Cells and Their Organelles as a Testing Ground for Process- and Substance-Based Ontologies in Biology

Abstract

Recently, a shift from substance-based to process-based ontologies of living beings and biological entities has been widely advocated, largely on the grounds that traditional substance thinking, by encouraging biological reductionism, fails to adequately capture the nature of biological wholes. Process-based approaches are instead taken to provide a more appropriate metaphysical framework for the constitutive dynamicity of living systems. These arguments, however, have been criticized for relying on overly reductive characterizations of substances, which both classical and contemporary accounts describe as inherently involving change and activity. In this essay, I address the substance-versus-process debate from the perspective of contemporary cell biology. I argue that conceiving the cell as a substance is not only compatible with the centrality of processes, but that the cell continues to function as the fundamental reference point in biology precisely because it entails processuality as intrinsic to its dynamic mode of being. Within this framework, subcellular entities are identified by their functional subservience to the cellular whole. On this basis, I propose an empirically grounded criterion for distinguishing between purely processual and substance-like subcellular entities. Processual entities, such as the Golgi complex and the nucleolus, lack dedicated repair systems and tend to disassemble upon inhibition of specific metabolic activities. By contrast, substance-like entities, including cell-derived organelles such as the mitochondrion and the nucleus, depend for their persistence on specific repair systems, and their eventual dismantling under non-permissive conditions cannot be straightforwardly understood as the mere interruption of a process, but instead appears as the outcome of an active, regulated response.

1. Introduction

A contemporary school of thought in philosophy of biology, inspired by the tenet that in nature processes are ontologically more fundamental than things, proposes a processual view of living entities whereby, following both philosophical and empirical considerations, they should be taken to be processes rather than substances. According to its proponents, such a theoretical move entails a reversal of the commonly held, substantialist position, that takes processes as necessarily involving the doings of underlying substances, to a position that, by regarding dynamicity as the fundamental feature of reality, thinks of things/substances as being derived from, and thus ontologically subordinate to, processes [2]. Notably, in the intention of proponents, a processual metaphysics, conceiving reality (and the living world within it) as made up of dynamic patterns of interrelated events rather than a hierarchically ordered set of discrete entities endowed with relation-independent properties, has the advantage of counteracting the temptations of reductionist and mechanist views of organisms as complex machines whose meaning and rationale are entirely attributable to the nature of their components. In so doing, processual thinking in biology is thought to warrant a more suitable metaphysical foundation for the constitutively dynamic and relational nature of living entities as revealed by contemporary systems views in biology [2,3,4].

The need to discard substance metaphysics in order to establish an ontology of living entities that accounts for their constitutive dynamism and relationality has been questioned by several authors, mainly on the basis of two types of arguments. According to the first line of arguments, the characterizations of substance against which the need for a processual turn is invoked are reductive ones, as they do not capture some fundamental elements of both traditional and contemporary accounts of substance. In particular, while the processual ontology advocates claim that substances (or ‘things’) have stasis as their default state, and are thus unsuitable to grasp the intrinsic dynamicity of living entities [2,5,6], the defenders of substance ontology point out that the hylomorphic tradition has never supported the idea that substances are static; quite on the contrary, living entities are paradigmatic substances precisely because the determination of what they are is due to a principle of activity (substantial form) warranting persistence through change [7,8]. The view of substances as static entities has been attributed to a general underappreciation, by contemporary critics of substance metaphysics, of the dynamic aspect of Aristotelian ontology emphasized by the Aristotelian theory of potency and act [9] (pp. 201–202). A second line of arguments against the supposed need for abandoning substance thinking in favor of a processual reconceptualization of organisms focuses on the difficulties that a radical processualism encounters in accounting for the unity and distinctness of living particulars without borrowing from the substance ontology framework some of the principles it purports to replace [10]. Further blurring the dividing line between ‘processual’ and ‘substantial’ perspectives on living entities, recent accounts of the being and identity of organisms developed within contemporary strands of neo-Aristotelian thought are positively identifying, within the framework of Aristotle’s hylomorphism, the conceptual resources to make sense of organisms as irreducibly processual entities, where substantial form serves as an intrinsically dynamic principle of diachronic unity [11,12,13].

The current debate on the two ontological frameworks of organisms, whose theoretical opposition and intertwining have been briefly outlined above, obviously takes into account the main discoveries of contemporary biology. In particular, research progresses in biochemistry, molecular biology and developmental biology have revealed to an unprecedented degree of detail the intricate networks of molecular components that are continuously at work in living beings and support their unique performance, thus revealing the enormous difficulties of understanding organisms starting from their molecular constituents, as envisaged by the reductionist bioscience agenda. The emergence and growth of systems biology in the last 25 years has gone hand in hand with the ambition to push the limits of classical molecular biosciences through a variety of approaches, ranging from systematic collection and computational integration of biological big data to the development of novel formal systems theories of biological entities [14]. Remarkably, these recent developments occurred within a tacitly pre-established metaphysical framework characterized by the unproblematic coexistence in living organisms of a pervasive processuality together with forms to whose maintenance all processes contribute. The emphasis given to one or the other of these two aspects has accompanied biology during the last century, through the paths of two intellectual currents which, opposed to each other in the mid-twentieth century, have merged for several decades now: molecular biology, emphasizing growth and replication of biological forms and drawing initial inspiration from the ability of crystals to template themselves, and biochemistry, emphasizing the constant flux of metabolism as the hallmark of living organisms and relying on the whirlpool metaphor [15]. Significantly, the use of the term ‘form’ to indicate what makes a biological entity identifiable as such is documented both in early views of organisms as entities in constant flux (Cuvier claimed that “the living being is a whirlpool constantly turning in the same direction, in which matter is less essential than form”; cited in [15]) and in contemporary process-oriented views of biological entities (“Any given cell or any given tissue instantiates a dynamic steady state, only the form of which persists, while its material constitution is constantly being turned over by metabolic events” [2]). Evidently, there are different senses in which the term ‘form’ is used in contemporary philosophy of biology. Within a neo-Aristotelian perspective, ‘form’ refers to substantial form as an irreducible principle underlying unity and individuation of organisms [16]; by contrast, in radically processual views of organisms (also embracing human persons) form, while being recognized as a principle warranting synchronic and diachronic organismal identity, is itself attributed a processual nature, and thus considered as being in flux like the lower-order processes of which it is the form [17].

The current persistence of opposing metaphysical approaches to looking at organisms, together with the presence of contemporary theoretical positions that do not take the views of organisms as hylomorphic substances and processual entities as necessarily conflicting (see for example [12,13]), testify to the need of a more systematic and in-depth comparison of ontological paradigms with the knowledge of organisms and biological organization as it has accumulated and evolved especially during the last century. Ideally, such a scrutiny should take into account not only the body of biological knowledge gained empirically, but also the tacit (and possibly pre-reflective) pre-conditions of such a knowledge which, especially in the case of the inquiry into the phenomenon of life, cannot fail to include our experience of being alive2.

This essay intends to be a first attempt at such an investigation, which will be focused on contemporary molecular cell biology as a paradigmatic field. In fact, in spite of the centrality of the cell theory in biology since its formulation in the nineteenth century [20], of the broad consensus in considering the unicellular state as the minimal form of organismal life, and of the impressive amount of empirical knowledge now available on cellular organization and dynamics, philosophical investigations, and in particular the current debate about substance or process nature of living entities, were not mainly focused on cell, or at least not in a systematic way [21] (for notable exceptions, see [22,23,24,25]).

Taking the cell as the minimal cohesive whole in which an organism can be instantiated, and drawing on the vast body of knowledge about its organization and dynamics, characterized by the interweaving of what are generally called cellular processes, I will address the general questions of which ontological framework can best account for the distinctive characteristics of the cell as a unitary whole and for the processes that contribute to its maintenance. Can a cell be treated more perspicuously as a substance or as a process? And how can the ontological status of subcellular organelles and biological macromolecules best be placed within these frameworks? I will present arguments in favor of the thesis that the cell conceived as a substance is not only compatible with the centrality of processes, but it continues to serve as the fundamental reference in biology precisely because it entails the category of process as a fundamental factor of its own dynamical being. In contrast, conceiving the cell as a process, although formally possible (given the full docility to thermodynamics of the cell as a physical object), suffers from the ultimate lack of a criterion of cell identity that is free from circularity (i.e., not colluding with the same substantialist thinking that should be programmatically banned). Due to such a lack, it becomes difficult/arbitrary, in a purely processual perspective, to establish any hierarchy of lower- and higher-order processes, any priority on which (nested) process should be considered functional/subservient to which other, with the extreme consequence of a vanishing of the cell as something that deserves explanation more than any other process traceable in the same space-time environment. Unlike the whole cell, a number of subcellular organelles (e.g., the Golgi complex) can instead best be conceptualized as manifestations of ongoing intracellular processes contributing to the overall self-organizing, dynamic architecture of the cell [25], while other organelles (e.g., the mitochondria) are better conceived as substance-like, consistent with their derivation from ancestral autonomous cells.

In support of a metaphysical perspective recognizing cells as substantial entities3 enduring throughout replacement of their parts and featuring specific principles of change and being unchanged, I will draw from current literature in molecular cell biology, in particular regarding the identity and dynamics of the cell as a whole and of various subcellular organelles, with the specific aim to highlight empirical landmarks possibly allowing to distinguish substance-like and processual entities in the subcellular world. I propose that one such landmark is the presence, in the former but not in the latter case, of active repair responses to damage, such that the fact of persistence is best comprehended as an ongoing act of self-restoration. Another landmark, not unrelated to the previous one, is the way in which the entity meets its end as a result of disturbances that are not compatible with its persistence: process-like entities disappear by passively undergoing interruption, while substance-like entities tend to actively undertake death and corruption as a self-determined fate.

