The brain is not mental! coupling neuronal and immune cellular processing in human organisms

Significant efforts have been made in the past decades to understand how mental and cognitive processes are underpinned by neural mechanisms in the brain. This paper argues that a promising way forward in understanding the nature of human cognition is to zoom out from the prevailing picture focusing on its neural basis. It considers instead how neurons work in tandem with other type of cells (e.g., immune) to subserve biological self-organization and adaptive behavior of the human organism as a whole. We focus specifically on the immune cellular processing as key actor in complementing neuronal processing in achieving successful self-organization and adaptation of the human body in an ever-changing environment. We overview theoretical work and empirical evidence on “basal cognition” challenging the idea that only the neuronal cells in the brain have the exclusive ability to “learn” or “cognize.” The focus on cellular rather than neural, brain processing underscores the idea that flexible responses to fluctuations in the environment require a carefully crafted orchestration of multiple cellular and bodily systems at multiple organizational levels of the biological organism. Hence cognition can be seen as a multiscale web of dynamic information processing distributed across a vast array of complex cellular (e.g., neuronal, immune, and others) and network systems, operating across the entire body, and not just in the brain. Ultimately, this paper builds up toward the radical claim that cognition should not be confined to one system alone, namely, the neural system in the brain, no matter how sophisticated the latter notoriously is.

Keywords: neural system, immune system, self-organization, cellular systems, embodiment

The idea that the mind is distinct from the body and somehow at home in the human brain has deep roots in a longstanding philosophical and scientific thinking, stretching from Antiquity to the present day (Bennett and Hacker, 2003). At least two underlying and intertwined assumptions guided heated debates around the mind and body distinction in the past centuries. First there is the assumption that “inner” mental psychological states such as pain are distinct from physical matter. Second, there is the idea that there is a theoretical problem of how humans can know or cognize the “external” physical world. Starting mid- 1960s, the view that humans and other psychological organisms are best viewed as information-processing systems cognizing the world became dominant (Fodor, 1968). This view accepted the idea that one must appeal to “inner” states (e.g., pain) to explain ‘visible’ external behavior (e.g., crying), provided the former are construed as physical states. Mental states thus are not ghostly or non-physical, but rather neurophysiological events occurring in the individual’s nervous system (Smart, 1959).

Cognition thus was mainly defined as a rule-governed manipulation of mental representations in the brain, following the example of digital computers. The study of mental and cognitive states and the brain became thus intertwined, as exemplified by a plethora of handbooks and popular introductions on mind and cognition (Lycan, 1990; Braddon-Mitchell and Jackson, 1996). Broadly speaking, the field of cognitive psychology organized its research agenda around the key question: “how does this organism receive information through its sense-organs, process the information, store it, and the mobilize it in such a way as to result in intelligent behavior?” (Lycan, 1990: 8). Similarly, the field of cognitive neuroscience focuses on how the brain receives and process the information in a such a way to result in adaptive behavior.

The embodied cognition paradigm has been heralded as an alternative to the mainstream cognitive science (Varela et al., 1991). A central tenet of this approach is that the mechanisms of cognition have evolved to assist biological organisms in their adaptive interactions with the environment (Maturana and Varela, 1980). Cognition is thus first and foremost a process of information processing geared to sustain and maintain the physico-, biochemical-, and bioelectrical processes that constitute a biological self-organizing organism: the human body (Thompson, 2007; Lyon, 2020; Levin, 2021a,b). Here we define cognition minimally as information processing within a self-organizing system.

The notion of self-organization was seminally introduced in the field of cybernetics (Ashby, 1947; Foerster, 1960) and expanded subsequently to various disciplines including physics, biology (Camazine, 2003) and neuroscience (Kelso, 1997; Friston, 2010; Tognoli and Kelso, 2014). Self-organization is typically defined as the spontaneous emergence of spatio-temporal order or pattern-formation processes in both physical and biological systems resulting from interactions of its components with the environment (Camazine et al., 2001; Rosas et al., 2018).

