Thomas Pradeu

The aim of this chapter is to address the conceptual, theoretical, and methodological questions bearing on the foundations of today’s life sciences. It discusses the main themes of the philosophy of evolutionary biology, asking what is meant by the idea of adaptation and reviewing the various answers to the units of selection problem. The latter considers on which biological entities—genes, genomes, cells, organisms, groups, species, and so forth—natural selection operates and is a nice illustration of how philosophy of biology situates itself at the frontier between philosophy and the most theoretical parts of biology. The chapter also presents recent debates over the notions of genetic programming and organismal development and the reduction of macromolecular biology to molecular biology.

This chapter raises a traditional philosophical question, that of the definition of the identity of a living thing, and asks whether immunology can shed light on it. The notion of biological identity has in fact two main aspects: uniqueness and individuality. The crucial and specific contribution of immunology concerns biological individuality, because the immune system offers a principle of inclusion, and therefore is critical in delineating the boundaries of the organism at a truly systemic level. Thus, contrary to what many philosophers of biology have long said, a field pertaining to physiology, namely immunology, can offer a theoretical framework to understand biological individuality. I suggest a new definition of the organism as a heterogeneous reality, made of genetically diverse constituents, the unity of which is ensured by the permanent action of the immune system. Finally, I articulate my conception of the immunological individual with current conceptions of evolutionary individuals.

This chapter compares the continuity theory that I propose with the other theories available in today’s immunology, including the self-nonself theory, the systemic theory of the immune “network” (Jerne), the autopoiesis framework (Maturana, Varela, Coutinho), the self-organization theory (Cohen and Atlan), and the danger theory (Matzinger). I emphasize the aspects that the continuity theory borrowed or inherited from these theories, as well as the many aspects on which it differs from them. I show that some frameworks elaborated to understand the immune system are not genuine scientific theories, but rather mere “viewpoints” on immunity. I insist that no framework has, up to now, succeeded in taking into account the importance of both innate immunity and immune tolerance – two aspects that are at the center of the continuity theory.

This chapter offers a new theory in order to explain the triggering of an immune response, called the “continuity theory.” According to this theory, the triggering of an immune response is due to a strong modification of the antigenic patterns with which the organism’s immune receptors continuously interact. The continuity theory is built upon the two observations made in the previous chapter in order to reject the self-nonself theory, that is, normal autoreactivity and immune tolerance. One of the main advantages of the continuity theory is that it gathers under a unique explanation phenomena that have until now received different explanations, and even sometimes _ad hoc_ explanations: immune responses to tumor cells, the phagocytosis of dying cells, or the triggering of immune regulatory mechanisms, among others. I show how the continuity theory explains a wide range of phenomena, and how it can be applied to every organism, including unicellulars.

This chapter offers a critique of the self-nonself theory. I first analyze data on autoreactivity and normal autoimmunity, in particular phagocytosis and regulatory cells, in order to reject the idea that self constituents do not trigger immune responses. In a second step, thanks to a description of immune tolerance to genetically foreign entities, including the fetus and huge amounts of commensal and symbiotic bacteria, I reject the idea that every nonself triggers an immune response of rejection. I show that every organism is “impure” in so far as it contains a great number of “nonself” constituents. I conclude that the self-nonself theory is experimentally inadequate, and conceptually too vague to still be used as a satisfying scientific framework to explain the triggering of immune responses.

This chapter aims at clarifying the notions of self and nonself through a historical analysis. I show that the relationship between immunity and the identity of the organism, as well as the idea that an immune response is due to the penetration in the organism of foreign bodies, both preexist Burnet’s self-nonself framework. The crucial step accomplished by Burnet is that he transformed these apparently self-evident observations in a scientific problem, asking how the organism learns to not attack its own constituents. Explaining the tolerance to the self is thus the starting point of the self-nonself theory. Thanks to a detailed analysis of Burnet’s scientific writings, I demonstrate the link between the self-nonself framework and Burnet’s famous clonal selection theory. I make clear how the very conception of the self changed significantly throughout Burnet’s scientific reflection. Finally, I show that the self-nonself theory is still dominant in today’s immunology.

This chapter investigates the different definitions of immunology, in particular the dominant definition stating that immunology is the discipline that studies the defense of organisms against pathogens. The different steps towards the autonomy of immunology as a discipline are examined, from immunization to the elaboration of a theory of immunity, and eventually the institutionalization of the domain. I propose my own definition of immunology as the discipline that studies specific interactions between immune receptors and antigenic patterns, triggering mechanisms that destroy or prevent the destruction of target antigens. I show that, contrary to what has long been believed, every organism has an immune system. I describe several examples of immune systems (in mammals, insects, plants, and even unicellulars). I close this chapter by an analysis of the concepts generally considered as central in immunology, those of “self” and “nonself.”