2. Centrality of the Cell and Diversity of Subcellular Organelles

The cell is one of the most important unifying concepts in biology. The tenets that all living organisms are composed of one or more cells, and that all cells without exception come from pre-existing cells, have never been contradicted by any empirical observation. Of particular relevance is the largely shared idea that the simplest living individuals are unicellular, an idea corroborated by the fact that life on Earth has been exclusively unicellular for at least 2 billion years, before the first multicellular organisms appeared [26]. As a consequence, the cell is considered as the basic unit of any form of life, and it is by studying cellular composition, structure, activities and behavior that the basic questions of what life is and how it works can be most appropriately addressed (see for example [27], p. 1). In other words, the cell is the level of organization of living entities that more than any other proved to be fundamental for a scientific interpretation of the phenomenon of life. In further support of its centrality, the existence of unicellular organisms makes the cell the simplest level at which an organism can become intelligible as an autonomous whole4.

The biosphere hosts an impressive variety of unicellular organisms, which can be divided into two major domains of prokaryotes and eukaryotes. Prokaryotes, in turn, are divided into Bacteria and Archaea, corresponding to unique evolutionary lineages. Complex multicellularity, typical of organisms with many specialized cell types such as multicellular animals (Metazoa) and land plants, evolved exclusively from unicellular eukaryotes. The most prominent distinguishing feature of prokaryotic and eukaryotic cells is the presence in the latter of a nucleus acting as a haven for the genetic material three-dimensionally organized and compacted in the form of chromatin. While the average bacterial and archaeal cells tends to be structurally simple and to lack internal compartmentalization, the inside of eukaryotic cells contains a nucleus delimited by a discontinuous double membrane envelope, a complex endomembrane system including the endoplasmic reticulum (ER), which is in continuity with nuclear envelope, the Golgi complex and the endosomal compartments, as well as a few types of additional membrane-bound organelles including mitochondria, lysosomes, peroxisomes, chloroplasts (specific to plants and algae), vacuoles and other more specialized organelles.

The delimitation of the nucleus with respect to the rest of the cell, which is thus collectively called cytoplasm, is peculiar, in that it is constituted by a double membrane envelope that can be topographically depicted as a particularly flattened district or section of the ER specialized in segregating the genomic DNA, all the proteins associated with it and all the primary products of DNA transcription in a controlled environment, the nucleoplasm. The nucleoplasm, however, is in continuous communication with the cytoplasm through large multiprotein structures, the nuclear pores, that are permeable to all small molecules and ions, but extremely selective for the nucleo-cytoplasmic traffic of macromolecules (proteins and RNA) [30] (pp. 614–620). A significant component of this traffic consists of the export of messenger RNA (mRNA), which ensures the continuous delivery of templates for translation in the cytosol, where protein synthesis specifically takes place thanks to the presence of a complex translation apparatus whose most prominent component is the ribosome, composed of a few large RNAs and dozens of associated proteins.

Historically, the term organelle was used with reference to intracellular structures identifiable by light or electron microscopy. With this criterion, even intracellular formations not delimited by a membrane, such as the centrosome and the nucleolus, have been generally referred to as organelles up to the present day. The list of membrane-less organelles has recently grown considerably, to include more or less dynamic biomolecular condensates whose boundary layer is phase-defined and in which specific, functionally related macromolecules are segregated [27] (pp. 688–694). Even though prokaryotic cells are much less compartmentalized than their eukaryotic counterparts, advances in imaging technologies have recently revealed a diverse array of subcellular organelles in both bacterial and archaeal prokaryotes [31,32].

The analogy between subcellular organelles and sub-organismal organs is obvious. In both cases, the etymological origin from Latin organum (Greek organon), meaning instrument, that which performs some function, recalls a relationship of subservience, whereby the organ/organelle carries out specific tasks that contribute to the correct functioning of the whole. Accordingly, just as organs are clearly defined by the functions they perform within the organism, organelles are often identified—sometimes more clearly than by their morphology—by the specific roles they play within the cell, frequently serving as sites where particular cellular processes are spatially segregated. The analogy with the body of organisms such as ourselves is clear also in the case of the so-called cytoskeleton, an array of interconnected and more or less dynamic protein filaments essential for cell shape maintenance, cell motility and the ordered internal segregation of organelles [30] (pp. 752–755), in close resemblance to the functions of our musculoskeletal system.

The cell turned out to be the elementary constitutive unit of biological organization even in the case of highly integrated systems like the nervous system, for whom an anatomically discontinuous structure based on discrete cells certainly did not appear as something intuitive at the time of its discovery [33]. In truth, neurons exemplify to the highest degree the astonishing possibilities of morphological and functional specialization of the cell [34], thus confirming its unique versatility in the constitution of all living entities and in the foundation of all biological phenomena.

Further supporting the idea that the most distinctive organismal features can be found recapitulated in a single cell, the influential theory of autopoiesis saw the cell as the minimal instantiation of living autonomy entailing the instauration of an inner source of individual self-concern and basic cognition [35]. Likewise, a recent trend in biological theory proposes that even bacteria and unicellular eukaryotes possess capacities generally encompassed by the concepts of cognition [36] and sentience [37], and that an elementary form of intrinsic intentionality and goal-directedness is embodied by each of the cells composing multicellular organisms [38]. Intentionality and goal-directedness are also key concepts in the recent increasing emphasis on organismal agency [39], which has been claimed to be minimally displayed by a single intact, functioning cell [40].

More phenomenologically informed philosophical accounts, which emphasize the inward dimension of organisms, also consider unicellular life as the simplest instantiation of a deep continuity of life and mind [41] (pp. 128–165). According to other non-physicalist frameworks, emphasizing the foundational character of semiosis in the living world, the single cell has been accorded the status of a real semiotic system consisting of signs, meanings and codes [42], and it has been recognized as the simplest instantiation of vegetative semiosis/protosemiosis [43,44], or as the simplest occurrence of the subject-object (or, more broadly, symbol-matter) distinction which grounds the very possibility of phenomena [45].

Perhaps the universal cellular structure contributing most to the identification of the cell as an entity endowed with ontological autonomy is the plasma membrane, which gives physical form to cellular individuality. This is achieved by the membrane’s ability to close on itself three-dimensionally, enclosing a content and thus creating a separation between an inside and an outside. The fundamental feature of cellular membranes is their organization as a lipid bilayer in which many different proteins are embedded. All cell membranes display asymmetry, both in protein topology and in lipid distribution, and they are formed and maintained from within the cell itself. The lipid component of the membrane impairs non-specific membrane crossing by water, ions and most hydrophilic molecules, while some membrane proteins act as specific transporters of small chemical species thus giving rise to selective permeability profiles on which the composition of the inner milieu depends. Other membrane proteins act as surface receptors whose specific interaction with signal molecules in the cell’s surroundings profoundly influences cell behavior by activating signal transduction pathways [30] (pp. 444–467). Furthermore, specific sets of proteins acting as ion channels make cell membranes capable of excitability, which gives certain types of cells the ability, based on transient variation in ion flow permeability, to sense and respond to stimuli within milliseconds, thus laying the ground both for irritability of unicellular eukaryotes like Protozoa and for perception, neural cognition and motor activity in Metazoa [46]. Plasma membrane is thus an extremely thin yet actively selective interface constituting both a physical and a relational boundary between what can unambiguously be considered the intracellular and extracellular environments, with membrane asymmetry being fundamental for its boundary function. Significantly, in the autopoietic/enactive account of cellular autonomy, it is at the level of the plasma membrane that the cellular network closure to selfhood, and correlative otherness, are thought to happen [41] (pp. 48–49). Similarly, in a biosemiotic perspective, the presence and maintenance through endogenous biogenesis of cell membranes actively separating an inside and an outside has been conceptualized as a semiotic bridge between a cellular self and its world [47] (pp. 28–38).

In addition to the plasma membrane that surrounds the entire cell, eukaryotic cells also possess a large number of intracellular membrane-bound organelles. In this case, the membrane guarantees the existence of these organelles as individual compartments, with a specific composition different from that of the cytoplasmic milieu and of other organelles. Like plasma membrane, organellar membranes also contain specific transport and receptor proteins, influencing the composition and activity of organelles so as to harmonize their behavior with the one of the cell as a whole. Therefore, to some extent membrane-bound organelles are entities for which there is a key individuation factor, the membrane, similar to that of the plasma membrane delimiting the entire cell. More subtly, just as cellular processes can be studied and grasped in their biological significance only if placed in the natural context of a membrane-bound cell, similarly the appreciation of the intracellular architecture which rests on the internal membrane compartments, as well as on the cytoskeleton, is highly relevant for a full understanding of key intracellular processes (such as protein secretion), as it constitutes a complex interplay of constraints which delimit, and at the same time enable, the integrated action of biological macromolecules resulting in cell functions [48].

Two organelles, mitochondria and chloroplasts, have peculiar characteristics (e.g., a double membrane) linked to their evolutionary origin. According to the popular endosymbiont hypothesis, mitochondria are thought to derive from an ancient aerobic bacterium engulfed by an archaeon thus allowing for the emergence of a cellular lineage precursor of all extant eukaryotes [49]. Chloroplasts are also thought to have evolved from bacteria by endosymbiosis, involving a fully fledged eukaryotic cell and its cyanobacterial host [50]. In accordance with their origin, mitochondria and chloroplasts display cell-like features, the most evident of which is that they contain their own DNA genome carrying a small number of residual genes resembling bacterial genes, whose transcription and subsequent translation are carried out inside the organelles by organellar gene expression machineries resembling the bacterial ones [30] (pp. 523–526).

