require the presence of cells and vice versa. Resolution of this dilemma requires distinguishing between physico-chemical and biological symbols as well as between physico-chemical and biological information. Our analysis of the concepts of symbol, rule and code suggests that they all rely implicitly on biological laws or principles. We show that the problem is how to establish physico-chemically arbitrary rules assigning biological functions without the presence of living organisms. We propose a solution to that problem with the help of a generalized action principle and biological harnessing of quantum uncertainties. By our proposal, biology is an autonomous science having its own fundamental principle. The biological principle ought not to be regarded as an emergent phenomenon. It can guide chemical evolution towards the biological one, progressively assigning greater complexity and functionality to macromolecules and systems of macromolecules at all levels of organization. This solution explains some perplexing facts and posits a new context for thinking about the problems of the origin of life and mind. (shrink)

When posing the question "is artificial life possible?", our immediate answer is that on the one hand : of course it is - people make it, and indeed very interesting and even breathtaking structures have already been constructed, such as `aminats', self-reproducing patterns and the other things, we have seen already. In this sense we are forced to take artificial life as a fact (at least as a fact about a new branch of research), nearly in the same way that (...) the philosopher Kant took the theoretical physics of his days, Newtonian physics, as a matter of fact, and then asked: What are the conditions of possibility for this kind of theoretical science? On the other hand: The situation differs from Kant's. Artificial Life does not confront us with an analogy of theoretical mechanics within the field of biology. We face a curious situation: It is not obvious to the majority of biologists that Artificial Life is possible at all, at least in the purely computational sense of `software life'. Probably, most biologists would never call these artificial constructs `living'. Why not? Because the intuitive notions of life and living systems within biology implies, among other things, that living beings are a result of a long, ongoing evolutionary process that have created autonomous organisms, single-celled and multi-celled, that are highly organized, open (non-equilibrium), material thermodynamic systems based on metabolism and some kind of genetic information supported by macromolecules, that only metaphorically resemble a computer program. It is not that.. (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)

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)

Dissatisfied with the descriptive and speculative methods of evolutionary biology of his time, the physiologist Jacques Loeb , best known for his “engineering” approach to biology, reflected on the possibilities of artificially creating life in the laboratory. With the objective of experimentally tackling one of the crucial questions of organic evolution, i.e., the origin of life from inanimate matter, he rejected claims made by contemporary scientists of having produced artificial life through osmotic growth processes in inorganic salt solutions. According to (...) Loeb, the answer to the question of whether or not life could be created artificially had to come from macro-molecular chemistry, in particular from the research on the recently discovered DNA. He was convinced that a prerequisite for making living matter from inanimate substances was the chemical synthesis of nuclear material capable of self-replication. Moreover, Loeb, experimentally refuting some vitalistic explanations as well as colloidal chemists’ far-reaching claims that biologically relevant macromolecules follow colloidal rather than chemical laws, pioneered research on the physical and chemical explanations of biological phenomena. (shrink)

A fundamental aspect of biological systems is their spatial organization. In development, regeneration and repair, directional signals are necessary for the proper placement of the components of the organism. Likewise, pathogens that invade other organisms rely on directional signals to target vulnerable areas. It is widely understood that chemical gradients are important directional signals in living systems. Less well recognized are electrical fields, which can also provide directional information. Small, steady electrical fields can directly guide cell movement and growth (...) and can generate chemical gradients of charged macromolecules against the leveling action of diffusion. At the site of a lesion in an ion‐transporting epithelium, for example, a substantial electrical field is instantly generated and may extend over many cell diameters. There are numerous other situations in which relatively long‐range electrical fields have been shown to exist naturally. Recently, there has been substantial progress in identifying specific processes that are controlled, to some extent, by these endogenous electrical fields. This review highlights these recent data and discusses possible mechanisms by which the fields might affect biological processes. BioEssays 25:759–766, 2003. © 2003 Wiley Periodicals, Inc. (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 concepts of hierarchical organization, genetic determinism and biological specificity have played a crucial role in biology as a modern experimental science since its beginnings in the nineteenth century. The idea of genetic information and genetic determination was at the basis of molecular biology that developed in the 1940s with macromolecules, viruses and prokaryotes as major objects of research often labelled “reductionist”. However, the concepts have been marginalized or rejected in some of the research that in the late (...) 1960s began to focus additionally on the molecularization of complex biological structures and functions using systems approaches. This paper challenges the view that ‘molecular reductionism’ has been successfully replaced by holism and a focus on the collective behaviour of cellular entities. It argues instead that there are more fertile replacements for molecular ‘reductionism’, in which genomics, embryology, biochemistry, and computer science intertwine and result in research that is as exact and causally predictive as earlier molecular biology. (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)

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)

The concepts of hierarchical organization, genetic determinism and biological specificity have played a crucial role in biology as a modern experimental science since its beginnings in the nineteenth century. The idea of genetic information and genetic determination was at the basis of molecular biology that developed in the 1940s with macromolecules, viruses and prokaryotes as major objects of research often labelled “reductionist”. However, the concepts have been marginalized or rejected in some of the research that in the late (...) 1960s began to focus additionally on the molecularization of complex biological structures and functions using systems approaches. This paper challenges the view that ‘molecular reductionism’ has been successfully replaced by holism and a focus on the collective behaviour of cellular entities. It argues instead that there are more fertile replacements for molecular ‘reductionism’, in which genomics, embryology, biochemistry, and computer science intertwine and result in research that is as exact and causally predictive as earlier molecular biology. (shrink)

