Guglielmo Militello

This chapter explores how eukaryotic cells achieved new levels of functional integration through the division of their internal space into intracellular membrane-bound compartments. By comparing the internal membranes of prokaryotes and eukaryotes, it argues that these organelles partition the intracellular space in different ways and perform distinct functions, enhancing overall cellular operations. In prokaryotes, constitutive processes primarily occur in the cytoplasm, which exerts near-total control over the microcompartments. In eukaryotes, however, control over these processes is distributed between the cytoplasm and organelles, leading to a more balanced regulation of the cell’s global physiology. These varying modes of control create distinct forms of integration between the cytoplasm and microcompartments.

This chapter explores the role of system-level reproduction in achieving functional integration in biological individuals by analysing and comparing binary fission in bacteria with mitosis in unicellular eukaryotes. It argues that coordinated system-level reproduction necessitates the integration of reproduction, growth, and metabolism. These processes form the physiological foundation for unifying intra- and cross-generational functions, providing insight into the continuity between constitutive processes and reproductive functions. This organisational closure is crucial for establishing physiological and evolutionary individuality, offering a cohesive perspective on what defines a biological individual.

This chapter explores the concept of biological autonomy as interpreted through Maturana and Varela’s autopoietic framework and the organisational account. It examines the type of functional integration necessary for a biological system to achieve autonomy and teleology. The chapter argues that autonomy requires the mechanistic integration of functions contributing to self-maintenance and agential capacities. This integration demands a specific organisation of the system’s components, allowing it to establish its own norms. Consequently, an autonomous system exhibits teleology determined by its internal organisation (internal teleology), rather than by an external agent (external teleology). This distinction between internal and external teleology differentiates organisms from machines. In organisms, functional integration fosters autonomy and internal teleology, whereas in machines, it results in a quasi-autonomous system whose structure and function depend on human social contexts.

Biological regulation is a fundamental characteristic of living organisms, enabling them to satisfy internal physiological needs and adapt to environmental changes. This chapter explores the relationship between biological regulation and functional integration. I argue that there is an organisational closure between the regulatory subsystem (R), the processes responsible for self-maintenance (C), and the signalling subsystem (S). Clarifying the functional integration between R, C, and S has two important explanatory outcomes: firstly, it highlights a fundamental organisational dimension of functional integration shared by both prokaryotes and eukaryotes; secondly, it provides a theoretical basis for understanding the evolution of complexity and the emergence of new forms of functional integration during eukaryogenesis.

This chapter synthesises the findings from the previous eight chapters to define functional integration. It introduces a broad concept of functional integration and critically assesses its explanatory value in understanding eukaryogenesis. Following this, it provides a more precise and robust characterisation of functional integration, exploring its theoretical implications within the ongoing philosophical debate on organismality, individuality, collective organisations, autonomy, major evolutionary transitions, and various forms of collective synchronic organisations. The chapter argues that functional integration arises from four biological dimensions: spatial constraints, system-level regulation, spatio-temporal coordination among the component parts, and system-level reproduction.

This chapter examines three principal theories of eukaryogenesis and elucidates why the transition from prokaryotes to eukaryotes constitutes a major evolutionary transition, as defined by Maynard-Smith and Szathmáry. It argues that these theories, alongside Maynard-Smith and Szathmáry’s framework, offer intriguing insights into this evolutionary process, which remains an enigma. From a philosophical perspective, eukaryogenesis challenges our understanding of how new biological organisations attain a sufficient degree of functional integration to become autonomous, physiological, and evolutionary individuals. Therefore, the concept of functional integration is central to comprehending eukaryogenesis.

This chapter examines how constraints on the motility of individual components—such as symbionts and organelles—within eukaryotic cells affect their autonomous interactive capacities and how this influences the constitutive autonomy of the entire collective association. It argues that while the motility of most symbionts and organelles is controlled by the host, this control is exercised in different ways. Symbionts may lose their motile abilities but retain the capacity to interact autonomously with the host, with interactive processes controlled internally rather than by the host. In contrast, organelles lose their autonomous motility entirely but are moved via cytoskeletal-driven mechanisms controlled by the eukaryotic cell. The chapter contends that the emergence and maintenance of collective biological identities involve stringent regulation of the motile abilities of their constituent parts. This regulation restricts, but does not necessarily eliminate, the agential capacities of individual components.

This chapter introduces the book by examining the critical role of functional integration in both the life sciences and philosophical discourse. In life sciences—encompassing cell biology, evolutionary biology, physiology, and pathophysiology—functional integration describes the causal interconnections among an organism’s components (such as cells, tissues, and organs) that enable systemic functioning. Philosophically, it is central to debates on biological functions, where it underscores the systemic nature of functions, and in discussions about mechanisms, it highlights the interplay between different mechanisms that drive biological activities. Within the debate on biological individuality, functional integration primarily elucidates the physiological aspects of individuality, although its implications for evolutionary dimensions remain less explored. This chapter argues that the interpretation of functional integration varies across contexts, highlighting its multifaceted significance in understanding the complexity of life and individuality.