There is a massive and highly regulated exchange of macromolecular material between the different cell compartments and the cell membrane, which mostly relies on a sophisticated trafficking system based on the specific sorting of membrane-enclosed vesicles. Intracellular sorting is mainly devoted to the specific targeting of proteins to the subcellular compartments in which they exert their function. Vesicle trafficking is responsible for the sorting of proteins destined for the plasma membrane, for the ER, Golgi complex and other organelles connected to them, or for secretion into the extracellular space. The mRNA-templated synthesis of these proteins is carried out by ribosomes that, after translation initiation, are directed by the nascent protein to the membrane of the ER, to allow for the co-translational translocation of the protein into the lumen or the membrane of the ER itself. But several other vesicle-independent protein-sorting strategies are continuously put into action to deliver newly synthesized nuclear, mitochondrial, chloroplastic and peroxysomal proteins from their site of synthesis in the cytosol to their specific destination [30] (pp. 576–621).

In the summary description above, which reflects a consolidated body of knowledge reported in much greater detail in current cell biology textbooks and articles, and inspiring countless active fronts of biological research, the cell plays the role of a microcosm, delimited by an environment-sensitive boundary and populated by clearly identifiable substructures, in which thousands of interconnected processes, involving myriads of biological macromolecules, acquire their meaning. In describing a cell and its organization, it seems inevitable to employ the language used for material objects. Cells, subcellular organelles, biological macromolecules are generally treated as things by biologists. In standard laboratory practice they can be isolated, purified, individually analyzed both biochemically and morphologically. No particular efforts are made to define and possibly differentiate their ontological status; what matters is being able to single out and manipulate them in order to understand their biological function. In recent process-philosophical accounts, organelles are “but fleeting manifestations of ongoing processes of material exchange”, and the same view is extended to cells, tissues, organs and ultimately whole organisms, that are all taken to be fundamentally instantiations of dynamic steady states [2,4]. Therefore, on the one hand the scientific discourse and practices of investigators in cell biology tend to treat cells, organelles, macromolecular complexes and macromolecules as things endowed with their own individuality, without worrying about introducing ontological distinctions between them, and tend to conceptualize cellular processes as causally connected series of reactions, involving a great variety of biological macromolecules, whose significance is fundamentally linked to some ending state (e.g., photosynthesis, cell division, DNA repair, and regulated cell death). On the other hand, the ontological status of cells and subcellular entities has been the subject of reflection especially by process philosophers of biology, who tend to include them all in the category of process, differentiating them from each other only by their ‘higher’ or ‘lower’ positioning in an all-encompassing hierarchy of intertwined and mutually dependent processes actively maintained at different timescales [2,5].

In the following sections, I will try to identify the basis for an ontological distinction of these biological entities (in particular of cells and subcellular organelles), which satisfactorily explains the fact that we cannot avoid conceptualizing organelles as subservient to the cell to which they belong, if we do not want to lose sight of the nature of both. To this end, in Section 3 I will compare the two perspectives, processual and ‘substantial’/hylomorphic, for their robustness, autonomy and shortcomings in accounting for aspects of the cellular microcosm depicted in the preceding Sections, by mainly focusing on eukaryotic cells. Given the complexity and plurality of views present even within individual schools of thought, I will base my discussion mainly (but not exclusively) on the recent, influential collection of articles entitled “Everything flows: towards a processual philosophy of biology” [51], exploring from different angles, and overall supporting, the metaphysical thesis that the biological world is fundamentally constituted by processes, and on recent attempts to conceptualize biological entities within a neo-Aristotelian, hylomorphic perspective centered on substantial form as an irreducible metaphysical posit warranting both the identity and the dynamic self-achievement of the organism [9,12,13,52,53]. A relevant reason to compare the recently revived processualist and substantialist paradigms on the test ground of cell biology is that both paradigms appear to be motivated by the need to overcome the limits of biological reductionism, whereby the properties of organisms would be ultimately determined by the properties and activities of their basic components through bottom up causation (see for example [2,13]), and both of them tend to take the tenets and acquisitions of systems biology as an invitation to adopt their (metaphysically distinct if not opposed) conceptions of the dynamicity lying at the heart of organismal being (see for example [6,11]).

3. Comparing the Suitability of Process and Substance Metaphysics for Grounding a Non-Reductive Understanding of the Cell

3.1. Unique Features of the Cell

Taking the cell as the simplest instantiation of a fully accomplished organism, the main aim of the following discussion is to explore the possibility of providing a metaphysical account of cells and their constituents, as empirically revealed by cell biology, capable of supporting a non-reductionist, non-mechanistic view of them without losing sight of the way of thinking of biologists, and in particular their implicit reliance on experiencing the organism as the fundamental explanandum [54]. As recently reiterated by Frank et al., taking up the idea brought forward by Hans Jonas sixty years ago [18], the experience “from within” of our living bodies “is a condition of possibility of biology, even though biology enriches and revises it. (…) It takes life to recognize life (…) Biology presupposes life’s experience of itself.” [19] (ch.6). A phenomenological/hermeneutic standpoint granting a key role to lived experience in biological understanding, so that “the meaning of the behavior of a living being can be understood only by embodied beings”, is also a common feature of Plessner philosophical biology and of the recent theoretical framework of autopoietic enactivism [55]. Recognizing the implications of this state of affairs at an ontological and not simply heuristic level entails a reevaluation of the dimension of life as a lived experience, involving agency and purposes, which claims for a non-physicalist understanding of organisms as constituting an “order of nature that is qualitatively distinct from mere physical order” [41] (p. 75) (see also [56]).

There are, I think, three key, intertwined aspects (representing as many widely debated problems) that must be accounted for metaphysically in order to gain a robustly non-reductive understanding of the cell inclusive enough to accommodate the accumulated knowledge in molecular cell biology and the inevitable reliance on the experience of selfhood as a genuine primary reality: (i) the cell as a dynamical unity, whereby all entities within its span, be they categorized as events, processes or structural parts, find their meaning and participate in the overall goal of the best state of the cell as a self-achieving unit, be it coextensive with the whole of a unicellular organism or a part of a multicellular organism; this issue entails the problem of the part-whole relationship, connected with the one of individuating the whole to whose achievement subservient entities dynamically concur; (ii) the cell as the locus of co-emergence of mutually specifying ‘inner’ and ‘outer’ domains of being; this idea is already adumbrated in cell irritability, which can be viewed as the primordial occurrence of the condition of ‘having a world’—alien to the mere physical order but inseparable from the condition of being an organism [18] (p. 99); deeply connected with this aspect is the appearance, with the cell, of “an individual in a sense that begins to be worthy of the term self” [41] (p. 75), and thus of a self-world polarity; (iii) strictly related to the idea of cell selfness/’having a world’ is the one of the cell as the minimal instantiation of organismal agency [40,57,58,59]5, whereby the cell as an integrated whole exercise powers allowing it to persistently self-individuate through the active engagement with its world for adaptive purposes, so that its being is inseparable from its doing in an experienced world; an ontologically well-grounded cell agency would entail the existence and relevance in nature of cellular goals, means, norms, errors and teleology [61].

In the remainder of this section, I will compare substance-based and process-based metaphysics with respect to their ability to provide a valid foundation for the cell as (i) a unitary whole, (ii) a relational self and (iii) an agent.

3.2. Dynamical Unity

As detailed in the preceding sections, the concept of the cell as an integrated whole is one of the cornerstones of biology. In biological discourse, countless macromolecules, macromolecular complexes, biochemical reactions and processes are nominated in association with the adjective ‘cellular’, i.e., as aspects, parts or properties of the cell, with the cellular context being necessary to grasp their nature, their sense of being. In the case of unicellular organisms, the cellular and the organismic whole coincide, thus strengthening the idea of the cell as an ontologically independent entity. The condition of being an ontologically independent, irreducible whole and the ability to act as a common, unifying substratum for different parts/properties are among the characteristic features of substance [62]. Importantly, ontological dependence or independence are not to be understood in the sense of physical/natural causation, but in the sense in which the existence of an entity is distinguishable from the existence of its properties, whereby “substances can exist ‘on their own’ while properties must inhere in something” [7]6. The discomfort with this point by many thinkers rejecting the centrality of substance might be traced back to the Cartesian slippage from the idea of existing “in itself” of the classical definition of substance to the one of existing “by itself”. “In itself” does not deny relatedness or causal dependence, it implies only a subject of existence that is not a part or a property of any other being but an original “center of acting and being acted upon”, while “by itself” tends to imply self-sufficiency, self-enclosure and essential unrelatedness [64]. In contemporary neo-Aristotelian, hylomorphist accounts of organisms, the key unifying principle of the organismal whole is substantial form understood as a dynamicity principle by virtue of which unity is the outcome of a continuous, self-sustaining activity [11,12,13]. The proper being, the nature of an organism thus relies on a principle of distinctively orchestrated change which metaphysically grounds unity as a recursive unifying activity [11]. Aristotle’s notion of ‘actuality’/energeia, coupled with ‘potentiality’/’dynamis’ within his theory of potency and act, emphasizes the dynamic aspect of organisms. Their unity and identity are not the expression of a static persistence but the manifestation of a restless movement of unification and identification whereby the capacity/ability (dynamis) of matter is exercised according to form as a specific principle of active being (energeia). According to this lecture of Aristotelian hylomorphism, living organisms, that in Aristotle’s view are paradigm instances of substance, disclose the nature of being as activity, revealing that to be is fundamentally to be in act [65,66].

