This paper focuses on physiological integration in multicellular systems, a notion often associated with biological individuality, but which has not received enough attention and needs a thorough theoretical treatment. Broadly speaking, physiological integration consists in how different components come together into a cohesive unit in which they are dependent on one another for their existence and activity. This paper argues that physiological integration can be understood by considering how the components of a biological multicellular system are controlled and coordinated in (...) such a way that their activities can contribute to the maintenance of the system. The main implication of this perspective is that different ways of controlling their parts may give rise to multicellular organizations with different degrees of integration. After defining control, this paper analyses how control is realized in two examples of multicellular systems located at different ends of the spectrum of multicellularity: biofilms and animals. It focuses on differences in control ranges, and it argues that a high degree of integration implies control exerted at both medium and long ranges, and that insofar as biofilms lack long-range control (relative to their size) they can be considered as less integrated than other multicellular systems. It then discusses the implication of this account for the debate on physiological individuality and the idea that degrees of physiological integration imply degrees of individuality. (shrink)

It is frequently claimed that our species is responsible for climate change, for a new impending mass extinction, for destabilising ecosystems dynamics etc. These claims might be interpreted literally as meaning that it is our species, not merely its constituent organisms, that is causing climate change, biodiversity loss and ecosystem upheaval. Such literal interpretation depends on what kind of answer is given to the general theoretical question concerning whether supra-organismal biological entities such as groups, populations and species can be morally (...) responsible for anything as collectives. I shall argue that organismality is the biological property grounding species collective moral responsibility. The question is thus whether our species is organismal enough to make it a morally responsible causal agent. (shrink)

Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can (...) be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research. -/- . (shrink)

Originating in the work of Ernst Haeckel and Wilhelm Preyer, and advanced by a Prussian embryologist, Wilhelm Roux, the idea of struggle for existence between body parts helped to establish a framework, in which population cell dynamics rather than a predefined harmony guides adaptive changes in an organism. Intended to provide a causal-mechanical view of functional adjustments in body parts, this framework was also embraced later by early pioneers of immunology to address the question of vaccine effectiveness and pathogen resistance. (...) As an extension of these early efforts, Elie Metchnikoff established an evolutionary vision of immunity, development, pathology, and senescence, in which phagocyte-driven selection and struggle promote adaptive changes in an organism. Despite its promising start, the idea of somatic evolution lost its appeal at the turn of the twentieth century giving way to a vision, in which an organism operates as a genetically uniform, harmonious entity. (shrink)

In 2015, Tomasetti and Vogelstein published a paper in Science containing the following provocative statement: “… only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells.” The paper—and perhaps especially this rather coy reference to “bad luck”—became a flash point for a series of letters and reviews, followed by replies and yet (...) further counterpoints. In this paper, I critically assess Tomasetti and Vogelstein's argument, discuss the meaning of “luck” (or, better: “chance”) in the context of the debate, and use this case study to address larger questions about methodological criteria for causal explanations of population level patterns in biomedicine. (shrink)

Twentieth-century theoretical efforts towards the articulation of general system properties came short of having the significant impact on biological practice that their proponents envisioned. Although the latter did arrive at preliminary mathematical formulations of such properties, they had little success in showing how these could be productively incorporated into the research agenda of biologists. Consequently, the gap that kept system-theoretic principles cut-off from biological experimentation persisted. More recently, however, simple theoretical tools have proved readily applicable within the context of systems (...) biology. In particular, examples reviewed in this paper suggest that rigorous mathematical expressions of design principles, imported primarily from engineering, could produce experimentally confirmable predictions of the regulatory properties of small biological networks. But this is not enough for contemporary systems biologists who adopt the holistic aspirations of early systemologists, seeking high-level organizing principles that could provide insights into problems of biological complexity at the whole-system level. While the presented evidence is not conclusive about whether this strategy could lead to the realization of the lofty goal of a comprehensive explanatory integration, it suggests that the ongoing quest for organizing principles is pragmatically advantageous for systems biologists. The formalisms postulated in the course of this process can serve as bridges between system-theoretic concepts and the results of molecular experimentation: they constitute theoretical tools for generalizing molecular data, thus producing increasingly accurate explanations of system-wide phenomena. (shrink)