Biological self-organization is a notion extensively used in theoretical biology to refer to processes and mechanisms allowing biological systems to resist the natural tendency to disorder. The special case of biological systems in the natural world is nicely captured in an aphorism by La Cerra and Bingham reported by Lyon (2020): “the first law of psychology is the second law of thermodynamics.” The second law stipulates that closed physical processes tend toward a state of increasing statistical probability and decreasing order, leading ultimately to a thermodynamic equilibrium (Schr’´odinger, 1944).

Recent work has described the remarkable capacity of biological organisms such as human bodies to maintain themselves in a state far from thermodynamic equilibrium (Von Bertalanffy, 1968; Friston et al., 2017) by building upon the Free Energy Principle (FEP) (Friston, 2010). FEP is a formalization and extension of the Schr’´odinger (1944) seminal idea that living organisms avoid entropy, by engaging in self-organization with the goal of maintaining their internal states within optimal limits for survival (Maturana and Varela, 1980). The continuous process of minimizing free energy allows biological systems to avoid increase of entropy and hence dissipation and decay (Clark, 2013; Hohwy, 2014; Perunov et al., 2014; Chvykov et al., 2021).

Biological self-organization encompasses the emergence of coherent structural configurations and patterns that distinguish microscopic (e.g., cells) and macroscopic (e.g., organisms) systems from their environment (Sultan, 2015; Sultan et al., 2022). Specifically, it has been proposed that the spatial confinement enables cells to function in a form of self-organizing chemical activity patterns (Turing, 1952), and to control the flow of matter and energy in order to maintain themselves in entropy-dissipating non-equilibrium conditions (Schr’´odinger, 1944; Prigogine and Nicolis, 1967). A richly detailed body of evidence illustrated that biological organisms such as complex bodies need to develop and sustain robust yet flexible self-organizing and self-regulatory mechanisms implemented via multilevel hierarchical organization: organelles constitute cells which form tissues which in turn form organs, etc., Zeng (2022).

The dynamics of biological systems include complex phenomena such as chaos, bifurcation, patterning, dissipation, and synchronization (Kapitaniak and Jafari, 2018). It also includes context –responsiveness to developmental, metabolic, immune and endocrine processes. In their seminal work, the biologists Maturana and Varela (1987) proposed the notion of “autopoiesis” to describe the minimal self-organization of living systems, focusing on the metabolic self-production of single-cell organisms and homeostatic regulation. Homeostasis is defined as “the regulation by an organism of the chemical composition of its body fluids and other aspects of its internal environment so that physiological processes can proceed at optimum rates. It involves monitoring changes in the external and internal environments by means of receptors and adjusting the composition of the body fluids accordingly; excretion and (osmotic) regulation are important in this process” (Martin and Hine, 2000). Biological systems also expand on this basic scheme to implement allostasis (McEwen, 1998; Schulkin and Sterling, 2019), and homeorhesis (Colditz, 2020; Matsushita and Kaneko, 2020).

Which enable the organism to take a more active role in dealing with its environment and its own components.

Self-organizing autonomous systems are organizationally closed such that the network of processes is recursively dependent on each other in the generation and realization of the processes themselves (Rosen, 2005). Moreover, they constitute the system as “unity recognizable in the space (domain) in which the processes exist” (Varela, 1979:55). Self-organization in living systems must feature the emergence of boundaries that define an internal space – the boundaries of the Self (Levin, 2021a), while keeping the states coupled with their surroundings (Palacios et al., 2020). Dynamical and precarious systems endowed with open boundaries may be seen as a self-organizing system striving to maintain its functional and structural integrity.

In line with the embodied cognition view (Maturana and Varela, 1980), it has been suggested that a promising way forward is to regard the “principles of biological organization and the requirement of survival and reproduction present the most productive route to a general understanding of the principle of cognition” (Lyon, 2006:12). A corollary of this approach is to define cognition as “the sensory and other information-processing mechanisms an organism has for becoming familiar with, valuing, and interacting productively with features of its environment (exploring, exploiting, and evading) in order to meet existential needs, the most basic of which are survival/persistence, growth, thriving, and reproduction” (Lyon, 2006: 416).