The above discussion, which is generally referred to organisms, can also apply, in my view, to cells as living individuals. The simplest case of such applicability is obviously that of unicellular organisms, such as one of the thousands of species of Protozoa: a single-cell organism can easily be conceived as a substance in the hylomorphic sense outlined above [22]. But even individual cells in a multicellular organism can be included in the same metaphysical framework, considering that any such cell is informed by the substantial form of the whole organism, and it is thus present not in act but “virtually” or “by power”. Accordingly, as expected for the virtual presence of elements in mixed bodies in a hylomorphic perspective, many types of cells can be recovered from the body of multicellular organisms and put under extra-organismal conditions enabling them to live, grow and reproduce themselves, thus empirically confirming the notion of their virtual presence and virtual powers [22].

A fundamental issue of cell biology that can be compellingly accounted for in a hylomorphic framework is the relationship between cell as a whole and subcellular organelles, which can be hylomorphically construed by getting inspiration from a metaphysical distinction between organs and organisms based on substantial form as recently proposed [16]. In Oderberg’s account, “the organ is subservient to the organism [of which it is a part] in a way that the organism is not subservient to anything” (ibid. p. 213). I suggest that the same applies to subcellular organelles with respect to the cell7. While the whole cell lends itself as “a distinct and ultimate subject of being” endowed with ontological independence, i.e., as a substance possessing a substantial form, subcellular organelles like the nucleus, the ER, peroxisomes or mitochondria metaphysically depend, for being what they are, on the cell to which they belong8. And what they are is entirely due to their being “thoroughly permeated by the substantial form” of the cellular whole to which they are subservient [16] (p. 220). The same reasoning may apply to other kinds of intracellular entities, such as the many stable macromolecular complexes that are easily identifiable compositionally and functionally (e.g., the ribosome, the signal recognition particle, the proteasome or, within the nucleus, the nucleosomes and the various small nuclear ribonucleoproteins), or even to individual macromolecules, such as each one of the thousands of different proteins populating any cellular district, where they provide key activities (e.g., catalysis, structural scaffolding, small molecule or ion transport) made possible by their molecular recognition capabilities. Even though proteins can be purified and studied in isolation as individual chemical species endowed with specific properties, their existence can hardly be conceived as independent from the whole to which they are subservient. What is more, in a hylomorphic account of the cell and its chemical components (including macromolecules, small molecules and ions), any such component is substantially altered upon entering the whole of a cell, it is literally transformed, i.e., permeated by a new substantial form9, while remaining nevertheless traceable and retrievable as predicted by the Aristotelian-Thomistic metaphysical theory of the “presence by power” of elements in mixed bodies, whereby elemental substantial forms cease to be in act but elemental powers are somehow retained [9] (ch.6). The hylomorphic view of the cell and its components is thus eminently non-reductionist, as the components of a living cell, inasmuch as they re-identify by being subsumed within the cellular whole, take on an ontological status different from their status in isolation, and such an ontological change arises from the actuality of the substantial form of the cellular whole in-forming each of its parts, in a way reminiscent of downward causation, whereby parts participate and at the same time are subjected to irreducible causal powers of the whole [68] or, more generally, of the operation in organisms of a systemic form of causation shaping the way subsystems behave [69]. This view also limits the scope of mechanistic explanations which tend to have a mereological, bottom-up character.

Let us now address the issue of cell’s dynamical unity in a process metaphysical perspective. Two of the main emphases of recent accounts of organisms, cells and subcellular entities according to process metaphysics point to dynamicity, assumed to be the fundamental, primitive feature of nature and thus of any living entity, and to the anti-reductionist idea that understanding biological wholes such as cells in terms of their components needs a systems-level perspective whereby “the visible and tangible entities at each level are not simply given (as they are in a structural hierarchy of things), but are rather dynamically maintained by continuous activity taking place at higher and lower levels in the same hierarchy” so that “causal influences can flow in different directions” [2] (p. 29). Importantly, under this perspective, organisms, cells, subcellular components are all fundamentally processes, “exquisitely regulated conglomerates of nested streams of matter and energy” with no ontologically or causally primary levels (ibid. p. 27). Undoubtedly, the process view perfectly accounts for the profound dynamism of every biological entity, in particular of the cell. However, as detailed in the preceding part of this subsection, even in a hylomorphic perspective activity is at the heart of the being of a cell. Therefore, as extensively argued by others [7,8], the arguments against the metaphysics of substance, based on which some invoke the need to abandon it in favor of a process metaphysics, seem to be largely linked to a reductive conception of this metaphysical framework.

A point at which the process perspective has, in my view, much greater difficulty compared to the hylomorphic view is that of singling out, from the all-encompassing conglomerate of intertwined/nested processes that is nature, the real entities that can be given a relevant, meaningful characterization, that is, that can act as focal points for a biological explanation. If only process is there, if the biological world fundamentally corresponds to one composite living process [8] in whose continuous weaving specific instantiations, categorized as stable process patterns, are to be recognized as living individuals, then the issue of individuation/identity of such instances is crucial in order to establish which is the processual whole with respect to which the contributing, nested sub-processes can be identified. The inevitability of establishing a hierarchical order to construe the all-encompassing living process in any biologically meaningful way is revealed by the very frequent reference, in process ontological accounts of living entities, to the idea of a dynamic, organizational hierarchy of processes, comprising higher and lower levels, with each level being causally dependent on, and in turn being a material condition of, both higher- and lower-level processes [2,5,17,23,70]. Importantly, DiFrisco suggested criteria of identity/individuation of processes aimed at the development, in a process ontology framework, of the “category of concrete independent processes” that, unlike process patterns, “have the right categorical features to replace the category of individual substances” [71]. The proposed approach is a causal cohesion account of individuation, whereby a cohesive entity is singled out because “the causal interactions among its parts are stronger than the causal interactions between these parts and their environment” (ibidem, p. 84). As recognized by the author, this definition is exposed to the risk of being circular/impredicative, as the definiendum appears in the definiens (“its parts”). A biological individual, like an organism or a cell, is first intuitively identified as such, so that it is decided in advance which parts are parts of the individual. Unbiased screening of arbitrary sets of putative parts to identify a cohesion regime corresponding to a meaningful processual whole is formally possible, but real situations admittedly require some kind of pre-theoretical bias about where to look and what kinds of interactions to look for (ibid. pp. 85–86), such that circularity is not avoided. Let us try to imagine how one might look at an amoeba as a mere processual pattern, or as a causal cohesion regime, with an unbiased gaze, uninfluenced by the pre-theoretical identification of the amoeba, which involves the “inside” knowledge one always already has of what it is like to be a living being. This hypothetical observer resembles the disembodied ‘divine mathematician’ imagined by Jonas, whose approach to nature and thus to organisms is missing the experience of being alive. For this pure intellect focusing on an organism, “there is no reason to posit a special entity for that particular form of togetherness with its normal set of interactions. (…) the apparent sameness and individuality of the organic whole will resolve itself (…) as an incidental result into the network of all physical lines which converge here and now from the universe, and in whose interweavings its pattern fleetingly appears; and all the features of a self-related autonomous entity would, in the end, appear as purely phenomenal, that is, fictitious” [18] (p. 78). The lack, in a radically processual perspective, of privileged foundation points for the articulation of being into meaningful entities (a role played by substances in Aristotelian metaphysics) opens the door to possible interpretations of biological phenomena that any biologist would recognize as distortions. For example, from such a perspective, what would stop one from considering the entire cell as a mere expansion of the endoplasmic reticulum, or assuming the mitochondria as what truly matters, as what all the other causally co-regimented entities are subservient to? More generally, what would compel one to consider a small-scale process nested within a larger one as lower-level process, with the larger one taken to be of a higher level and thus imparting meaning to the entire ‘cohesion regime’, rather than instead considering the larger process as a subservient offshoot of the smaller one, which would thus take the place of the higher-level, meaning-generating process? How to distinguish what really matters in the all-encompassing processual fabric? These difficulties arise if we discard the metaphysical posit that there are entities that are something in themselves, i.e., ontologically independent, individuals that can only be conceived as wholes, and thus irreducible, and acting according to their natures within the fabric of the world: substances. Embodied self-experience, which Jonas’ ‘divine mathematician’ is crucially lacking, is what grounds the idea of substance as ontologically independent. Indeed, it has been convincingly argued that for Aristotle the knowledge of natural phenomena, in particular biological ones, is constituted starting from the experience of man as a natural being who knows for himself what his parts, his organs are suitable for [72] (p. 52). The manifestation of nature as a multiplicity of entities distinct from each other, in which the “what” and the “towards what” are composed in a unity whose form is also its purpose10, is deeply connected with human original self-experience as a pre-condition of any access to nature [72] (pp. 50–52).

Overall, the arguments articulated in this subsection prompt me to conclude that organisms, and thus cells as well, can be coherently be construed as dynamic unitary wholes within a hierarchical framework based on substance ontology, while the attempts to fully account for them as ontologically secondary results of all-encompassing Heraclitean flux, while providing a valid foundation for organism/cell dynamicity, suffers from serious limitations as to their ability to ensure individuality and distinctness of these fundamental biological entities. This is evidenced, first, by the frequent appeal among process philosophers of biology to hierarchical models that distinguish higher- and lower-level processual entities, and, second, by their processual accounts of the cohesiveness, wholeness, and unity of central biological entities such as organisms and cells. Both moves—no less than the very determination of what counts as “higher” or “lower” within such hierarchies—tacitly presuppose the prior operation of criteria informed by assumptions about the nature of the bearers of these states, namely cells and organisms themselves [54]. Lastly, it is also worth noting that the widespread use of the term ‘process’ in cell biology presupposes an idea of directionality11 which is not purely physical but entails a reference to a final result. The idea of a cellular process is imbued from the very beginning with a sense of its function in the cellular context. The basic definition of process, in process metaphysics, as “a coordinated group of changes in the complexion of reality, an organized family of occurrences that are systematically linked to one another either causally or functionally (…), an integrated series of connected developments unfolding in conjoint coordination in line with a definite program” [74] (p. 38), a definition entirely suitable for the case of cellular/organismal processes, is characterized by a heavy use of concepts (coordination, organization, system, function, integration, program) drawing from prior recognition of entities endowed with wholeness, organization and internal purposiveness that closely remind substances.

