Here comes the sun: the central role of human and clinical physiology in the era of multi-omics and inter-organ crosstalk

Abstract

Over the course of the 20th century, physiology emerged as a quantitative research field, addressing novel questions in animal models and human volunteers with unprecedented precision. Most current physiological disciplines were defined during this period and emerged as independent disciplines, including human physiology (cell, tissue, organ and whole-body function in the healthy human body) and clinical physiology (the same line of attack but in the context of disease). However, since this time the crusading thrust of human and clinical physiology has waned in comparison to the growth of animal model- and epidemiology/population-focused research. Animal models have and continue to provide important mechanistic insight. Rodent models, particularly mice and rats, are valuable due to their anatomical, physiological and genetic similarities to humans, ease of maintenance, short lifecycles, and abundant genetic resources, allowing for cost-effective and large-scale studies. However, it is irrefutable that the human is the most appropriate and valid model to understand acute responses and chronic adaptation to environmental stressors and disease in the human. For example, the mechanisms underlying the ageing process in mice and humans are distinct. Importantly, rodents have higher metabolic rates and poorer metabolic stability (the capacity of cellular regulatory networks to maintain metabolic homeostasis in response to stress) compared to humans (Demetrius, 2005). Species with lower metabolic rates and highly stable metabolic networks, such as humans, have a strong capacity for maintaining steady-state concentrations of regulatory metabolites under conditions of physiological stress, whilst species with high metabolic rates and weakly stable metabolic networks, such as mice, have a lower capacity to maintain their homeostatic condition. This is borne out by a plethora of studies; for example, fasting, feeding and exercise interventions in mice result in perturbations of energy and fuel metabolism that differ considerably from the same scenarios in humans (Fuller & Thyfault, 2021). Furthermore, the loss of muscle mass in response to immobilisation impacts rodents more rapidly and to a greater extent than human volunteers, and the mechanistic basis of these differences appears to differ between species (Rennie et al., 2010). Such species differences are critically important to successful translation of research findings to practical applications and interventions that can improve human health and well-being. The proliferation of epidemiology- and population-level research has delivered greater clarity of understanding of broad trends, patterns and outcomes within populations, and has offered insights into health outcomes, demographics and societal issues, which have been important in informing public health interventions and policies. However, the discipline has received criticisms around the robustness of data quality, potential for bias, difficulty in controlling confounding factors and, important in the context of this editorial, the limited ability to establish mechanisms and causality (Christen & Schnell, 2023; Rothman & Greenland, 2005).

Recognition is emerging that the integration of research at molecular, cellular and organ levels with the whole individual phenotype will bring physiological function of the whole human into focus. Currently, however, scientific progress is limited because researchers have yet to link genomic, transcriptomic, proteomic and metabolomic signatures to precise measures of physiological function or physiological adaptations over time. For example, studies have revealed that variations in the serum metabolome and gut microbiome are associated with low handgrip strength (Guo et al., 2024), but it is unequivocal that handgrip strength is a rudimentary functional measure. Moreover, it seems logical that the serum metabolome and gut microbiome cannot be representative or a determinant of muscle, tendon and neural tissue functionality, which determines grip strength. In short, clarity of understanding of the biological role and clinical significance of quantifying the universal presence of molecules and metabolites and how they interact (the integrome; Bueno, 2018) will ultimately be limited by the quality of the physiological phenotyping performed, because change in physiological function represents the definitive manifestation of the connection of networks and their interaction. Such clarity would also bring important insight into the role that changes in physiological function over time plays in modulating the integrome, rather than the current common predisposition that molecular and cellular events determine physiological function. A further level of complexity to consider is that whole human responses and adaptations may probably be determined by the outcome of coordinated biological activity across different cell types and organs, thereby necessitating multidisciplinary studies examining adaptive responses at a multi-organ level, alongside their complex inter-relationships with the integrome and metabolic and physiological function in human health and disease (Herrlich et al., 2022).

The Journal of Physiology publishes research in all areas of physiology and pathophysiology that illustrates new physiological principles, mechanisms or premises. Papers on work at the molecular level, cell membrane, single cells, tissues or organs, and on systems physiology are all encouraged. However, we are particularly keen to publish research that has a clinical or translational focus, to help further highlight our understanding of the role physiology plays in human health and disease. Importantly, technological advances in non-invasive techniques such as magnetic resonance imaging, combined with powerful ‘omics technologies and stable isotope tracers, now allow us to approach the human as the ultimate experimental animal. These advances bring unprecedented scientific understanding and opportunity, highlighting that human and clinical physiology has a central role to play in realising scientific progress and translational impact. The Journal of Physiology avidly seeks to publish these types of human and clinical studies. To be true to our mission, however, we right now advocate for studies to better integrate observational outcomes to functional endpoints to achieve compelling insights and novel premises for further study. In so doing, one can envisage a day when human and clinical physiology will be at the core of biomedical research, and to an extent that biomarker and health intervention discovery will be restricted by the quality of the human physiological phenotyping performed. For the moment, however, the challenge for clinical and translational physiology is to better integrate these new scientific technologies with function to progress the field forward. The Journal of Physiology seeks to help lead this charge.