The general question of biological identity has two main aspects, uniqueness (what makes each living thing unique?), and individuality (what ensures that a living thing remain “itself” while constantly changing?). Contemporary immunology, dominated by the concepts of self and nonself, considers these two questions as its province. An important task is to assess this assertion. This chapter defines the two questions of uniqueness and individuality, and explains how immunologists claim to respond them. It emphasizes the necessity to define more precisely the notions of self and nonself, and to articulate the immunological perspective on biological uniqueness and individuality with other biological perspectives, in particular the evolutionary one.

Functional ascription in biology is contentious, particularly when it takes a teleological form, that is, when the question being raised is the “purpose” of a biological item (a trait, an organ, or a system). Is it legitimate to ask what a trait, an organ, or a system is “supposed to do”? Traditional physiological “systems” (digestive, respiratory, and so on) are a typical case of functional ascription: it is often said, for example, that the function of the digestive system is to ensure digestion. More specifically, among biological systems, the immune system has been used in the literature on biological functions as a paradigmatic example of functional ascription in a teleological sense (Matthen M, Levi E, J Philos 81(7):351–372, 1984; Melander P, Philos Sci 60(2):223–241, 1993). One important corollary of that analysis is that autoimmune diseases have been seen as an example of a dysfunction: when an autoimmune disease occurs, the argument goes, we can say that the immune system does not do what it is “supposed to do.” The aim of this chapter is to put into question the usefulness of this etiological approach to the immune system and to defend instead a systemic approach to the immune system.

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

Is it possible, and in the first place is it even desirable, to define what "development" means and to determine the scope of the field called "developmental biology"? Though these questions appeared crucial for the founders of "developmental biology" in the 1950s, there seems to be no consensus today about the need to address them. Here, in a combined biological, philosophical, and historical approach, we ask whether it is possible and useful to define biological development, and, if such a definition is indeed possible and useful, which definition can be considered as the most satisfactory.

Cancer is most commonly viewed as resulting from somatic mutations enhancing proliferation and invasion. Some hypotheses further propose that these new capacities reveal a breakdown of multicellularity allowing cancer cells to escape proliferation and cooperation control mechanisms that were implemented during evolution of multicellularity. Here we critically review one such hypothesis, named “atavism,” which puts forward the idea that cancer results from the re‐expression of normally repressed genes forming a program, or toolbox, inherited from unicellular or simple multicellular ancestors. This hypothesis places cancer in an interesting evolutionary perspective that has not been widely explored and deserves attention. Thinking about cancer within an evolutionary framework, especially the major transitions to multicellularity, offers particularly promising perspectives. It is therefore of the utmost important to analyze why one approach that tries to achieve this aim, the atavism hypothesis, has not so far emerged as a major theory on cancer. We outline the features of the atavism hypothesis that, would benefit from clarification and, if possible, unification.

The unexpected roles of the microbiota in cancer challenge explanations of carcinogenesis that focus on tumor-intrinsic properties. Most tumors contain bacteria and viruses, and the host’s proximal and distal microbiota influence both cancer incidence and therapeutic responsiveness. Continuing the history of cancer–microbe research, these findings raise a key question: to what extent is the microbiota relevant for clinical oncology? We approach this by critically evaluating three issues: how the microbiota provides a predictive biomarker of cancer growth and therapeutic responsiveness, the microbiota’s causal role(s) in cancer development, and how therapeutic manipulations of the microbiota improve patient outcomes in cancer. Clarifying the conceptual and empirical aspects of the cancer-associated microbiota can orient future research and guide its implementation in clinical oncology.

In this contribution, I show that Jean Gayon’s work operates an original synthesis between the history of scienceHistory of science, the philosophy of science and the life sciences. I propose that the philosophy of biology as it has been constructed since the 1970s could usefully draw inspiration from this synthesis to develop a much richer and more open analysis of current biological sciences. While the philosophy of biology is very strongly dominated by the biology of evolution, the history of biologyGayon, Jeanon the history of biology has opened up to practically all the major fields of contemporary biology (for example, cell biology, molecular biologyMolecular biology, or virology, among many others). Perhaps Jean Gayon’s work is an invitation to draw inspiration from this thematic diversity to construct a new philosophy of biology and, beyond that, a new synthesis between philosophy, history, and biology.