3.3. Relational Selfness

As mentioned above, the cell can be viewed as the most primitive form of inside-outside dichotomy: “a self-encapsulated system with an active border”, the plasma membrane [75]. Most constructive cellular processes are physically located within the cell, including plasma membrane biogenesis. Interactive processes, entailing selected flows of matter and energy across the border and involving a specific profile of molecular recognition capacities instantiated in the same border, ensure the maintenance of the inside processes by constituting the outside as a meaningful world of opportunities and dangers [75], i.e., of ‘affordances’ understood as “a joint property of a purposive system and the conditions with which it interacts” [39] (p. 163)12. The cell thus appears as a paradigmatic instantiation of relational existence, consisting in a fundamental polarity between self-immanence and self-transcendence13. According to a contemporary recovery of the Aristotelian idea of being in its Thomistic interpretation, the sense of being of substances consists of “an intrinsic dynamic orientation toward self-expressive action, toward self-communication with others” so that relationality (acting and being acted upon) is an intrinsic dimension of substantial being [64,76]. Such a view is ultimately grounded in the Aristotelian theory of potency and act, for which change “occurs always due to a realization of active potencies to bring a change and of passive potencies to receive it”, and such potencies are real causal powers possessed by hylomorphic substances, in which “primary matter is the principle of passive potentiality, while substantial form determines actuality, realized and manifested in actual and perceivable characteristics” of the substance “as well as in its not yet realized (not yet manifested) active powers and dispositions.” [9] (ch.6). Therefore, the classical notion of substance, unlike its generally impoverished variants in influent early modern (Cartesian and post-Cartesian) philosophical views [64], appears capable of providing a metaphysical foundation to the relational selfness of the cell.

Process metaphysics tends to emphasize interactive relatedness of entities as opposed to their discrete individuality, making the scales clearly tip towards the former [74] (p. 35). Highlighting the relationality of biological entities undoubtedly helps to grasp their nature and to correctly set up their study in biological practice. However, positing any entity as being nothing but a pure relation, without admitting anything with its own being to which the relation applies, risks making the relation disappear into emptiness [64]. Of particular relevance to the focus of the present study, it has recently been claimed that biological macromolecules such as proteins or DNA “are relational entities that can only be fully accounted for by a process ontology”, while the commonly held substance (or at least thing-like) view of these biological macromolecules as “well-defined, distinct entities that have inherent properties owing to their material constitution” does not satisfactorily account for the dynamicity of their behavior, thereby preventing the recognition of their ontological status as processual entities, and favoring their reductive view as machines [3]. A process metaphysical framework for molecules, molecular change and enzyme catalysis had previously been proposed in order to overcome limitations due to the roots of traditional chemical thinking in substance ontology. According to such a view, enzymes (representing a paradigm for proteins in general) are not deterministic machines, but dynamic molecular ecosystems whose transitions between different dynamic states are the expression of teleological aims [77]. While I agree (as I think most biochemists would) that the view of proteins as deterministic machines is reductive, I doubt that there is a close connection between such a view and a hylomorphic perspective on organisms, and that substance thinking should therefore be abandoned. Apart from the above argument that relationality (acting and being acted upon) is an intrinsic dimension of substantial being, there are two further arguments that I would like to present against the need to see biological macromolecules as processual entities in order to account for their relational nature.

First, although the “sequence-structure-function” paradigm, whereby the function of a protein is determined by its three-dimensional structure, which in turn is determined by its amino acid sequence, is an oversimplification missing the fact that each protein is represented by many conformational isomers strictly depending on its physicochemical environment, there is nevertheless no doubt that the amino acid sequence (or primary structure) of each protein is a fundamental, unchanging characteristics, constitutive of its identity as a macromolecule. The high, yet finite number of conformers corresponding to a given amino acid sequence is constrained by this very sequence. Even a slightly different sequence corresponds to a different protein identity. In analytical studies, the presence of proteins in complex samples is detected by identifying them by primary sequence through fingerprinting methodologies that are increasingly powerful and sensitive [78,79]. Moreover, in the last few years, molecular biology is being revolutionized by novel AI-based computational approaches that have succeeded in predicting the three-dimensional structure of proteins from their amino acid sequence with an accuracy reaching that of empirical approaches such as protein X-ray crystallography [80]. Current limitations of these technologies, whose output structural models usually represent a single conformational state, are being promisingly improved towards broadening the predictive exploration of the conformational space corresponding to a single protein sequence, a space which is especially wide for the many proteins containing intrinsically disordered regions [81]. A protein sequence can hardly be conceived as processual, even though its individual instantiations are highly dynamical entities, whose active and passive powers can even be exercised in unprecedented contexts, contributing to the generation of biological innovations [82] (p. 412). As noted by Barbieri, “a given sequence cannot be described by anything simpler than itself”, it is an indivisible whole [42]. The sequence of a protein thus lends itself as an unchanging core grounding its identity by constraining it to a finite and distinctive set of possible conformations.

A second argument against the need to replace a substance framework with a processual one to grasp the ontological status of proteins derives from the fact that, in a hylomorphic view of the cell, proteins and other macromolecules are not substances, because they are ontologically dependent on the whole to which they are subservient, as already discussed in Section 3.2. Protein synthesis and degradation is orchestrated by the cell as a whole and, as highlighted in a recent process ontology approach to proteins [82], “it only makes sense to speak of them as biochemical entities within the cellular context, where certain properties or functions are attributed to them”. In disagreement with the conclusion of that study, that “this can only be captured by a processual framework”, I think that what lies behind the expression ‘cellular context’ is nothing other than the actuality of the substantial form of the cellular whole in-forming each of its parts, including all macromolecules. To consider each cellular macromolecule as an ecosystem-in-process, nested within progressively larger processes, suffers from a difficulty in grounding the identity of concrete independent processes, as already argued in Section 3.2. In particular, in a purely processual view, especially if committed to a naturalistic metaphysics, the total reliance on more or less stable patterns of physical processes in looking at cells, subcellular components and extracellular milieu does not seem to be able to provide a basis for the inside-outside distinction without which the cell becomes unintelligible unless one tacitly relies on the (‘substantial’) preconception of a unitary wholeness from the heart of which the in-out dichotomy is asymmetrically generated [10,75].

3.4. Agency

In recent years, organismal agency has become a hotly debated topic, whose comprehensive discussion goes beyond the scope of this paper. The need to reconsider organisms as agents has among its supporters both process philosophers (e.g., [4,58,83]) and authors inclined to a view of organisms as hylomorphic substances (e.g., [84] (pp. 177–183), [61,66]). Agency is a thorny issue as it is closely linked to the aim-directedness of organisms and therefore to the place of teleology in biological theory [85,86,87,88,89]. In approaches that are primarily concerned with remaining within the realm of science as it is most commonly understood, and thus with maintaining the posit of a fundamental blindness-to-aims of natural entities and causality, the prevailing tendency is to deny that organismal/cellular agency has any scientific utility, except as a (perhaps unbanishable) way of human thinking with possible heuristic value, but no ontological relevance (e.g., [60,90]). However, one of the main theoretical motivations—one that I also share—for rejecting the idea that biological agency is an empty concept is not a desire to recast biology in vitalistic terms, but rather the need to provide a metaphysical grounding for human purposiveness, normativity, and rationality without abandoning the continuity of life [18,56,83,91]. In fact, such a continuity and commonality of being is also the source of an intuitive understanding of life without which it is difficult to overestimate how much biology would be impoverished [56,92].

Recently, in the framework of a revitalized and empirically grounded proposal for a non-reductionistic organismic biology, agency, defined as “as the overall autonomous activity of the organism to maintain life functions, to establish and defend its processual relative autonomy, and to operate within the environment” [40] has been advocated as one of the key distinguishing properties of living organisms that are not reducible to mere physicochemical interactions [57] (pp. 131–140). Since life’s minimal (and original) instantiation is the single cell, the issue of cellular agency represents a testing ground par excellence to compare process-centered and substance-centered views for their capacity to autonomously account for agency. To this end, it seems important to note first that biological agency, as it is most commonly understood, minimally requires the cell as a whole [40,75,93,94]. This is in line with the fact that no subcellular entity can be attributed a biologically meaningful activity outside the context of the cell14. Along this line of reasoning, the metaphysical framework that provides a more solid foundation for cell’s dynamical unity is also the one that performs better with respect to agency. Therefore, the arguments exposed in Section 3.2 in favor of cells as hylomorphic substances to account for their unitary wholeness also apply to the issue of cellular agency.

That said, there is an aspect of organismal (and thus cellular) agency that deserves to be addressed in greater depth as it is often a source of ambiguity and difficulties. This aspect has to do with organism’s having a world and acting in the world by pursuing ends in a way that causally affects the world itself. The organism being a locus of self-concern rooted in its “needful freedom”15 co-constituted with the affordance landscape16 of its own world, its action is characterized by dynamic, ontologically irreducible end-directedness. What is emphasized in this view of agency is a self-directed strive: “living things act for themselves” therewith instantiating “a kind of causation that begins with the agent and terminates in the agent for the sake of the agent” [84] (p. 180, italics in the original). A view of the organism emphasizing its agency cannot but entail, whether this is made explicit or not, attributing to the organism some form of embodied experience, seeing it as an ontological locus where the condition of being alive is not simply an objectifiable physical state but a lived experience [56]. This is in turn related to the issue organismal/cellular sentience and/or cognition, where sentience and cognition are not to be understood as a mere projection of human ways of being on non-human entities, but as related to the fundamental and evolutionarily omnipresent affectability of organisms which depends on the presence, even in the simplest form of life, of complex detection-reaction systems which also ground agential behavior and adaptivity [36,57,97] (pp. 195–213).

