From Claude Bernard to Walter Cannon. Emergence of the concept of homeostasis

Appetite 51 (2008) 419–427

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Research review

From Claude Bernard to Walter Cannon. Emergence of the concept of homeostasis Steven J. Cooper 1 School of Psychology, University of Liverpool, Eleanor Rathbone Building, Bedford Street South, Liverpool L69 7ZA, UK

A R T I C L E I N F O

A B S T R A C T

Article history: Received 2 January 2008 Received in revised form 30 May 2008 Accepted 20 June 2008

Roots of current conceptions of the regulation of states of the body through negative feedback mechanisms are traced back to Bernard’s ideas on active stabilisation of bodily states against disturbances from the outside, revived by Henderson and Haldane, and crystallised in Cannon’s concept of homeostasis. ß 2008 Elsevier Ltd. All rights reserved.

Keywords: Claude Bernard Walter B. Cannon Lawrence J. Henderson John S. Haldane Norbert Weiner Physiological regulation History of homeostasis

Contents An introduction to this historical review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bernard’s major contributions: experimental, methodological and conceptual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chemical breakdown achieved by digestive juices Production and storage of sugar by the liver . . . . Body heat and the nervous system . . . . . . . . . . . Equilibrium between neural regulators . . . . . . . . Bernard’s ‘Introduction’ . . . . . . . . . . . . . . . . . . . . . . . . Le milieu inte´rieur . . . . . . . . . . . . . . . . . . . . . . . . . . . . Haldane and Henderson: philosophical physiologists . Cannon’s achievements and legacy . . . . . . . . . . . . . . .

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420 420 420 421 . . . .

From digestive movements to fear and rage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cannon’s formulation of homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ‘The Wisdom of the Body’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Negative feedback: a mechanism for homeostasis Concluding perspective. . . . . . . . . . . . . . . . . . . . . . Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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An introduction to this historical review

1

E-mail address: [email protected]. Deceased.

0195-6663/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.appet.2008.06.005

Drinking and eating obviously have major roles in the body’s uses and contents of water and metabolic energy. Compared with the daily rates of intake and expenditure of drinks and foods, the amounts of fluid and energy sources stored in the body are

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remarkably stable, notwithstanding the problem of obesity, and despite continuing controversy on how (or even whether) the control of intake is related to the regulation of physiological states in human beings. The stabilisation of bodily states is now termed homeostasis, a word introduced 70 years ago by the physiologist, Walter Cannon. Shortly afterwards, the engineering mathematician, Norbert Weiner, introduced the concept of negative feedback which became central to physiologists’ ideas of how homeostasis worked. Of course, this consensus about the biological bases of eating and drinking did not appear from nowhere. Indeed, it was developed over a long period and with considerable difficulty. This paper follows earlier accounts in tracing the key idea back to the 19th century physiologist, Claude Bernard, and his conception of processes that defend physiological states against disturbances from outside the body. Bernard’s major contributions: experimental, methodological and conceptual Chemical breakdown achieved by digestive juices Claude Bernard’s first major discovery came from research into the physiology of digestion that he had pursued after his M.D. thesis in 1843. Armed with anatomical knowledge and surgical skills, a working collaboration with experimental chemists, and an enquiring, resourceful mind, Bernard confidently established his presence as a leading physiologist. As recorded in laboratory notebooks that survive, after inconclusive work for nearly 5 years, the critical experiments were accomplished and reported within a month (Bernard, 1849): ‘‘I have found that the pancreatic juice is the indispensable agent for the digestion of fatty matters’’ (cited in Holmes, 1974, p. 387). ‘‘Important as was Bernard’s discovery of the action of the pancreatic juice, he soon came upon a far greater one’’ (Foster, 1899, p. 61). His single-handed discovery of the glycogenic function of the liver has attracted much attention, and illustrates both his singular competence as an experimentalist and his openmindedness to new ideas (Foster, 1899; Grmek, 1968, 1970; Holmes, 1974; Larner, 1967; Young, 1937). Production and storage of sugar by the liver When Bernard began experiments on the fate of sugar in the body after its absorption, he accepted the general view that green plants alone synthesised sugars, while in animals sugars were only destroyed in a process then thought of as combustion (e.g., Dumas & Boussingault, 1844). Moreover, he believed that the combustion of sugar took place either in the lungs or in the capillaries of the general circulation (Grmek, 1968). So he tried to locate where the combustion took place and sugar was destroyed. In 1848, with numerous failed experiments behind him, Bernard realised that he had been on the wrong track. After fewer than 3 months of further work, Bernard was able to report, ‘‘Sugar is manufactured in the liver, which must therefore be considered as an organ which produces or secretes sugar’’ (cited in Young, 1937, p. 50). The next stage in Bernard’s investigations led to the discovery of the storage form of sugar in animals (Larner, 1967; Young, 1937). In a famous experiment, Bernard flushed a liver with cold water to wash out any sugar contained in it. When the liver was allowed to stand at room temperature for a few hours, large quantities of sugar could again be detected. Hence the sugar that was formed must have come from the tissue itself, and not from the blood. Bernard later succeeded in extracting a sugar-forming substance (matie`re glycoge`ne) from liver and was able to describe the