In an instant classic paper ; 2002: 179–182) biologist Yuri Lazebnik deplores the poor effectiveness of the approach adopted by biologists to understand and “fix” biological systems. Lazebnik suggests that to remedy this state of things biologist should take inspiration from the approach used by engineers to design, understand, and troubleshoot technological systems. In the present paper I substantiate Lazebnik’s analysis by concretely showing how to apply the engineering approach to biological problems. I use an actual example of electronic circuit (...) troubleshooting to ground the thesis that, in engineering, the crucial phases of any non-trivial troubleshooting process are aimed at generating a mechanistic explanation of the functioning of the system, which makes extensive recourse to problem-driven qualitative reasoning possibly based on cognitive artifacts applied to systems that are known to have been designed for function. To show how to translate these findings into biological practice I consider a concrete example of biological model building and “troubleshooting”, aimed at the identification of a “fix” for the human immune system in presence of progressing cancer, autoimmune disease, and transplant rejection. The result is a novel immune system model—the danger model with regulatory cells— and new, original hypotheses concerning the development, prophylaxis, and therapy of these unwanted biological processes. Based on the manifest efficacy of the proposed approach, I suggest a refocusing of the activity of theoretical biologists along the engineering-inspired lines illustrated in the paper. (shrink)

It has long been recognized that cancer onset and progression represent a type of reversion to an ancestral quasi‐unicellular phenotype. This general concept has been refined into the atavistic model of cancer that attempts to provide a quantitative analysis and testable predictions based on genomic data. Over the past decade, support for the multicellular‐to‐unicellular reversion predicted by the atavism model has come from phylostratigraphy. Here, we propose that cancer onset and progression involve more than a one‐off multicellular‐to‐unicellular reversion, and are (...) better described as a series of reversionary transitions. We make new predictions based on the chronology of the unicellular‐eukaryote‐to‐multicellular‐eukaryote transition. We also make new predictions based on three other evolutionary transitions that occurred in our lineage: eukaryogenesis, oxidative phosphorylation and the transition to adaptive immunity. We propose several modifications to current phylostratigraphy to improve age resolution to test these predictions. Also see the video abstract here: https://youtu.be/3unEu5JYJrQ. (shrink)

Evolution exploits the physics of non‐neural bioelectricity to implement anatomical homeostasis: a process in which embryonic patterning, remodeling, and regeneration achieve invariant anatomical outcomes despite external interventions. Linear “developmental pathways” are often inadequate explanations for dynamic large‐scale pattern regulation, even when they accurately capture relationships between molecular components. Biophysical and computational aspects of collective cell activity toward a target morphology reveal interesting aspects of causation in biology. This is critical not only for unraveling evolutionary and developmental events, but also for (...) the design of effective strategies for biomedical intervention. Bioelectrical controls of growth and form, including stochastic behavior in such circuits, highlight the need for the formulation of nuanced views of pathways, drivers of system‐level outcomes, and modularity, borrowing from concepts in related disciplines such as cybernetics, control theory, computational neuroscience, and information theory. This approach has numerous practical implications for basic research and for applications in regenerative medicine and synthetic bioengineering. (shrink)

Editor's suggested further reading in BioEssays: Fields and field cancerization: The preneoplastic origins of cancer Abstract.