It is generally accepted that the body and the brain are distinct and partially independent subsystems working in tandem to ensure the organism’s survival in an ever-changing environment. It is also established that the human brain actively participates in this vital task by sustaining and maintaining optimal and flexible neurophysiological and cognitive processing subserving bodily integrity and adaptive worldly interactions. It is less understood however, how cognitive processing emerge from neural processing. Despite significant combined efforts from neurobiology and neuroscience using increasingly sophisticated tools such brain imaging, genetic manipulation and fluorescent labeling (Dennett, 1992; Damasio, 2000; Seth and Tsakiris, 2018), the question how exactly brain (i.e., neural) activity generates cognitive and mental states remains fairly open.

In this paper, we suggest that one promising way forward in addressing this key question is to zoom out from the prevailing focus on the neural/mental states relationship and to consider instead how neurons (i.e., a certain type of cells) work in tandem with other type of cells (e.g., immune) to subserve self-organization and adaptive behavior of the human organism as a whole.

We build upon the key fact that the brain is (part of) the body and as such, like any other bodily organ, the brain is made of cells. The focus on cellular rather than neural, brain processing allows us to underscore the idea that flexible responses to changes in the environments requires flexible adjustments not only through neural, but also through metabolic, cellular and immunological processing at multiple organizational levels of the biological system. We focus specifically on the immune system processing as key actor in complementing brain systems processing to achieve successful self-organization and adaptation of the human organism. Ultimately, shifting the focus from neural to cellular processing invites us to reconsider the received idea that cognitive processes can be linked solely to the neural system, and that the brain is somehow the natural home of mental states.

In (section “1. Introduction”), we motivate the shift in focus from neural to cellular processing and briefly describe their fundamental role of the latter in constituting biological self-organizing systems such as the human body. In (section “2. Cells: the fundamental units of the brain and body”), we discuss existing body of work on “basal cognition” (Baluška and Levin, 2016; Levin, 2019, 2021a,b; Lyon et al., 2021) questioning the prevailing idea that only brains (i.e., collectives of neuronal cells) has the ability to “cognize” or “learn.” This discussion motivates the idea that non-neural cells and simple organisms may also be perceived as active primitive “cognizers.” (section “3. Cells as “smart cognizers?” The simple minds-complex life continuity thesis”) introduces the idea that being fundamentally a bodily system, the brain needs to carefully orchestrate and align its neural processing with a complex network of other types of cellular processing (e.g., immune) to ensure the organism’s survival and viable interactions with the world. The focus on the immune system complementing the neural system to jointly support the cognitive processing underlying self-organization of the human body. In (section “4. Coupling neuronal and immune processing in human embodiment”) we suggest that cognitive processes are better understood as multiscale processes implemented at multilevel bodily systems and intricate cellular networks that compose the biological human organism as a whole.

A central tenet of prevailing approaches in brain sciences is the intrinsic link between brain (i.e., neural) processing and cognitive processing, as illustrated by a the name of the field: cognitive neuroscience. While neurons are fascinating indeed and rightfully placed under exploratory spotlight, here we focus on the more general class of agential materials from which bodies are made: cells.

Neurons are one particular type of cells - the basic, fundamental units of living organisms such as the human body (Mazzarello, 1999). Importantly, it has been proposed that “understanding the organization and function of cells within an organisms lays the essential foundation for understanding how an organism works” (Zeng, 2022: 2739), and it has been suggested that the remarkable capabilities of brains reflect an evolutionary pivot across problem spaces. Neurons are speed-optimized versions of cells that enable them to shift from their solving problems in various spaces, such as anatomical morphospace, by using developmental bioelectricity, to solving behavioral problems in 3D space via rapid control of muscle motion (Fields and Levin, 2022).

Studies going back to Ramon y Cajal revealed that cell types in the brain and body display several properties in many modalities (e.g., molecular, morphological, physiological, and functional) (Zeng and Sanes, 2017; see Zeng, 2022 for a recent review). Cellular identity as defined through morphology and function is a product of intracellular signaling networks that communicate between cells (Koseska and Bastiaens, 2017).

