Relativistic aspects of physiology: Expanding our understanding of conventional control loops

Traditionally, physiology has been viewed through the lens of control loops. These control loops are designed to regulate and maintain stable conditions within the human body. Conventionally, these control loops are understood as mechanisms that aim at returning the human body's physiological parameters back to its pre-fixed, unambiguous target values. Control loops consist of three components: sensors, controllers, and actuators. The sensor provides information about a specific physiological parameter (e.g., skin temperature).1, 2 Then, the controller (e.g., hypothalamus) evaluates whether the measured parameter is in an adequate predetermined target range.3 If this is not the case, the controller activates the actuator (e.g., cutaneous blood vessels) to modulate the physiological parameter and consequently influence the following sensor output4, 5 (Figure 1). However, this static perspective is an inadequate representation of reality, as it oversimplifies or disregards relevant influences on the body's homeostasis. In fact, the true target values of our control loops are gravely influenced by changes in our surroundings. Extremes in temperature, variations in gravity, physical exertion, organ system pathologies, or psychological stressors change what our regulatory systems consider as normal.6, 7 These circumstances necessitate adaptations in our physiology, which can be temporary, lead to a new hemostatic balance, or progressively alter and possibly harm our long-term functionality.8, 9 Such adaptations prompt questions: How to evaluate their pathological significance?10-12 Under which conditions do they become harmful? How to recalibrate expected outcomes of measurements to account for these changes? Do conventional methods and locations of measurement continue to hold relevance?13 Do we need different approaches to evaluate measurement accuracy?14-16 These considerations challenge our understanding of physiology and have implications for therapeutic strategies and pathomorphological considerations.11, 17, 18 However, incorporating additional dimensions in our classically monolithic representation of control loops will improve our understanding of human physiology. These dimensions can be inevitable, such as time or preexisting illness. They can be induced by choices like physical exercise or sleep deprivation, or by changes in our surroundings like hypo- or hyperbaric conditions or alterations in altitude or gravitational force or the state of physical exercise.19, 20 Taking a closer look at different but similar examples can help to clear the picture. All of them represent the need for considering a unique set of additional dimensions when interpreting the function of our physiological control loops: Thermoregulation refers to the physiological process of maintaining a stable internal body temperature across varying conditions.21 The importance of precise thermoregulation becomes critical during specialized scenarios like cardiac surgery conducted under deep hypothermia, where inaccurate temperature readings can have severe consequences. Traditional approaches to thermoregulation, which often rely on a single core body temperature measured at conventional sites like the rectum or bladder, may not accurately reflect temperature variations in critical organs like the brain or the heart. This can have drastic effects, leading clinicians to fallacious conclusions and not treating the temperature at the actual target of treatment.22 Consequently, we must integrate two additional dimensions: Locality and time play crucial roles in thermophysiology. The downstream effects and consequences of a sensed cooling at peripheral (skin) and central (hypothalamus) thermoreceptors differ immensely. Further, brain temperature undergoes changes over time. The hypothalamic function and therefore its proclivity to regulatory action alter.23, 24 This becomes particularly important in the context of cerebral hypo- or hyperthermia. Astronauts undergo a multitude of physiological changes during space missions.25 Thermoregulation in space is complicated by unique physiological challenges that astronauts face, such as fluid redistribution towards the cranial region. This fluid shift not only impacts thermal and hemodynamic regulation but also leads to conditions like cerebral edema and Space Associated Neuro-Ocular Syndrome (SANS), affecting brain and eyesight.26 The absence of convection in the microgravity environment further complicates thermoregulation, potentially causing overheating.27 These issues do not resolve immediately upon return to Earth but evolve over time, underscoring the need for a more integrated understanding of physiology in space, especially concerning thermoregulation and fluid distribution. In consequence, it becomes evident that the extreme changes in environment experienced during spaceflight mandate a more holistic and integrated view on physiology. Space and its effects on the human body underscore the complex interplay between thermoregulation, fluid distribution, and cardiovascular adaptations in the microgravity environment of space. In high-altitude conditions, the reduced oxygen partial pressure triggers physiological responses including increased breathing and heart rate, as well as a rise in 2,3-BPG (2,3-bisphosphoglycerate) to improve oxygen delivery and dissociation from hemoglobin. While these mechanisms aim to adapt to hypoxia, they can also have negative consequences, such as high-altitude cerebral edema and cardiovascular exhaustion. Individual genetic factors influence tolerance to these low-oxygen conditions, and the effects are further complicated by the duration of exposure and repetition of stays at high altitudes. Adaptation mechanisms exist, but prolonged exposure can still lead to irreversible changes, especially in the brain.28-31 The inherent adaptability of humans to their environments, even those of an extreme nature, underscores the dynamic and resilient nature of human physiology. This adaptability can result in profound physiological adaptations: Parameters that would typically be considered pathological under “normal” conditions may not only be tolerated but potentially offer benefits in altered environmental circumstances. This is particularly evident in the temporal dimension of these adaptations. A crucial aspect of this adaptability resides in the body's physiological control loops. These systems, responsible for regulating various physiological parameters such as body temperature or blood pressure, are designed to maintain homeostasis in under varying environmental conditions. However, in extreme environments, these control loops themselves may undergo substantial changes. Understanding these alterations and their implications is a key aspect of understanding the body's response to extreme conditions. The response to extreme environmental conditions necessitates a comprehensive reevaluation of our understanding of physiological variables, including said control loops. This is particularly true when considering these variables in a temporal context. The body's physiological responses are not static but evolve over time, adapting to the prevailing environmental conditions. As we continue to push the boundaries of human exploration and exposure to extreme environments, it is essential that the understanding of human physiology evolves in tandem. This progress will not only enhance our ability to survive and thrive in extreme environments but also provide valuable insights into the fundamental mechanisms of human physiology and pathophysiology. Understanding the changes in control loops and how to interpret them will improve how we think about and in consequence how we treat patients—in the clinic and the extreme alike. T. L. Bothe and O. S. Opatz: Conceptualized and wrote the manuscript draft. H. C. Gunga, N. Pilz and V. Heinz: Identified relevant literature and reviewed the manuscript. All listed authors wrote the final manuscript. There are no relevant acknowledgements for this article. No, there is no conflict of interest.