Recently, a positive case for the need to maintain a metaphysics of substances has been proposed precisely to justify the existence of organismal agency and sentience. To the extent that processes are naturalistically understood as entities attributable to the operation of dynamic physical systems, however complex they may be, it becomes hard to figure out how fundamentally blind processes can really have experiences, and how processes can act on their own behalf thereby making things happen by exercising their own powers. In contrast, substance thinking grounds life on entities that are not reducible to a transient state of something else, but that are recognized as substantial wholes, “as causally potent realities over and above the realities constituted by their smaller parts, and over and above the realities constituted by the causal processes going on in those parts.” [7] (pp. 59–60).

In this regard, however, it must be recognized that, in the varied field of contemporary philosophical biology, the authors who most firmly argue against any system-theoretical physicalistic solutions for organismic agency and intrinsic teleology are process metaphysicians directly inspired by Alfred N. Whitehead’s philosophy of the organism [83,98]. With Whitehead, they see “our ability to directly sense the causal continuity of our experiential processes as the key to understanding the causal continuity of nature in general”, including both organic and inorganic entities [92] (p. 30). The normative (and therefore agential) grounding of a simple autocatalytic network as ‘functional’ or even ‘functionally closed’ cannot be provided by blind processual occurrences, and the same goes for “the model of a complex organism based on a systems-theoretical theory”, as there is no categorical difference between minimal and very complex autocatalytic networks [83] (p. 187). From this perspective, the adoption, by several non-reductionist philosophers of biology, of dynamic systems theory to explain teleology is explicitly criticized, as it is bound to exclude the ontologically fundamental character of organismal inwardness [98], which is instead guaranteed by Whitehead’s pan-experientialist account of nature [99]. While Whiteheadian process philosophers do not appear to seek explicit differentiation from other advocates of a process-oriented turn in the philosophy of biology, I suggest that their criticism should also extend to process philosophers whose accounts of processes, organization, constraints, and biological autonomy ultimately rely on physical principles drawn from non-equilibrium thermodynamics [6,100,101]. This is particularly the case when such philosophers openly distance themselves from Whiteheadian metaphysics—especially from what they characterize as the “panpsychist foundations of Whitehead’s system,” which they regard as incompatible with a naturalistic and empirically grounded metaphysics [2]. With respect to the claim to naturalize teleology and agency without broadening the concept of nature to fully include the experiential dimension, I feel more in tune with Whiteheadian than with physicalistically oriented process philosophers17. However, I ground this position on metaphysical premises that are more sympathetic with Aristotelian metaphysics as interpreted by Robert Spaemann, especially in relation to the issue of natural ends and teleology. According to Spaemann, in attempting to grasp what life is, we have no option but to begin from a phenomenological standpoint, namely from our conscious experience. Through lived consciousness, we encounter ourselves as original and fundamental realities. “I do not experience myself as a state of something non-human” [102]. Rather, I understand myself as constituted by a selfhood, or ipseity (Selbstsein), which involves a certain independence from purely causal determinations of existence, along with an orientation toward realizing the possibilities inherent in that selfhood. As already noted in Section 3.2, in Spaemann’s view, the paradigm for the Aristotelian concept of substance is precisely “the unity of the subject as a series of acts and states, a unity that experiences itself as a teleologically structured event, which embraces these particular events.” [103]. This grounds a view of reality as comprised of entities endowed with ipseity, i.e., of ontologically independent substances. In reference to organisms, the notion of ipseity captures the idea that they are agents acting on their own behalf [104] (p. 111). But even when we consider the distant, nonliving material world, treating it as real—acknowledging that it exists in its own right—already involves interpreting it through a likeness to ourselves. In this sense, we grasp it anthropomorphically: not merely as an object, but as something that participates in reality with us [als Mitsein] [102] (p. 85). This line of thinking is equipped to overcome the talk “about subjects and objects as two independent spheres of being that are in principle opposed to one another” (ibid. p. 82). Such an overcoming is also one of Whitehead’s main concerns which leads him to emphasize that the fully concrete can be conceived only as a unity of subject and object18. However, to preserve the idea that only actual occasions are what is truly concrete, Whitehead denies that organisms, including animals and human beings, are ultimate ontological units, as their identity would have to be conceived of as a substantiality that precedes the acts of its (the identity) being experienced [103] (pp. 161–162). This view entails an organismal (and universal) social ontology, where the problem of what unifies and teleologically structures each distinct society of actual occasions is more difficult to solve than in a substance-based perspective, where substances are conceived as concrete actualities whose unity of being and action is warranted by substantial form. At the same time, any substance, be it animate or inanimate, is endowed with a natural tendency to realize what is proper to its nature, and is thus more than pure positivity and objectivity, analogously to our experience, as living beings, of the inward dimension of “being oriented towards” [56] (pp. 379–380)19.

In this section, I have argued that a non-reductive account of the cell requires a metaphysical framework capable of grounding unity, agency, and self–world polarity without dissolving them into an undifferentiated flux of processes. Process metaphysics, though well suited to describing change and relationality, struggles to account for cohesive biological wholes, repeatedly relying on hierarchical and functional criteria that implicitly presuppose unity rather than explain it. By contrast, metaphysically positing substantial form as a unifying principle grounds cell unity as dynamic self-achievement, which in turn entails minimal agency and normative self-world engagement.

In the next section, on the basis of these premises and the relevant empirical evidence, I will develop arguments in favor of an ontological differentiation among the various entities through which the cellular world is realized.

4. Distinguishing Diverse Ontological Status in the Cellular Realm

4.1. Non-Uniform Modes of Being Within the Eukaryotic Cell

A way to emphasize the flowing nature of organisms in process biophilosophical accounts is to start from empirical observations of the labile existence of eukaryotic subcellular organelles (e.g., the Golgi complex) as quasistationary patterns prone to appear and disappear upon simple perturbation, thus revealing them as temporary configurations of ongoing material turnover, i.e., as processes, and then to attribute the very same way of being to all organelles, whole cells, tissues, organs and organisms [2,23,25] (pp. 50–51). This reasoning, however, if applied to the cellular realm, only highlights that both the cell and its organelles are unstable over time, labile, and that conditions can easily arise under which they undergo corruption (to use a term in the Aristotelian-Thomistic tradition) or, in a more general sense, they break down or disintegrate. Under this view, it is taken for granted that, having dynamicity and impermanence as common features, the cell and its organelles also have in common the ontological status which, given the static and fixed character that is improperly attributed to substances, can only be processual. In this last section I will try, relying on a substance-based hylomorphic metaphysics, to provide arguments in favor of a difference in ontological status (i) between the eukaryotic cell as a whole and its subcellular organelles, and (ii) between one peculiar kind of subcellular organelles (including mitochondria, plastidia and the nucleus) whose evolutionary origin can be traced back to ancestral cells, and which can thus be viewed as former cellular substances having undergone a substantial change (synthetically: Ontologically Superseded Cellular Predecessors, OSCPs), and organelles (minimally including the Golgi and most membraneless organelles) which can more properly be viewed as processual entities manifesting as microscopically distinguishable morphological elements by virtue of a distinctive spatiotemporal contiguity of sets of macromolecular transactions (synthetically: Morphologically Prominent Subcellular Processes, MPSPs).

The difference in ontological status between the whole cell and its organelles is supported by arguments already presented in Section 3.2, which can be summarized in the statement that subcellular organelles are subservient to the cell in a way that the cell is not subservient to anything20. This issue will thus not be discussed further in this section.

As to the ontological difference between OSCPs and MPSPs, it is proposed to rely on two main empirical criteria: (1) the existence of specific quality control/repair systems devoted to the organelle, generally available for OSCPs but not for MPSPs and (2) the way in which the organelle ceases to exist as a coherent biological entity under incompatible conditions: while in the case of OSCPs it stems from an active death response leading to the breakdown of identity-conferring organization, in the case of MPSPs it merely follows from cessation of processual continuity.

Before presenting in detail the evidence for the proposed distinction, it is worth recalling here, as a premise, some ideas drawn from empirically based hypotheses on the origin of the eukaryotic cell. A key point, already highlighted in Section 2, is that mitochondria of all extant eukaryotic cells have been established, beyond reasonable doubt, to derive from endosymbiotic α-proteobacteria which gradually integrated into a host cell related to Asgard Archaea [106,107,108]. Among the various hypotheses on how this happened, one of the most recent and suggestive proposes, by parsimoniously accommodating diverse kinds of cell biology data, that the ancestral Archaeon extruded membrane-bound blebs to facilitate material exchange with initially ectosymbiotic α-proteobacterial cells. Through further bleb expansion and fusion events, the bacteria would have been engulfed and internalized, with continuous inter-bleb spaces evolving into the endoplasmic reticulum, of which a portion surrounding the genomic archaeal DNA would have given rise to the nuclear envelope, interrupted by nuclear pores originated at the extrusion necks through specific protein assemblies [109,110]. Therefore, according to such an “inside-out” model, the cell’s propensity to project bodily extensions towards its exterior would be at the basis at the same time of the formation of a nuclear compartment separated from the cytoplasm, of the endomembrane system with a lumen topologically corresponding to the outside milieu, and of mitochondria by endosymbiosis21.