Cancer is a singular cellular state, the emergence of which destabilises the homeostasis reached through the evolution to multicellularity. We present the idea that the onset of the cellular disobedience to the metazoan functional and structural architecture, known as the cancer phenotype, is triggered by changes in the cell's external environment that occur with ageing: what ensues is a breach of the social contract of multicellular life characteristic of metazoans. By integrating old ideas with new evidence, we propose that with (...) ageing the environmental information that maintains a multicellular organisation is eroded, rewiring internal processes of the cell, and resulting in an internal shift towards an ancestral condition resulting in the pseudo‐multicellular cancer phenotype. Once that phenotype emerges, a new local social contract is built, different from the homeostatic one, leading to tumour formation and the foundation of a novel local ecosystem. (shrink)

The Somatic Mutation Theory has been challenged on its fundamentals by the Tissue Organization Field Theory of Carcinogenesis. However, a recent publication has questioned whether TOFT could be a valid alternative theory of carcinogenesis to that presented by SMT. Herein we critically review arguments supporting the irreducible opposition between the two theoretical approaches by highlighting differences regarding the philosophical, methodological and experimental approaches on which they respectively rely. We conclude that SMT has not explained carcinogenesis due to severe epistemological and (...) empirical shortcomings, while TOFT is gaining momentum. The main issue is actually to submit SMT to rigorous testing. This concern includes the imperatives to seek evidence for disproving one’s hypothesis, and to consider the whole, and not just selective evidence. (shrink)

Cancer research is experiencing ‘paradigm instability’, since there are two rival theories of carcinogenesis which confront themselves, namely the somatic mutation theory and the tissue organization field theory. Despite this theoretical uncertainty, a huge quantity of data is available thanks to the improvement of genome sequencing techniques. Some authors think that the development of new statistical tools will be able to overcome the lack of a shared theoretical perspective on cancer by amalgamating as many data as possible. We think instead (...) that a deeper understanding of cancer can be achieved by means of more theoretical work, rather than by merely accumulating more data. To support our thesis, we introduce the analytic view of theory development, which rests on the concept of plausibility, and make clear in what sense plausibility and probability are distinct concepts. Then, the concept of plausibility is used to point out the ineliminable role played by the epistemic subject in the development of statistical tools and in the process of theory assessment. We then move to address a central issue in cancer research, namely the relevance of computational tools developed by bioinformaticists to detect driver mutations in the debate between the two main rival theories of carcinogenesis. Finally, we briefly extend our considerations on the role that plausibility plays in evidence amalgamation from cancer research to the more general issue of the divergences between frequentists and Bayesians in the philosophy of medicine and statistics. We argue that taking into account plausibility-based considerations can lead to clarify some epistemological shortcomings that afflict both these perspectives. (shrink)

The building of a global model of carcinogenesis is one of modern biology’s greatest challenges. The traditional somatic mutation theory is now supplemented by a new approach, called the Tissue Organization Field Theory. According to TOFT, the original source of cancer is loss of tissue organization rather than genetic mutations. In this paper, we study the argumentative strategy used by the advocates of TOFT to impose their view. In particular, we criticize their claim of incompatibility used to justify the necessity (...) to definitively reject SMT. First, we note that since it is difficult to build a non-ambiguous experimental demonstration of the superiority of TOFT, its partisans add epistemological and metaphysical arguments to the debate. This argumentative strategy allows them to defend the necessity of a paradigm shift, with TOFT superseding SMT. To do so, they introduce a notion of incompatibility, which they actually use as the Kuhnian notion of incommensurability. To justify this so-called incompatibility between the two theories of cancer, they move the debate to a metaphysical ground by assimilating the controversy to a fundamental opposition between reductionism and organicism. We show here that this argumentative strategy is specious, because it does not demonstrate clearly that TOFT is an organicist theory. Since it shares with SMT its vocabulary, its ontology and its methodology, it appears that a claim of incompatibility based on this metaphysical plan is not fully justified in the present state of the debate. We conclude that it is more cogent to argue that the two theories are compatible, both biologically and metaphysically. We propose to consider that TOFT and SMT describe two distinct and compatible causal pathways to carcinogenesis. This view is coherent with the existence of integrative approaches, and suggests that they have a higher epistemic value than the two theories taken separately. (shrink)