This chapter explores the structural constraints and physiological mechanisms that enable symbiotic associations among prokaryotes to develop into physiologically integrated organisations. Specifically, it investigates the conditions that facilitate the transformation of endosymbionts into organelles, as exemplified by the evolution of mitochondria and plastids. The chapter argues that biofilms and bacterial endosymbiosis exhibit diverse spatial organisations that impose unique constraints on their constituent organisms, thereby providing distinct mechanisms of collective control. These spatial organisations confer a specific type of stability over time and open up various evolutionary pathways for converting a collective association into an integrated individual. By elucidating key physiological dimensions of functional integration, this chapter contributes to a more precise definition of “functionally integrated individuality”.

This book explores the main biological dimensions underlying functional integration and examines how they contribute to defining a biological individual as both a physiological and evolutionary unit. Functional integration lies at the heart of most definitions of both organisms and biological individuals, making it explanatorily relevant to biology as well as to the philosophy of biology. However, the notion—typically referring to any causal interdependence among biological functions—remains broad and lacks a coherent theoretical framework. This work addresses that gap by focusing on functional integration at the cellular level, which presents both a minimal degree of complexity (relative to multicellular organisms) and maximal conceptual significance for this inquiry. By analysing the transition from prokaryotes to eukaryotes, the book sheds light on how spatial constraints, system-level regulatory mechanisms, spatio-temporal coordination, and system-level reproduction contribute to characterizing biological organization as a functionally integrated physiological unit. This study opens the way for a fresh reflection on the foundations of biological individuality, offering insights not only for researchers, but also for students and non-specialist readers.

Much of the current research in regenerative medicine concentrates on stem-cell therapy that exploits the regenerative capacities of stem cells when injected into different types of human tissues. Although new therapeutic paths have been opened up by induced pluripotent cells and human mesenchymal cells, the rate of success is still low and mainly due to the difficulties of managing cell proliferation and differentiation, giving rise to non-controlled stem cell differentiation that ultimately leads to cancer. Despite being still far from becoming a reality, these studies highlight the role of physical and biological constraints (e.g., cues and morphogenetic fields) placed by tissue microenvironment on stem cell fate. This asks for a clarification of the coupling of stem cells and microenvironmental factors in regenerative medicine. We argue that extracellular matrix and stem cells have a causal reciprocal and asymmetric relationship in that the 3D organization and composition of the extracellular matrix establish a spatial, temporal, and mechanical control over the fate of stem cells, which enable them to interact and control (as well as be controlled by) the cellular components and soluble factors of microenvironment. Such an account clarifies the notions of stemness and stem cell regeneration consistently with that of microenvironment.

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’.

Both physiological and evolutionary criteria of biological individuality are underpinned by the idea that an individual is a functionally integrated whole. However, a precise account of functional integration has not been provided so far, and current notions are not developed in the details, especially in the case of composite systems. To address this issue, this paper focuses on the organisational dimension of two representative associations of prokaryotes: biofilms and the endosymbiosis between prokaryotes. Some critical voices have been raised against the thesis that biofilms are biological individuals. Nevertheless, it has not been investigated which structural and functional obstacles may prevent them from being fully integrated physiological or evolutionary units. By contrast, the endosymbiotic association of different species of prokaryotes has the potential for achieving a different type of physiological integration based on a common boundary and interlocked functions. This type of association had made it possible, under specific conditions, to evolve endosymbionts into fully integrated organelles. This paper therefore has three aims: first, to analyse the organisational conditions and the physiological mechanisms that enable integration in prokaryotic associations; second, to discuss the organisational differences between biofilms and prokaryotic endosymbiosis and the types of integration they achieve; finally, to provide a more precise account of functional integration based on these case studies.

Organoids and organs-on-a-chip are currently the two major families of 3D advanced organotypic in vitro culture systems, aimed at reconstituting miniaturized models of physiological and pathological states of human organs. Both share the tenets of the so-called “three-dimensional thinking”, a Systems Physiology approach focused on recapitulating the dynamic interactions between cells and their microenvironment. We first review the arguments underlying the “paradigm shift” toward three-dimensional thinking in the in vitro culture community. Then, through a historically informed account of the technical affordances and the epistemic commitments of these two approaches, we highlight how they embody two distinct experimental cultures. We finally argue that the current systematic effort for their integration requires not only innovative “synergistic” engineering solutions, but also conceptual integration between different perspectives on biological causality.