Biochemistry and molecular biology have been focusing on the structural, catalytic, and regulatory proper- ties of individual macromolecules from the perspective of clarifying the mechanisms of metabolism and gene expression. Complete genomes of ‘primitive’ living organisms seem to be substantially larger than necessary for metabolism and gene expression alone. This is in line with the findings of silent phenotypes for supposedly important genes, apparent redundancy of functions, and variegated networks of signal transduction and transcription factors. Here we propose that (...) evolutionary optimization has been much more intensive than to lead to the bare minima necessary for autonomous life. Much more complex organisms prevail. Much of this complexity arises in the nonlinear interactions between cellular macromolecules and in subtle differences between paralogs (isoenzymes). The complexity can only be understood when analyzed quantitatively, for which quantitative experimentation is needed in living systems that are as simple and manipulatable as possible, yet complex in the above sense. We illustrate this for the glutamine synthetase cascade in Escherichia coli. By reviewing recent molecular findings, we show that this cascade is much more complex than necessary for simple regulation of ammonia assimilation. Simulations suggest that the function of this complexity may lie in quasi-intelligent behavior, including conditioning and learning. (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)

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 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)

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)

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)

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)

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)

I attempt to define the concept of ‘living organism’. Intuitively, a living organism is a substantial entity with a capacity for certain relevant activities. But biology has discovered that living organisms have a particular compositional or microstructural nature. This nature includes carbon-based macromolecules and water molecules. I argue that such living organisms belong to a natural kind of compound physical object, viz., carbon-based living organism. My definition of a living organism encompasses both the intuitively relevant activities and the empirically (...) discovered compositional nature. The definition is designed to deal with a variety of problem cases, e.g., viruses, proteinoid microspheres, sterile organisms, suspended animation cases, and living parts of organisms. (shrink)

It is widely held that (1) there are autonomous levels of organization above that of the macromolecule and that (2) at least sometimes macromolecular processes are best explained in terms of such autonomous kinds. I argue that molecular developmental biology honors neither of these claims, and I show that the only way they can be rendered consistent with a minimal physicalism is through the adoption of controversial claims about causation and explanation which undercut the force of these two antireductionism claims.

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)

Endothelial cells in culture have, in the past, been a valuable but capricious tool to test hypotheses on the role of components of the blood vessel wall in such functions as blood pressure homeostasis, hemostasis, permeability, transport of macromolecules and the processing of circulating biologically active substances. Now techniques are becoming available for raising long‐term, large‐scale cultures that can be maintained reproducibly and without loss of phenotypic characteristics. The outlook for establishing endothelial cell factories invites speculation on some far‐reaching (...) possibilities, such as endothelial cell banks that could be used for seeding autogenous cells on vascular prostheses, artificial kidney tubing, heart valves, or corneas, or for virus production, or for synthesis by endothelial cells of products at present beyond the reach of bacterial cells. (shrink)

Graphical AbstractScientific illustrations, such as this cross-section through part of an E. coli cell, can give an impression of the complexity of a cell's interior and of the way its macromolecules are arranged.

Phototoxicity frequently occurs during live fluorescence microscopy, and its consequences are often underestimated. Damage to cellular macromolecules upon excitation light illumination can impair sample physiology, and even lead to sample death. In this review, we explain how phototoxicity influences live samples, and we highlight that, besides the obvious effects of phototoxicity, there are often subtler consequences of illumination that are imperceptible when only the morphology of samples is examined. Such less apparent manifestations of phototoxicity are equally problematic, and can (...) change the conclusions drawn from an experiment. Thus, limiting phototoxicity is a prerequisite for obtaining reproducible quantitative data on biological processes. We present strategies to reduce phototoxicity, e.g. limiting the illumination to the focal plane and suggest controls for phototoxicity effects. Overall, we argue that phototoxicity needs increased attention from researchers when designing experiments, and when evaluating research findings. (shrink)

The history of what we call molecular biology today is not just the story of DNA. Molecular biology emerged from and was supported by a multiplicity of widely scattered, differently embedded, and loosely, if at all connected experimental systems for characterizing living beings to the level of biologically relevant macromolecules. By implementing different modes of technical analysis, these systems created a new space of representation in which the central concepts of molecular biology gradually became articulated. The paper describes the (...) establishment of the rat liverin vitro protein synthesis system of Paul Zamecnik and his group a the Collis P. Huntington Memorial Hospital of Harvard University between 1947 and 1952. Insofar as such systems orient the research activity, they may also prove helpful for the orientation of the historian. Experimental systems „have a life of their own. (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)

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 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)

Biology is seen not merely as a privileged oppressor of women but as a co-victim of masculinist social assumptions. We see feminist critique as one of the normative controls that any scientist must perform whenever analyzing data, and we seek to demonstrate what has happened when this control has not been utilized. Narratives of fertilization and sex determination traditionally have been modeled on the cultural patterns of male/female interaction, leading to gender associations being placed on cells and their components. We (...) also find that when gender biases are controlled, new perceptions of these intracellular and extracellular relationships emerge. (shrink)