The question of the division of cognitive labor has given rise to various models characterizing the way scientists should distribute their efforts. These models often consider the scientific community as a self-governed sphere constituted by rational agents making choices on the basis of fixed rules. Such models have recently been criticized for not taking into account the real mechanisms of science funding. Hence, the question of the utility of the DCL models in guiding science policy remains an open one. In (...) this paper, we show that two unconsidered dimensions would have to be taken into account. First, DCL studies miss the existence of distinct levels of epistemic objectives organizing the research process. Indeed, the scientific field is structured as a system of hierarchical, interconnected practices which are defined both by their inherent purposes and by various superposed external functions. Second, I criticize the absence of ontological considerations, since the epistemological significance of pluralism is highly dependent on the nature of the object under study. Because of these missing dimensions, current DCL models might have a limited usefulness to identify good practices of research governance. (shrink)

The question of the division of cognitive labor has given rise to various models characterizing the way scientists should distribute their efforts. These models often consider the scientific community as a self-governed sphere constituted by rational agents making choices on the basis of fixed rules. Such models have recently been criticized for not taking into account the real mechanisms of science funding. Hence, the question of the utility of the DCL models in guiding science policy remains an open one. In (...) this paper, we show that two unconsidered dimensions would have to be taken into account. First, DCL studies miss the existence of distinct levels of epistemic objectives organizing the research process. Indeed, the scientific field is structured as a system of hierarchical, interconnected practices which are defined both by their inherent purposes and by various superposed external functions. Second, I criticize the absence of ontological considerations, since the epistemological significance of pluralism is highly dependent on the nature of the object under study. Because of these missing dimensions, current DCL models might have a limited usefulness to identify good practices of research governance. (shrink)

In a previous paper recently published in this journal, we argue that the two main theories of carcinogenesis should be considered as compatible, at the metaphysical, epistemological and biological levels. In a reply to our contribution, Bizzarri and Cucina claim we are wrong since SMT and TOFT are opposite and incompatible paradigms. Here, we show that their arguments are not satisfactory. Indeed, the authors go through the same mistakes that we already addressed. In particular, they confuse reductionism, as an ontological (...) frame, and genetic determinism, as a causal pathway. Beside, they make an inadequate use of the Kuhnian notion of paradigm shift. Finally, we confirm our previous conclusion: there is no strong argument to totally abandon the somatic mutation theory. It describes a partial causal pathway, compatible with the one proposed by TOFT. (shrink)

A major approach to cancer research in the late twentieth century was to search for genes that, when altered, initiated the development of a cell into a cancerous state or failed to stop this development. But as researchers acquired the capacity to sequence tumors and incorporated the resulting data into databases, it became apparent that for many tumors no genes were frequently altered and that the genes altered in different tumors in the same tissue type were often distinct. To address (...) this heterogeneity problem, many researchers looked to a higher level of organization—to mechanisms in which gene products participated. They proposed to reduce heterogeneity by recognizing that multiple gene alterations affect the same mechanism and that it is the altered mechanism that is responsible for the cell developing one or more hallmarks of cancer. I examine how mechanisms figure in this research and focus on two heuristics researchers use to integrate proteins into mechanisms, one focusing on pathways and one focusing on clusters in networks. (shrink)

Contemporary philosophy of science has seen a growing trend towards a focus on scientific practice over the epistemic outputs that such practices produce. This practice-oriented approach has yielded a clearer understanding of how reductive research strategies play a central role in contemporary scientific inquiry. In parallel, a growing body of work has sought to explore the role of non-reductive, or systems-level, research strategies. As a result, the relationship between reductive and non-reductive scientific practices is becoming of increased importance. In this (...) paper, I provide a framework within which research strategies can be compared. I argue that no strategy is reductive or non-reductive simpliciter, rather strategies are more, or are less, reductive than one another according to a frame of reference. That frame of reference is provided by a continuum of possible ways in which the target system might be conceptualised. I illustrate the utility of the framework by deploying it to analyse a recent debate in cancer research. When set within the framework, a prominent reductive strategy—the somatic mutation theory—and a prominent non-reductive strategy—the tissue organisational field theory—do not stand opposed to one another. Rather, they serve as boundary markers to chart the territory of approaches to carcinogenesis within which most strategies in the field fall. (shrink)