chemical and physical properties of this glycogen in a paper in 1857. With the German physiologist Willy Ku¨hne, Bernard used the reaction of glycogen with iodine to detect the presence of glycogen in the cells of other tissues, such as muscle and skin (Larner, 1967). What was still unresolved was the source of the glycogen. Bernard’s further investigations led him to believe that sugar was not converted directly into glycogen, but that nitrogenous matter (protein) might be the principal source of sugar synthesised by the liver. Bernard’s methods were not above criticism, and controversy ensued; throughout the remainder of the nineteenth century and into the twentieth, investigators ruled in or out carbohydrate, protein and fat as the sources of the liver’s sugar (Young, 1937). These two major discoveries of Bernard, the digestion of alimentary fat by pancreatic juice and the glycogenic function of the liver, reveal not only his insight into important physiological phenomena but also his tenacity of purpose. Within Bernard’s corpus there are false paths, erroneous suppositions, inconclusive experiments and plain mistakes. Nevertheless he relied on his experimental method and his own astuteness to track down the truth. It is clear from the published accounts of his experiments and the thoughts committed to his laboratory notebooks that he took ‘‘ownership’’ of a problem, so that its solution, once found, belonged to him. This identification with an unresolved issue most likely explains his single-mindedness and perseverance. Body heat and the nervous system As Clarke and Jacyna (1987) have stressed, the early nineteenth century saw a revolution in scientific thinking about the nervous system, its anatomy and functions. At the outset, the primacy of the nervous system above all the organ systems of the body was strongly asserted. The highly influential French comparative anatomist, Georges Cuvier, characterised the major divisions of animal life (embracements) by the plan and pattern of their nervous systems (Desmond, 1989). The nervous system held the ‘‘top rank’’ or first position of all the organ systems, in at least two senses. First, it exerted a highly centralized control over other structures and physiological functions of the body. Second, the central nervous system was the ‘‘seat’’ of the mind, consciousness and intellectual faculties, reason, perception, memory and intelligence. Thus it would be altogether surprising if Bernard did not evince an abiding interest in nervous system structure and function (Bernard, 1858). Indeed, his first publication was devoted to the chorda tympani (Bernard, 1843). Bernard’s contributions to the discovery of neural regulation of the circulatory system illustrate well how he progressed from a rather vague hypothesis to a coherent physiological account (Hoff & Guillemin, 1967). He began following up an interest in the topic of animal heat by testing an idea that disruption of sympathetic innervation would lead to cooling of peripheral tissue. Much to his surprise, he found the opposite. As he reported later, ‘‘I have observed that immediately after the section of the cervical sympathetic fibres joining the sympathetic ganglia, there follows an increase in the heat of the corresponding side of the face. . . [I]t can be established that the temperature is 4 to 6 8C higher on the side on which the sympathetic fibres were cut’’ (Hoff & Guillemin, 1967, p. 95). In a subsequent paper, Bernard noted that ‘‘All parts of the head which get warm after section of the nerve, become the seat of a more active circulation of the blood. The arteries especially seem to be fuller and seem to beat harder’’ (Hoff & Guillemin, 1967, p. 96). Bernard’s attention at this stage seems to have been caught by the phenomenon of heat production itself. Formulation of a function for sympathetic innervation came another year later,