4.2. Capacity for Repair and Modes of Cessation of OSCPs

Under the above perspective on the origin of eukaryotic cells, the nucleus and the mitochondria, each of which contains its own DNA, appear as subcellular entities where an ancestral and independent cellular nature shines through more clearly22. Accordingly, both the nuclear and the mitochondrial DNA are actively replicated during cell proliferation. In cellular mitosis, each copy of the duplicated nuclear DNA is precisely sorted to each one of the daughter cells, which will have at the end a complete nuclear compartment. Individual mitochondria can contain several copies of mitochondrial DNA, that may be distributed among different mitochondria following mitochondrial fission, a cell-controlled process by which a single mitochondrion is divided into two or more daughter mitochondria [30] (pp. 520–531)23. In addition to the presence and maintenance of both nuclear and mitochondrial DNA, a particularly relevant point is the existence and continuous operation, both in the nucleus and in the mitochondria, of sophisticated systems for detecting and repairing DNA damage through the coordinated action of several evolutionarily conserved proteins possessing specialized molecular recognition and/or enzymatic properties [30,114]24. The other level of repair that, together with DNA repair, more directly and actively guarantees the integrity of the cell is the repair of the plasma membrane, constituting a privileged locus at which cellular affordances are instantiated. Plasma membrane injuries are detected and managed through various signaling and repair systems, the most important of which relies on Ca²⁺ influx at injured sites and the activities of numerous Ca²⁺-binding proteins [116]. Likewise, ruptures of the nuclear envelope, which can result from mechanical stress or other types of injury and cause a pernicious mixing of nuclear and cytoplasmic contents, are detected and repaired through a complex network of proteins participating in a more general nuclear remodeling apparatus also responsible for the reassembly of the nuclear envelope after mitosis [117]. As recently discovered, mitochondrial integrity also relies on an endogenous quality control system allowing damaged mitochondrial cristae (inner membrane formations enriched in proteins for energy production) to be pinched off and exposed to the cytoplasm for degradation, with repaired mitochondria resuming normal function [118]25.

With respect to the mode of cessation, occurring when conditions arise that render that any type of repair ineffective and the very existence of the entity compromised, the nucleus and the mitochondria, contributing in a closely integrated way to the fate of the cell as a whole, are at the same time operators and targets of a series of events that can hardly be seen as the interruption of a process, but rather constitute an active response to death-inducing conditions. This is clearly seen in the phenomenon of apoptosis as a paradigm of programmed (or regulated) cell death, generally referring to pathways of cellular self-termination in which a cell actively orchestrates its own dismantling26. Although the apoptotic pathway can be activated by a variety of stimuli, including DNA damage by physical or chemical factors, viral infection, mechanical stress, and others, the induction of the so-called intrinsic apoptosis pathway by irreparable DNA damage is particularly instructive for the purposes of this essay. When nuclear DNA damage is too severe for the endogenous DNA repair system to fix it, damage-sensing proteins modify a key transcription regulatory protein, p53, so as to induce it to activate the transcription of genes coding for proteins that initiate the apoptotic process. Among them, a key role is played by proteins, like Bax and Bak, which disrupt the integrity of the outer mitochondrial membrane, thus favoring the release into the cytosol of mitochondrial proteins, like cytochrome c, that in turn promote the activation of so-called executioner caspases. These proteolytic enzymes target for degradation hundreds of key cellular proteins, ultimately leading to the systematic dismantling of the cellular structure, with DNA fragmentation, membrane blebbing, and cellular breakdown into small membrane-bound apoptotic bodies [30] (pp. 1027–1040). Remarkably, among the targets of activated caspases are mitochondria themselves, whose integrity and function are thereby compromised [124]. Therefore, the cessation of existence of the cellular whole through intrinsic apoptosis involves a synergy between the two OSCPs, nucleus and mitochondria, whose crosstalk is essential for its initiation, and which are both key targets of disruptive activities in the instantiation of the death pathway. Importantly, and analogously to severe nuclear DNA damage, the impairment of cellular metabolism by inhibition of key enzymes of glycolysis (localized in the cytosol) or of citric acid cycle or mitochondrial respiratory chain (localized in the mitochondria) do not result in a generic, gradual loss of cellular integrity, somehow reminiscent of thermodynamic decay, but rather in the activation of cell death pathways through energy sensor pathways whose activity is modulated by the intracellular concentrations of key metabolites [125].

4.3. Capacity for Repair and Modes of Cessation of MPSPs

I propose to include into MPSPs both a few membrane-bound organelles (the Golgi complex and, by extension, the other districts of the endomembrane system to which the Golgi itself belong) and the vast majority of what are commonly referred to as membrane-less organelles (nucleolus, Cajal bodies, nuclear speckles, processing bodies, etc.; see [126] for a representative list). Although grouping together entities with such a different constitution may appear forced or out of place, it is motivated, as I will try to show, by empirical evidence interpreted within a substance-based metaphysical framework (which, as I argued in Section 3, provides a more solid ground for cell unity, relationality and agency).

The first, apparently trivial point to be highlighted is that none of the organelles forming the endomembrane system (ER, Golgi, endosomes and lysosomes) contains resident DNA, except for transient presence in pathological (e.g., DNA virus infection) or artificial (e.g., DNA transfection) contexts. The same holds true for membraneless organelles, with the exception of nuclear biomolecular condensates, like the nucleolus, who form by virtue of processes occurring at specific nuclear DNA loci and are thus best viewed as functional sub-compartments of the nucleus, organized to optimize specific nuclear tasks while remaining fully integrated with nuclear structure and regulation. Consequently, none of the organelles ontologically construed as MPSP hosts dedicated DNA instructions, and DNA repair systems working independently of nuclear DNA repair.

Membrane-bound MPSPs are deeply involved in the biogenesis and maintenance of the plasma membrane. The biosynthesis of both lipid and protein membrane components mainly occurs along the ER-Golgi axis, with the final products being released to the plasma membrane, delimiting the whole cell, as part of small membrane-bound vesicles continuously budding from the most distal portion of the Golgi complex and fusing with the plasma membrane. Consistent with their involvement in membrane biogenesis, these very dynamic organelles are also called into play when the plasma membrane is severely damaged and therefore cellular integrity is threatened. For example, a recent study using the worm Caenorhabditis elegans as a model Metazoan showed that large-scale wounding of the plasma membrane, which depletes membrane components at the wound sites, triggers the enrichment of membranous portions of the Golgi to the wound site, and this enrichment is required for membrane repair [127]. Therefore, more than a self-repairing entity, the Golgi complex appears as the embodiment of the very process of plasma membrane repair through intracellular vesicular trafficking. When the Golgi itself, due to various types of cellular stress, undergoes structural and functional alterations, cellular self-monitoring pathways may lead to changes in nuclear gene transcription aimed at the increased production of Golgi-restoring proteins [128]. Arguably, this is more to be considered as a cellular response to an impairment of intracellular traffic than a self-repair system of the Golgi complex. On the same note, various types of cellular perturbations may result in ER stress due to accumulation of unfolded/misfolded proteins in the ER lumen, which in turn triggers the nuclear transcription-mediated Unfolded Protein Response (UPR) aimed to restore cellular homeostasis [30] (pp. 600–602).

The ontological status of the Golgi complex as a MPSP, in particular as an intermediate of an overall process of intracellular membrane trafficking, is best evidenced by the effect of drugs like brefeldin A. Within minutes of cell treatment with this small hydrophobic compound produced by toxic fungi, the Golgi complex disassembles and redistributes into the ER, and the membrane traffic supporting membrane biogenesis and protein secretion is impaired. The molecular basis of the impressive power of Brefeldin A to make an entire organelle to suddenly disappear has been unraveled. Brefeldin A stabilizes a transient complex between two proteins (Arf1 and Sec7) whose interaction promotes a single biochemical reaction (GDP/GTP exchange by Arf1) required for vesicle formation in the early phases of membrane trafficking. In so doing, Brefeldin A compromises traffic downstream of the ER, leading to Golgi dissolution into the ER [129,130]. An organelle that (unlike mitochondria, the nucleus, or the whole cell) disappears upon the inhibition of a single biochemical reaction looks very much like a process that is interrupted27. The Golgi complex dissolution merely follows a specific break in the continuity of the membrane trafficking process, thus clearly exemplifying the mode of cessation of MPSP. The ER, like the Golgi complex, is a highly dynamic organelle involved in the early phase of membrane trafficking. Almost all plasma membrane protein and lipid biosynthesis is physically located at the ER, from which membrane vesicles originate that constitute the very material that the Golgi cisternae are made of. Saccharomyces cerevisiae temperature-sensitive mutants have been isolated in which the ER gets partially disrupted upon shifting the mutant cells to the non-permissive temperature. The affected components in these mutants are proteins involved in different, individual steps of either vesicle budding or targeting ribosome-nascent protein complexes to the ER membrane for protein translocation, which is the first, essential step of integration into membrane of plasma membrane proteins [131]. Therefore, similar to what happens with the Golgi, impairing individual steps of a processual continuum leads directly to the loss of ER integrity, suggesting that it too can be counted among MPSPs. Cellular membrane trafficking involves other organelles, like the various forms of endosome and the lysosome, to which, for reasons of space, it is not possible to extend the discussion. As they are highly dynamic and deeply integrated in the endomembrane system whose core is constituted by ER and Golgi, they too can reasonably be viewed as MPSPs.