Resident microorganisms, known as the microbiota, are essential for many physiological functions including protection against pathogens. Microbiota is indeed required for proper immune system development and function, and can also host-independently protect against infections. Thus, a co-constructed view of host protection involving both host and microbiota, named ’co-immunity,’ has been proposed, and the idea of an ’immunological holobiont’ has been suggested. Yet this view of co-immunity might be too limited, as experimental work has shown that the immune system is involved in functions other than protection, essentially development and repair. Microbiota, through co-immunity, is thereby most likely involved in these functions, although strong evidence is currently lacking. Moreover, as our point of view is mainly host-centered, we may miss the implications of co-immunity at broader scales, including cellular and population levels. Intriguingly, co-immunity effects could be beneficial for one function and/or one level, while being detrimental for others. All these elements should be taken into consideration for microbiota manipulation, in order to avoid potentially harmful side effects.

Since, it has become clear that individuality is not to be considered as a given, but rather as something which needs to be explained. How has individuality emerged through evolution, and how has it subsequently been maintained? In particular, why is it that multicellular organisms appeared and persisted, despite the obvious interest of each cell of favoring its own replication? Several biologists see the immune system as one of the key components for explaining the maintenance of multicellular organisms’ individuality. Indeed, the immune system exerts a constant surveillance on all the constituents of the organism, including “cheaters” like tumor cells, which favor their own replication at the expense of the whole organism. In most cases, the immune system eliminates those cheaters. This is the “immune surveillance” hypothesis, first suggested by Burnet and Thomas. In this paper, I account for recent findings on immune surveillance in order to determine the precise role of the immune system in the emergence and maintenance of individuality. This investigation gives rise to a critical question for the domain of biological individuality: should immunity be considered as something unique to multicellular organisms? If it is indeed unique, should the multicellular organism be considered as an individual to a higher degree than any other living entity? If it is not unique, what precisely are the equivalents of the immune system in other living individuals?

The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome—the metagenome—are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host‐centric methods. Furthermore, the discoveries of intracellular and intra‐metastatic cancer bacteria necessitate fundamental changes in describing clonal evolution and selection, reflecting bidirectional interactions with non‐human residents. Reconsidering cancer clonality as a multispecies process similarly holds key implications for understanding metastasis and prognosing therapeutic resistance while providing rational guidance for the next generation of bacterial cancer therapies. Guided by these new findings and challenges, this Review describes opportunities to exploit cancer's metagenome in oncology and proposes an evolutionary framework as a first step towards modeling multispecies cancer clonality. Also see the video abstract here: https://youtu.be/-WDtIRJYZSs.

Most philosophers of science do philosophy ‘on’ science. By contrast, others do philosophy ‘in’ science (PinS), that is, they use philosophical tools to address scientific problems and to provide scientifically useful proposals. Here, we consider the evidence in favour of a trend of this nature. We proceed in two stages. First, we identify relevant authors and articles empirically with bibliometric tools, given that PinS would be likely to infiltrate science and thus to be published in scientific journals (‘intervention’), cited in scientific journals (‘visibility’), and sometimes recognized as a scientific result by scientists (‘contribution’). We show that many central figures in philosophy of science have been involved in PinS, and that some philosophers have even ‘specialized’ in this practice. Second, we propose a conceptual definition of PinS as a process involving three conditions (raising a scientific problem, using philosophical tools to address it, and making a scientific proposal), and we ask whether the articles identified at the first stage fulfil all these conditions. We show that PinS is a distinctive, quantitatively substantial trend within philosophy of science, demonstrating the existence of a methodological continuity from science to philosophy of science.

In this paper, we provide a macro level analysis of the visibility of philosophy of science in the sciences over the last four decades. Our quantitative analysis of publications and citations of philosophy of science papers, published in 17 main journals representing the discipline, contributes to the longstanding debate on the influence of philosophy of science on the sciences. It reveals the global structure of relationships that philosophy of science maintains with science, technology, engineering and mathematics and social sciences and humanities fields. Explored at the level of disciplines, journals and authors, this analysis of the relations between philosophy of science and a large and diversified array of disciplines allows us to answer several questions: what is the degree of openness of various disciplines to the specialized knowledge produced in philosophy of science? Which STEM and SSH fields and journals have privileged ties with philosophy of science? What are the characteristics, in terms of citation and publication patterns, of authors who get their philosophy of science papers cited outside their field? Complementing existing qualitative inquiries on the influence of specific authors, concepts or topics of philosophy of science, the bibliometric approach proposed in this paper offers a comprehensive portrait of the multiple relationships that links philosophy of science to the sciences.

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.