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when Bernard acknowledged that he had thought originally that the sympathetic system governed the characteristics of a tissue in the way that the blood did, but experiment had proved him wrong. ‘‘The circulatory phenomenon which follows the section of the sympathetic is active and not passive’’ (cited in Hoff & Guillemin, 1967, p. 98). Thus, the change in circulation to the skin and the rise in temperature were not mere consequences of loss of sympathetic activity. Instead, they arose from to an underlying process of active control. Equilibrium between neural regulators Much later, Bernard (1876) was able to set the results on sympathetic vasomotor control in a broader explanatory context of neural regulation to meet physiological purposes. ‘‘Thanks to the circulation, the calorific equilibrium can be maintained in the body by displacement of the mass of blood, which disappears from the parts that are too cold to enter the warmer parts, and vice versa. Thus there is a fully arranged mechanism for equilibrium. But what regulator sets in motion and directs its action? The nervous system . . . acting on the chemical phenomena of calorification at the same time as on the calibre of the vessels, accelerates or slows the course of the blood in an organ, augments or diminishes its quantity and thus regulates cooling. When temperatures tend to increase in the organism, the nervous system activates the peripheral circulation and transports the blood to the surface of the body. When, on the contrary, the temperature falls too much, the nervous system diminishes the peripheral circulation and accumulates the blood in the deep parts where it is not exposed to cooling’’ (cited in Hoff & Guillemin, 1967, pp. 98–99). In this way, Bernard moved completely beyond a consideration of animal heat and internal combustion to a much more sophisticated view involving thermoregulation. The regulatory controls exerted by the nervous system ensure that blood flow is directed to the periphery to facilitate cooling or to deeper tissue to counter heat loss, to fulfil the overriding requirement of maintaining body temperature in equilibrium. The nervous system works closely in association with the circulatory system but Bernard made clear that, although blood flow and distribution is the instrument, the precise control and its regulatory function lies with the nervous system. Bernard’s ‘Introduction’ On 21 August, 1865, aged 52, Bernard presented to the Acade´mie des Sciences seven volumes of his published lectures and his newly published An Introduction to the Study of Experimental Medicine (Bernard, 1865). He had intended this volume to become the introduction to a larger work but that project was never realised. The American physiologist Lawrence J. Henderson was a champion of Claude Bernard and wrote a foreword to the first translation of the Introduction into English (Bernard, 1927). The foundation of Bernard’s physiological thinking can be found here in the statement that ‘‘the behavior of living bodies, as well as the behavior of inorganic bodies, is dominated by a necessary determinism linking them with conditions of a purely physicochemical order’’ (Bernard, 1927, p. 61). Nevertheless plants and simpler animals have to be distinguished from more complex animals. ‘‘[T]he functions of man and of higher animals seem to us . . . independent of the physico-chemical conditions of the [external] environment, because its actual stimuli are found in an inner, organic, liquid environment. What we see from the outside is merely the result of physico-chemical stimuli from the

