Cellular signaling pathways as plastic, proto-cognitive systems: Implications for biomedicine

Many aspects of health and disease are modeled using the abstraction of a "pathway"-a set of protein or other subcellular activities with specified functional linkages between them. This metaphor is a paradigmatic case of a deterministic, mechanistic framework that focuses biomedical intervention strategies on altering the members of this network or the up-/down-regulation links between them-rewiring the molecular hardware. However, protein pathways and transcriptional networks exhibit interesting and unexpected capabilities such as trainability (memory) and information processing in a context-sensitive manner. Specifically, they may be amenable to manipulation via their history of stimuli (equivalent to experiences in behavioral science). If true, this would enable a new class of biomedical interventions that target aspects of the dynamic physiological "software" implemented by pathways and gene-regulatory networks. Here, we briefly review clinical and laboratory data that show how high-level cognitive inputs and mechanistic pathway modulation interact to determine outcomes in vivo. Further, we propose an expanded view of pathways from the perspective of basal cognition and argue that a broader understanding of pathways and how they process contextual information across scales will catalyze progress in many areas of physiology and neurobiology. We argue that this fuller understanding of the functionality and tractability of pathways must go beyond a focus on the mechanistic details of protein and drug structure to encompass their physiological history as well as their embedding within higher levels of organization in the organism, with numerous implications for data science addressing health and disease. Exploiting tools and concepts from behavioral and cognitive sciences to explore a proto-cognitive metaphor for the pathways underlying health and disease is more than a philosophical stance on biochemical processes; at stake is a new roadmap for overcoming the limitations of today's pharmacological strategies and for inferring future therapeutic interventions for a wide range of disease states.