Large organisms such as humans have billions to trillions of cells in the body (Regev et al., 2017; Armand et al., 2021). Community efforts have been made to create cell types atlases for all organs of the human body and the brain). The separation of the neuronal and non-neuronal cells classes constitutes a fundamental distinction [see Zeng (2022): 2743]. The basic architecture of the mammalian brain (Swanson, 2000, 2012) is composed of telencephalon, diencephalon mesencephalon (midbrain), and rhombencephalon (hindbrain). Within each of these major brain structures, there are multiple regions and subregions, each with many cell types. A cell type can be specific to a subregion, a region, or a major brain structure. In each of these areas, there are two neuronal classes based on the dominant neurotransmitters they release, namely, glutamatergic and GABAergic, as well as several non-neuronal classes. A significant body of work on the mammalian brain (typically mice) have revealed a hierarchical organization (Brain Initiative Cell Census Network [BICCN], 2021). These billions to trillions of cells need to carefully orchestrate their exchanges with each other and with the external environment to allow the organism to successfully survive and grow.

It is generally held that cognition requires a nervous system, without which no mental states can arise. Neuronal activities in brain circuits generate sensory perception, cognition and ultimately behavior. For example, it has been proposed that from an evolutionary and ontogenetic perspectives, at the lowest level of the mind are processes anchored in homeostatic neural processing (Damasio and Carvalho, 2013). Feelings, i.e., mental experiences of body states, “are rooted in events occurring at single-cell level, specifically in the unmyelinated axons conveying signals from humoral and visceral aspects of the body toward nuclei in the CNS.” (Damasio and Carvalho, 2013:143) Hence, the deep roots of sophisticated mental and cognitive processing may be traced back to the humble origins of information processing in the metabolic homeostatic mechanisms of ancient cells (Damasio and Carvalho, 2013).

Conversely, bodily states and movements may directly influence neural spiking and oscillatory activity–modulating information processing, perception, action, cognition, and emotion regulation (Critchley and Garfinkel, 2018). A commonly accepted model is that synaptic firing at the single-neuron level is amplified via temporal synchronization, into a system level phenomenon (Engel et al., 1999; Singer, 1999). In biological systems, system-level properties such as fear or boredom, say, are often highly emergent, with gene-regulatory or bioelectric circuits dynamics linking initial state information and transformation rules to large scale structure and function.

For developing biological self-organizing systems, “novelty and stability are the two sides of the same coin” (Sultan et al., 2022: 5). To attain and maintain stable end states in order to reliably secure the organism stability, cellular and neuronal processing need to constantly and flexibly adjust in a context-dependent manner. Even the most direct level of gene expressions is shaped by conditions within and outside the cells, revealing the importance of plasticity, adaptive responsiveness and developmental flexibility in maintaining biological self-organization of the system. Indeed, “processes mediated by the parent’s encounter with its environment may influence the development, physiology and behavior of its offspring, ecologically important ways” (Sultan et al., 2022:3).

An extensive discussion on how different type of cellular (neuronal and non-neuronal) mechanisms develop and function as responsive and adaptive systems influencing and integrating the effects of their cognitive, bodily and environmental processes, lies beyond the scope of this paper. In what follows, we briefly overview existing work addressing basic mechanisms and processing that can be characterized as “basal cognition” in simple organisms (Lyon et al., 2021). The aim is to provide potential evidence building toward the idea that neuronal processes in the brain may not hold a monopoly on cognition. Indeed, non-neural cells may have a causal effect on neural cells. The radical claim is that all cells are cognitive, in the relevant functional sense, and consequently many other body subsystems are cognitive (not just the neuronal one).1

Recently, several theorists leveraged a growing body of evidence from neurobiology and biochemistry to suggest that cognitive categories such as “sensing,” “memory” and “learning” can be applied non-metaphorically to the behavior of simple organisms such as bacteria (Lyon, 2015; Prindle et al., 2015; Lyon et al., 2021; see Koseska and Bastiaens, 2017 for a review). This approach echoes the so-called “biogenic explanations of cognition” (Lyon, 2006) which starts with the facts of biology as the basis for theorizing and works “up” to the human case by asking psychological questions as if they were biological questions. This approach is to be contrasted with the “anthropogenic” approach which assumes human cognition as the paradigm and works “down” to a more general explanatory concept. The key assumption underlying the biogenic approach is that the “information-processing dynamics of “simpler” forms of life are part of a continuum with human cognition” (Lyon et al., 2021:2; see also Baluška and Levin, 2016).