Both biosemiotics and evolutionary epistemology are concerned with how knowledge evolves. (Applied) Evolutionary Epistemology thereby focuses on identifying the units, levels, and mechanisms or processes that underlie the evolutionary development of knowing and knowledge, while biosemiotics places emphasis on the study of how signs underlie the development of meaning. We compare the two schools of thought and analyze how in delineating their research program, biosemiotics runs into several problems that are overcome by evolutionary epistemologists. For one, by emphasizing signs, biosemiotics (...) needs to delineate a semiotic threshold, which is a problem not encountered by evolutionary epistemologists. Instead, the latter recognizes that all organisms are knowers that evolve knowledge, which they recognize to extend toward phenomena produced by organisms such as behavior, cognition, language, culture, science, and technology. Secondly, biosemiotics attempts at continuing adaptationist notions on how organisms relate to their environment, while especially Applied Evolutionary Epistemology comes to redefine the nature of the organism–environment relationship in such a way that it recognizes the spatiotemporal boundedness of existence, which in turn makes adaptationist accounts obsolete. (shrink)

In the last decade, Systems Biology has emerged as a conceptual and explanatory alternative to reductionist-based approaches in molecular biology. However, the foundations of this new discipline need to be fleshed out more carefully. In this paper, we claim that a relational ontology is a necessary tool to ground both the conceptual and explanatory aspects of Systems Biology. A relational ontology holds that relations are prior—both conceptually and explanatory—to entities, and that in the biological realm entities are defined primarily by (...) the context they are embedded within—and hence by the web of relations they are part of. (shrink)

The aim of this paper is to provide a theoretical framework to understand how multicellular systems realize functionally integrated physiological entities by organizing their intercellular space. From a perspective centered on physiology and integration, biological systems are often characterized as organized in such a way that they realize metabolic self-production and self-maintenance. The existence and activity of their components rely on the network they realize and on the continuous management of the exchange of matter and energy with their environment. One (...) of the virtues of the organismic approach focused on organization is that it can provide an understanding of how biological systems are functionally integrated into coherent wholes. Organismic frameworks have been primarily developed by focusing on unicellular life. Multicellularity, however, presents additional challenges to our understanding of biological systems, related to how cells are capable to live together in higher-order entities, in such a way that some of their features and behaviors are constrained and controlled by the system they realize. Whereas most accounts of multicellularity focus on cell differentiation and increase in size as the main elements to understand biological systems at this level of organization, we argue that these factors are insufficient to provide an understanding of how cells are physically and functionally integrated in a coherent system. In this paper, we provide a new theoretical framework to understand multicellularity, capable to overcome these issues. Our thesis is that one of the fundamental theoretical principles to understand multicellularity, which is missing or underdeveloped in current accounts, is the functional organization of the intercellular space. In our view, the capability to be organized in space plays a central role in this context, as it enables (and allows to exploit all the implications of) cell differentiation and increase in size, and even specialized functions such as immunity. We argue that the extracellular matrix plays a crucial active role in this respect, as an evolutionary ancient and specific (non-cellular) control subsystem that contributes as a key actor to the functional specification of the multicellular space and to modulate cell fate and behavior. We also analyze how multicellular systems exert control upon internal movement and communication. Finally, we show how the organization of space is involved in some of the failures of multicellular organization, such as aging and cancer. (shrink)

The unpredictability of the development and results of a research program is often invoked in favor of a free, desinterested science that would be led mainly by scientific curiosity, in contrast with a use-inspired science led by definite practical expectations. This paper will challenge a crucial but underexamined assumption in this line of defense of scientific freedom, namely that a free science is the best system of science to generate unexpected results. We will propose conditions favoring the occurrence of unexpected (...) facts in the course of a scientific investigation and then establish that use-inspired science actually scores better in this area. (shrink)