Although there are many intracellular macromolecular assemblies that can be visualized as distinct morphological elements by electron microscopy or other types of high-resolution microscopy, what are currently referred to as membraneless organelles in the scientific literature are mesoscopic biomolecular condensates formed by phase separation. These condensates consist of specific proteins—many of which possessing intrinsically disordered regions (IDRs)—together with nucleic acids, typically RNA [126]. The prototypical membraneless organelle, easily detectable within the nucleus, is the nucleolus, which has long been recognized as constituted by the continuous, spatially localized coordination of ribosomal RNA (rRNA) transcription (by RNA polymerase I), maturation, and ribonucleoprotein assembly aimed at correct ribosome biogenesis [132,133]. Elegant, early studies in yeast showed that mutations affecting rRNA synthesis by RNA polymerase I compromise the structural integrity of the nucleolus [134], an observation recently confirmed in mouse [135]. Likewise, impairing the rRNA maturation process at precise steps strongly affects the nucleolar architecture [136]. The nucleolus thus behaves like a MPSP as it tends to disappear when the continuity of the processes of which it constitutes the morphologically prominent aspect is artificially interrupted28. Similar considerations apply to other nuclear membraneless organelles, like the Cajal bodies29, whose integrity and morphological prominence require ongoing U snRNP biogenesis [138], and nuclear paraspeckles30, whose maintenance requires active transcription of the gene coding for their key RNA component [139].

Membraneless organelles, such as those just exemplified, share three key interconnected features distinguishing them from other morphologically prominent supramolecular assemblies that are not usually counted among them (e.g., proteasomes and ribosomes): (i) they involve multivalent interactions between proteins rich in IDRs and long RNA molecules, with the intrinsic disorder (i.e., the conformational heterogeneity) of both type of macromolecules providing the structural flexibility necessary for multivalent interactions; (ii) they lack a fixed stoichiometry, and thus display a degree of compositional heterogeneity favoring the dynamic and flexible connectivity of the macromolecular network under changing conditions; (iii) the combination of the two above properties drives liquid-liquid phase separation whereby the membraneless organelle acquires its temporary and changing identity as well as its morphological prominence [140,141,142,143]. Unlike biomolecular condensates with the characteristics summarized above, other large, morphologically prominent supramolecular assemblies, like the ribosome, the proteasome, the mitochondrial ATP synthase or the nuclear pore complex, display specific, overall conserved structural architectures due to ordered interactions between many protein (or protein and RNA) macromolecules present in precise stoichiometric ratios and forming complexes with fixed partners for each interaction interface and very limited conformational heterogeneity. Consistent with this type of constitution, the architecture of these complexes could be investigated to the point of generating atomic resolution structural models (see for example [144,145]). This does not exclude the possibility that cell-specific or condition-specific variants may exist in the identity and stoichiometry of some individual components [146], nor that individual molecular components of the complex may undergo rapid turnover through exchange with a free, unassembled pool. (see for example [147,148]). The point is that while in typical membraneless organelles the multivalent interactions between conformationally and compositionally heterogeneous macromolecular assemblies generate a phase-separated microenvironment where the macromolecules themselves become part of the fluid solvent, in ordered, stoichiometric macromolecular complexes the protein and RNA components are not themselves part of the fluid solvent (even though they may often include aqueous internal cavities) [141], and the exchange of any individual component with the free pool occurs without changes in the overall stoichiometry and architecture of the complex. Accordingly, supramolecular assemblies with defined stoichiometry and sufficient structural order to permit atomic-level structure determination by X-ray crystallography or cryo-electron microscopy—assemblies that are sometimes inappropriately grouped with membraneless organelles—should instead be regarded as fundamentally different from biomolecular condensates. This distinction is underscored in particular by the fact that the genes encoding their constituent macromolecular components are subject to tight and coordinated regulation, thereby ensuring proper stoichiometry and assembly of the complex (ribosome [149,150] and proteasome [151] are paradigmatic examples)31. For these reasons, stable multiprotein complexes with fixed stoichiometry should not be attributed the same ontological status as MPSPs.

Overall, the analysis presented in this section challenges the tendency of process-oriented biophilosophy to flatten ontological distinctions within the cell by arguing, within a substance-based hylomorphic framework, that not all subcellular entities share the same mode of being. While the eukaryotic cell itself retains the ontological status of a substance, its organelles exemplify two fundamentally different ways of being instantiated at the subcellular level: on the one hand, OSCPs such as the nucleus and mitochondria, and on the other hand, MPSPs, such as the Golgi apparatus and, more generally, the membrane trafficking organelles, as well as membraneless biomolecular condensates. OSCPs have in common a derivation from ancestral cellular organizations that persist, in transformed and subservient form, within the eukaryotic cell—through endosymbiotic incorporation in the case of mitochondria (and plastids), and through the progressive compartmentalization and spatial reorganization of a pre-existing genomic and regulatory core in the case of the nucleus32. As to MPSPs, what unifies them, despite their different modes of material delimitation, is that their individuation is grounded in the ongoing realization of a localized nexus of macromolecular activities, whose interruption directly entails the loss of the entity itself. The ontological distinction between OCSPs and MPSPs is empirically grounded in the presence or absence of dedicated repair systems and, crucially, in different modes of cessation: OSCPs cease to exist through active, regulated death pathways integrated into cellular fate, whereas MPSPs dissolve when the continuity of the processes they embody is interrupted. Evidence from cell biology, including nuclear and organellar DNA maintenance, membrane repair, regulated cell death pathways, vesicular trafficking, and phase separation, supports this bifurcation. Consequently, the dynamism and impermanence shared by cellular components do not warrant a uniform process ontology; rather, they reveal a layered cellular organization in which both substance-like and processual features are differentially instantiated and coordinated under the unifying substantial form of the cell.

5. Conclusions

This article has addressed the question of how subcellular organization should be ontologically understood without collapsing the cell either into a mere aggregate of parts or into a flux of loosely coordinated processes. In Section 3, I compared the resources offered by process metaphysics and substance-based hylomorphic metaphysics for grounding a non-reductive account of the cell, arguing that while processual descriptions are indispensable to contemporary cell biology, a purely processual ontology struggles to secure cellular unity, persistence, and agency without reintroducing them implicitly or metaphorically. In particular, process metaphysics has difficulty in accounting for the asymmetrical dependence relations that obtain between the cell and its components, for the normatively structured nature of cellular maintenance and repair, and for the fact that cellular self-termination occurs through regulated pathways rather than through mere dissipation of activity.

On this basis, I defended a hylomorphic conception of the cell as a single living substance whose unity is grounded in a substantial form, and within which subcellular entities are metaphysically subservient. Building directly on this conclusion is the analysis of subcellular organelles developed in Section 4. Here, against the tendency, common in process-oriented biophilosophy, to infer a uniform ontological status from the dynamism and impermanence of intracellular structures, I argued that such features are compatible with, and indeed illuminated by, a differentiated ontological landscape internal to the cell.

In this framework, a principled distinction emerges between ontologically superseded cellular predecessors (OSCPs) and morphologically prominent subcellular processes (MPSPs). OSCPs—paradigmatically mitochondria and the nucleus—are unified by their derivation from ancestral cellular organizations that persist, in transformed and subservient form, within the eukaryotic cell. Consistent with this lineage-based continuity, OSCPs retain identity-conferring organizational features, including genome maintenance, regulated inheritance, and dedicated quality-control and repair systems, and they synergistically participate in active, regulated modes of cellular death. By contrast, MPSPs—including the Golgi apparatus, the endomembrane system, and biomolecular condensates—have in common the fact that their identity and persistence are exhausted by the continuous realization of a spatially localized pattern of coordinated macromolecular activity. Whether delimited by membranes or by phase-separated boundaries, MPSPs tend to disappear when the processes they manifest are interrupted, even by localized perturbations that compromise the continuity of the process as a whole. Their dissolution therefore exemplifies the mere interruption of a process rather than the outcome of a self-dismantling activity.

Integrating the metaphysical analysis of Section 3 with the empirical evidence surveyed in Section 4 shows that cellular dynamism does not entail ontological homogeneity. Rather, it reveals a layered organization in which subcellular entities instantiate distinct modes of being, all of which are metaphysically dependent on and coordinated by the single substantial form of the cell. Processes thus remain indispensable for describing how cells live and operate, but they do not replace or exhaust the substantial unity of the living cell itself.

The metaphysical analysis of the cell and of subcellular entities attempted in this essay is far from exhaustive. It does not address key morphologically prominent features collected under the general umbrella of the cytoskeleton, and the strictly connected issues of cell polarity and motility. Likewise, the highly complex phenomenon of cellular signaling, which somehow involves all cellular components in a tight and highly articulated network of connections, was not addressed, nor were the many intracellular molecular pathways that make up cellular metabolism. In particular, as discussed recently, the cytoskeleton can serve as a scaffold for the spatial organization of functionally related proteins, thus allowing specific and ontologically noticeable protein clusters to take shape, as is the case for the so-called metabolons [152].

What has been discussed in this paper was mainly focusing on entities that become manifest within the resolution of microscopy, which of course does not exhaust the inventory of all subcellular entities, including in particular countless macromolecules, metabolites, and their more or less stable complexes. The manifestation of entities, however, even only in the dimensional context of the typical objects of cell biology, should not be considered as something secondary or derived, which has nothing to do with the nature of the entities themselves. From a phenomenological perspective, which has been referred to several times throughout this essay, phenomenality—the very fact of appearing—is co-original with being as the condition under which being can be meaningfully disclosed at all. In particular, as emphasized by Jan Patočka in his phenomenological reading of Aristotle’s notion of motion [1] (pp. 127–138), Aristotle articulates a dynamic conception of being by assigning movement a genuine ontological function. Movement is not an external alteration or a mere change in relations, but an intrinsic, productive principle through which beings are constituted, individuated, and brought to manifestation. In this sense, movement links actuality to appearing: through actualization—whose finite form is movement—being comes to mean appearing [153]. On this view, phenomenality is not epistemically supervenient on being, but ontologically rooted in the dynamic actuality of form. Exploring the implications of this intuition for our interpretation of cellular—and more broadly, biological—phenomena, as revealed by scientific inquiry, opens a new and promising transdisciplinary path toward understanding life.