Homeostasis: The Underappreciated and Far Too Often Ignored Central Organizing Principle of Physiology

Abstract

The grand challenge to physiology, as was first described in an essay published in the inaugural issue of Frontiers in Physiology in 2010, remains to integrate function from molecules to intact organisms. In order to make sense of the vast volume of information derived from, and increasingly dependent upon, reductionist approaches, a greater emphasis must be placed on the traditional integrated and more holistic approaches developed by the scientists who gave birth to physiology as an intellectual discipline. Our understanding of physiological regulation has evolved over time from the Greek idea of body humors, through Claude Bernard's "milieu intérieur," to Walter Cannon's formulation of the concept of "homeostasis" and the application of control theory (feedback and feedforward regulation) to explain how a constant internal environment is achieved. Homeostasis has become the central unifying concept of physiology and is defined as a self-regulating process by which an organism can maintain internal stability while adjusting to changing external conditions. Homeostasis is not static and unvarying; it is a dynamic process that can change internal conditions as required to survive external challenges. It is also important to note that homeostatic regulation is not merely the product of a single negative feedback cycle but reflects the complex interaction of multiple feedback systems that can be modified by higher control centers. This hierarchical control and feedback redundancy results in a finer level of control and a greater flexibility that enables the organism to adapt to changing environmental conditions. The health and vitality of the organism can be said to be the end result of homeostatic regulation. An understanding of normal physiology is not possible without an appreciation of this concept. Conversely, it follows that disruption of homeostatic mechanisms is what leads to disease, and effective therapy must be directed toward re-establishing these homeostatic conditions. Therefore, it is the purpose of this essay to describe the evolution of our understanding of homeostasis and the role of physiological regulation and dysregulation in health and disease.

Keywords: Claude Bernard; Walter Cannon; control theory; cybernetics; feedback regulation—negative and positive; homeostasis; internal milieu; physiology.

FIGURE 1

Portrait of Jean Fernel (ca. 1497–1558). He is the individual who coined the term physiology. Source: National Library of Medicine (the history of medicine public domain image files).

FIGURE 2

Photograph of Claude Bernard (1813–1878). He developed the concept of “a fixité du milieu intérieur,” that is, organisms maintain a stable internal environment despite changing external conditions. Source: National Library of Medicine (the history of medicine public domain image files).

FIGURE 3

Photograph of Walter B. Cannon (1871–1945). He built upon the work of Claude Bernard and coined the word homeostasis to describe a self-regulating process by which biological systems maintain stability while adjusting to changing conditions. Source: National Library of Medicine (the history of medicine public domain image files).

FIGURE 4

Schematic representation of James Watt’s steam engineer flyweight governor. See text for details. Source: public domain, as modified from, https:www.mpoweruk.com/figs/watt_flyball_governor.htm.

FIGURE 5

A schematic representation of negative feedback regulation. A solid line indicates that the connected components are directly related (an increase in one component leads to increase the connected component, while a decrease will lead to decrease in the connected components). A dashed line indicates the connected components are inversely related (an increase in one component leads to a decrease in the connected component while a decrease will lead to an increase in the connected component). An odd number of dashed lines are a necessary condition for any negative feedback cycle of causation. Negative feedback acts to maintain the controlled variable within a narrow range of values (see text for a detailed description).

FIGURE 6

A schematic representation of the regulation of room temperature to illustrate the concept of negative feedback regulation. A solid line indicates that the connected components are directly related (an increase in one component leads to an increase the connected components, while a decrease will lead to a decrease in the connected components). A dashed line indicates that the connected components are inversely related (an increase in one component leads to a decrease in the connected component while a decrease will lead to an increase in the connected component). Negative feedback acts to maintain the room temperature within a narrow range of values despite changes in ambient temperature (see text for a detailed description).

FIGURE 7

A simplified schematic representation of the regulation of arterial blood pressure as a physiological example of negative feedback regulation. A solid line indicates that the connected components are directly related (an increase in one component leads to an increase the connected components, while a decrease will lead to a decrease in the connected components). A dashed line indicates the connected components are inversely related (an increase in one component leads to a decrease in the connected component while a decrease will lead to an increase in the connected component). Negative feedback regulation acts to maintain the arterial blood pressure within a narrow range of values (see text for a detailed description). NTS = nucleus tractus solitarius, the site where sensory information is processed and the efferent response is initiated. It acts as a “barostat” analogous to the “thermostat” in room temperature regulation. SV = stroke volume (the amount of blood ejected by the heart with each ventricular contraction), HR = heart rate, the number of beats (ventricular contractions) per minute, TPR = total peripheral resistance, the resistance to the forward movement of blood (inversely related to the blood vessel diameter).

FIGURE 8

A simplified schematic representation of the central neural structures involved in baroreceptor reflex regulation of arterial blood pressure. Arterial pressure receptors located in the carotid sinuses and aortic arch (nerve firing increases as arterial pressure increases) convey afferent information via the glossopharyngeal (IXth) and vagus (Xth) nerves to the brain, respectively. This information is first processed by neurons located in the nucleus tractus solitarius (NTS). The NTS then alters parasympathetic and sympathetic efferent nerve activity. Specifically, the NTS alters the activity of neurons (monosynaptically) located in the nucleus ambiguus (NA, parasympathetic pre-ganglionic neurons) and neurons (polysynaptically, via interneuron connections) in the caudal ventrolateral medulla (CVLM). The CVLM, in turn, regulates the tonic sympathetic activity that originates in the rostral ventrolateral medulla [RVLM, that regulates sympathetic pre-ganglionic neurons located in the intermediolateral column (IML) of the spinal cord]. + = excitatory neurotransmitters (shown in black); – = inhibitory neurotransmitters (shown in blue); SAN = sino-atrial node. As an example, an increase in arterial blood pressure would increase baroreceptor nerve firing, increasing NTS neuron activity which, via interneurons, would trigger both an increase in the activity of the parasympathetic pre-ganglionic neurons located in the NA and decrease the firing of sympathetic pre-ganglionic neurons located in the IML (less directly via CVLM mediated inhibition of the tonic activity of the RVLM). The net result would be a decrease in heart rate (? cardiac parasympathetic and↓ cardiac sympathetic nerve activity), stroke volume (↓ cardiac sympathetic nerve activity), and arteriolar vasoconstriction (↓ total peripheral resistance, ↓ cardiac sympathetic nerve activity). Reductions in arterial blood pressure would provoke changes in the opposite direction. Note that the sign changes at the heart (parasympathetic effects on the SAN) and within the medulla (CVLM mediated inhibition of the RVLM). This “sign change” is necessary for negative feedback regulation.

FIGURE 9

A simplified schematic representation of the higher order control of homeostatic regulation. This hierarchical control results in a finer level of control and a greater flexibility that enables the organism to adapt to changing environmental conditions (see text for details). CNS = central nervous system.