Importantly, as Lyon et al. (2021) note, “the molecular infrastructure for capacities typically associated with brains long predated the evolution of neurons” (2). For example, Liu et al. (2015) observed a close relationship between electrical signaling in bacterial biofilms and information-processing in mammalian brains, proposing a “parallel between neurons and bacteria” related to encoding memory by changes in the membrane potential [echoing prior work on electrical excitability in bacteria (Kralj et al., 2011) and cancer cells]. As Lyon et al. (2021) note, even more remarkable was the finding that more than 95% of these nervous system related genes, including some involved in neural and brain morphogenesis, were commonly shared with Drosophila, C. elegans, and Homo sapiens: “(approximately)” 30% of planarian system-related genes had homologous sequences in the (plant) Arabidopsis and yeast, which do not possess a nervous system. This implies that the origin of the nervous system-related genes greatly predated the emergence of the nervous system, and that these genes might have been recruited toward the nervous system.” (Mineta et al., 2003: 7666).

More recently, one of us (ML) proposed that “regenerative biology and controlled chimerism reveal that studies of cognition in intact, “standard” evolved animal bodies are just a narrow slice of a much bigger and as-yet unexplored reality: the incredible plasticity of dynamic morphogenesis of biological forms that house and support diverse types of cognition” (Levin, 2019:1). Many fascinating examples from experimental biology illustrate that the boundaries separating somatic and cognitive Selves are fluid. Specifically, we have argued that developmental (pre-neural) bioelectricity sheds new light on how the dynamic control of growths and form of the body evolved into complex cognitive abilities (Levin, 2021a,b). This view holds also for synthetic biology and offers support in favor of a “bacterial paradigm for memory-capable biological systems” (Yang et al., 2020).

Taken together, these empirical findings and theoretical work seem to support the idea that basal cognition may not require nervous system or brain (Levin, 2019). This is because many organisms, including aneural ones display proto-cognitive functions such as memory, prediction and learning. In addition, many aneural organisms show the capacity to flexibly adapt and learn in new contexts (Balázsi et al., 2011). Hence, in order to understand how the physiological activity in individual cells and organisms leads to coherent behavior, one needs to widen the cognitive landscape in order to include aneural organisms, somatic organs, and novel bioengineered synthetic forms among basic cognitive systems (Baluška and Levin, 2016; Levin, 2019; Lyon et al., 2021). Crucially, all of these basal organisms (and individual cells) routinely solve problems (illustrating varying degrees of learning and other capacities) in a variety of unconventional spaces, such as metabolic, transcriptional, physiological, and anatomical (Fields and Levin, 2022) @. Moreover, cognitive abilities are typically taken to be “the properties of a fixed, embodied Agent; the fact that it is a collection of cells or subcellular fragments, which proliferate and actively interact to build up its body, is relegated to developmental biologists. That phase of a subject’s life is usually ignored as behind-the-scenes setup, after which real study can begin” (Levin, 2019:2). Thus, it is essential to broaden consideration of key issues in the field of cognitive science to include the evolutionary and developmental stages (i.e., unconventional embodiments) that smoothly and continuously lead to the appearance of individual organisms. That is, after the embodied turn, cognitive science may need a developmental turn.

Now, as we saw earlier in (section “1. Introduction”), the architecture of the human brain supports a remarkable amount of communication and integration of neural cell signaling. This complex signaling is however, directed at and connected to other non-neuronal cells and network systems subserving the viable functioning of the self-organizing organism as a whole. Indeed, neurons need not only to “fire and wire” together. They also need to wire with and respond to a vast array of other type of cellular networks and bodily organs to produce flexible responses and behavior. Biochemical components and exchanges between neuronal and non-neuronal cells networks constantly interact in influencing downstream processes in multiple systems (cardiac, respiratory, endocrine, immune, gastric, etc.). Empirical evidence illustrates bidirectional influences between bodily physiological signals (e.g., such as heart activity, gastric), brain function and behavior (Park and Tallon-Baudry, 2014; Park and Blanke, 2019; Bhat et al., 2021; Criscuolo et al., 2022; Grund et al., 2022).