homeostasis

homeostasis (Greek: staying the same) is a fundamental idea in our understanding of the workings of the body. The concept had its origin in the 1870s, when the French physiologist Claude Bernard showed that, although the concentration of sugar in the blood could be raised or lowered by a number of processes, the net effect of these processes was to keep the concentration of sugar within certain limits. Bernard extended the idea to other constituents of blood — for which he had less evidence — and in a timeless phrase referred to the constancy of the internal environment (‘le milieu intérieur’): ‘La fixité du milieu intérieur est la condition de la vie libre, independante.’

Bernard contrasted this constancy with that of the changeable world that surrounded the animal (‘le milieu extérieur’). He likened the protective function of the internal milieu to that of a greenhouse, though to us this may seem rather an odd analogy. The constitution of the internal milieu (extracellular fluids, including blood and lymph) has been suggested to represent some primal sea in which vertebrates have evolved. It is a likeable hypothesis, but one which is rather difficult to test.

Bernard's proposal attracted little contemporary attention, which was hardly surprising, for it was about 50 years ahead of its time. But during the period 1915–35 two American physiologists, W. B. Cannon (1871–1945) and L. J. Henderson (1878–1942), revived it. Cannon was particularly concerned with demonstrating the importance of the autonomic nervous system in maintaining the constancy of the milieu intérieur: he realized that the constancy of blood pressure was an essential part of the maintenance. It was Cannon who actually coined the word ‘homeostasis’, and in his Wisdom of the body (1932) he described how several of the body's systems were involved in homeostatic mechanisms.

Cannon's fellow professor at Harvard, L. J. Henderson, analysed the way in which the body maintained the hydrogen ion concentration of body fluids (usually expressed as pH) within narrow limits. There is a short-term pH homeostasis which is a property of blood itself: a bicarbonate-buffering system. If this is not adequate, the kidneys cope with any larger deviation. Henderson published his findings in a classic work, Blood: a study in general physiology (1928). The kidneys are, incidentally, the homeostatic organs par excellence: every renal activity is involved in maintaining the internal milieu, whether it is the concentration of ions in blood, blood volume, blood pressure itself, or the excretion of alien substances.

How do the body's systems actually maintain the constancy? The most conspicuous mechanism is generally known as ‘negative feedback’, illustrated below.

As an example, blood glucose concentration could be the ‘regulated variable’ in the diagram. The control system for the variable is the hormone insulin, whose main action is to accelerate the entry of glucose into many of the cells of the body, thereby lowering its plasma concentration. Insulin is released from cells in the Islets of Langerhans of the pancreas (the controller), the most important stimulus for its release being a rise in blood glucose concentration, as occurs after a meal (‘disturbance’ in the diagram). The reason for this being a ‘negative’ feedback system is that the action of insulin, by lowering the blood sugar, tends to remove the stimulus for its own release. Negative feedback is a ubiquitious principle in engineering and electronics.

It is clear from this example that the mechanism does not keep glucose concentration (the regulated variable) at a fixed level. The level oscillates, because there are delays in both arms of the system — it takes a finite time for insulin to lower blood glucose concentrations, and also for elevated glucose concentrations to increase the production of insulin from the pancreas.

Another regulated variable is carbon dioxide. The control of a constant partial pressure of carbon dioxide (PCO₂) in blood is a very precise feedback loop, and its control system is the act of breathing. The body produces the gas constantly, adding it to blood. The CO₂ sensor in this system consists of neurons in the medullary respiratory centre of the brain; the control system consists of motor nerves passing from the brain to the diaphragm and intercostal muscles. These nerves stimulate the act of breathing, which transfers carbon dioxide from blood into the lungs, lowers the blood PCO₂, and temporarily removes the stimulus to the medullary respiratory centre. Because the body is still producing carbon dioxide, the blood PCO₂ begins to rise again, the medullary receptors are stimulated, and the cycle repeats itself. A CO₂-sensitive electrode inserted into an artery shows small, regular oscillations whose frequency corresponds precisely to the act of breathing.

The speed of response of the carbon dioxide loop is far greater than that of the glucose loop, a difference that derives from nervous compared with hormonal mechanisms: the PCO2 varies by only about 10% around its average level, whereas glucose varies by about 40%. The concentration ranges of some other constituents of blood provide us with clues about the nature of the relevant homeostatic mechanisms. Sodium ions (135–145 mmol/litre) and chloride ions (95–105 mmol/litre) have narrow ranges; this is the result of a mixture of nervous and hormonal mechanisms; the range is wider for potassium (3.5–5.0 mmol/litre) which is adjusted by hormonal action in the kidneys. By contrast, the hormones that provide the control systems regulating these variables show far wider concentration ranges in blood, according to the changes in secretion rates stimulated by disturbances in the variable they control. Thus ACTH (adrenocorticotrophic hormone) has a range of 3.3–15.4 pmol/litre, aldosterone 100–500 pmol/litre, and insulin 0–15 mUnits/ml (unfed) and 15–100 Units/ml (after food).

Homeostasis can itself be reset or entrained by higher nervous centres. The diurnal variations shown by ACTH and cortisol demonstrate high concentrations between midnight and midday (cortisol concentration 280–700 mmol/litre) and midday and midnight (cortisol 140–280 mmol/litre). Similarly, on a longer time-scale, the changes seen in the female reproductive cycle represent a 28-day cycle of entrainment. On a longer time-scale still, the growth and development of the child must represent the ultimate homeostatic entrainment by the brain. We might envisage old age as representing a genetically programmed deterioration of homeostasis.

Claude Bernard's intuition about ‘le milieu intérieur’ has come a very long way in a century. The mechanisms of homeostasis are so ubiquitous, their patterns so subtly intertwined, that we are tempted to produce a teleological question, and ask why. What is so useful to the organism about this precision? We do not have to look far, because the workings of every cell in the body depend on the maintenance of a negative potential inside the cell. In turn, this negative potential depends upon the relative concentrations of ions inside and outside the cell: a high sodium concentration in the extracellular fluid, and a high potassium concentration inside the cell, the gradients across the cell wall being maintained by ionic pumps within the cell membrane. But these pumps could not begin to control this gradient if the ionic concentrations in blood (extracellular fluid) were not kept within narrow limits in the first place. The subject comes into sharp focus when we consider the situation in the heart, which is very dependent on a constant plasma potassium level, within the range of 3.5–5.0 mmol/litre. The elevation of this value by 1–2 mmol/litre constitutes a medical emergency: the excitable components of the heart begin to conduct nervous impulses spontaneously and, without treatment, death soon follows from uncoordinated contraction of different parts of the ventricles (ventricular fibrillation).

It soon becomes clear that the body's function involves countless homeostatic mechanisms, both within and outside cells. Not only are the mechanisms ubiquitous, but careful analysis often shows two or more feedback loops apparently serving the same function; a good example is the elaborate relationship that exists between the control of blood pressure and plasma volume. Perhaps the apparent redundancy provides the organism with back-up systems that improve evolutionary survival value. Improvement or not, such duplication makes the understanding of disease processes very much more difficult to disentangle.

J. R. Henderson

See also acid–base homeostasis; body fluids; hormones.