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inner environment; that is where physiologists must build up the real determinism of vital functions’’ (Bernard, 1927, p. 79). Hence, the internal environment serves not only to protect and to nurture the functions of living tissues but also constitutes the source of the stimuli that regulate the physiological phenomena studied during experimental investigations. It is the challenge to physiology to describe and to explain these inner causes which determine all the characteristics of physiological phenomena. In the next chapter of this section of the Introduction, Bernard sets out his analytical approach to such research. He believed that complex phenomena in living beings were built up from simpler phenomena, which could be associated together for a common final purpose. ‘‘The physiologist’s prime object is to determine the elementary conditions of physiological phenomena and to grasp their natural subordination, so as to understand and then to follow the different combinations in the varied mechanism of animal organisms.’’ (Bernard, 1927, p. 88). Nevertheless, ‘‘if we break up a living organism by isolating its different parts, it is only for the sake of ease in experimental analysis, and by no means in order to conceive them separately.’’ Bernard was well aware of the issue of how the mechanisms identified by analysis could combine and work together to achieve highly integrated operations across multiple tissues. In contrast to physical scientists, ‘‘physiologists are inclined to acknowledge an harmonious and pre-established unity in an organized body; all of those partial actions are interdependent and mutually generative’’ (Bernard, 1927, p. 89). Synthesis could not merely consist in the summation of simple phenomena uncovered in analytical experiments, for as Bernard points out the separate properties of hydrogen and oxygen cannot predict their properties in combination as water. Bernard appeared to understand synthesis in terms of combination and transformation, as well as interdependence to ensure ‘‘a harmonious unity.’’ However, he had no clear light to throw on these integrative issues. In his words, ‘‘I do not intend to go into these difficult yet fundamental problems about the relative properties of combined or combining bodies’’ (Bernard, 1927, p. 91). An important clue, nonetheless, is to be found in Bernard’s laboratory notebook, Le Cahier Rouge. There he accords an integrative and regulatory function to the nervous system. ‘‘The importance of the nervous system [is that it] communicates with the external world on the one hand, and causes the internal organs to function and establish the milieu inte´rieur in which they must live’’ (Hoff, Guillemin, & Guillemin, 1967, p. 50). This, in effect, is a restatement of the distinction drawn by one of the founders of experimental physiology, M.-F.-L. Bichat, between ‘‘animal life’’, directed externally under the control of the central nervous system, and inner ‘‘organic life’’ under the control of the ‘‘vegetative nervous system’’, later to be re-styled ‘‘the autonomic nervous system’’ (Clarke & Jacyna, 1987). Here we can see the germ of a supposition that the regulation of the internal environment is a function of the autonomic nervous system, a prominent theme in twentieth-century physiology. In reality, though, Bernard was stumped. ‘‘Whenever a science cannot be taught synthetically, it is because it is not yet perfected or sufficiently perfected. Physiology is in that state’’ (Hoff et al., 1967, p. 73). Le milieu inte´rieur Bernard’s classic account of the internal environment (le milieu inte´rieur) is in his posthumously published work, Lec¸ons sur les phe´nome`nes de la vie communs aux animaux et aux ve´ge´taux (Bernard, 1878). In the second lesson, he categorises life in three forms: la vie latente, a state of ‘‘indifference’’ or lack of chemical transactions; la vie oscillante, a state in which living processes fall

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under the influence of the external environment (Bernard puts all the plant kingdom into this category, and, in the animal kingdom, includes all invertebrates and all cold-blooded vertebrates); finally, characteristic of only the ‘‘highest vertebrates’’ (warmblooded animals) is la vie constante ou libre, where life is liberated from the external environment and succeeds in maintaining constant conditions within its own internal environment. For Bernard, the stability (la fixite´) of the internal environment allows the development of the most complex forms of organisation in living beings, reaching a pinnacle in human beings. Fulton (1966) provides a translation of key passages in Bernard’s volume. ‘‘The third form of existence, characterised by freedom and independence, is found in the more highly organised animals. Here life is never suspended, but flows steadily on apparently indifferent to alterations in its cosmic [i.e. external] environment or changes in its material surroundings. Organs, structural mechanisms and tissues all function uniformly and their operations show no sign of the considerable variations present in organisms where conditions are inconstant. This is due to the fact that the milieu inte´rieur surrounding the organs, the tissues and their elements never varies; atmospheric changes cannot penetrate beyond it and it is therefore true to say that the physical conditions of environment are unchanging in a higher animal: each one is surrounded by this invariable milieu which is, as it were, an atmosphere proper to itself in an ever-changing cosmic environment. Here we have an organism which has enclosed itself in a kind of hot-house. The perpetual changes of external conditions cannot reach it; it is not subject to them, but is free and independent.’’ Bernard is specific about how this freedom is achieved: ‘‘stability of environment implies an organism so perfect that it can continually compensate for and counterbalance external variations. Consequently, far from the higher animals being indifferent to their surroundings, they are on the contrary in close and intimate relation to them, so that their equilibrium is the result of compensation established as continually and as exactly as if by a very sensitive balance.’’ This is a much more important idea, which takes us from a static, structural notion of a hot-house, to a highly dynamic, physiological conception of life held in equilibrium only through continual compensatory adjustment. Constancy and equilibrium are not default conditions but have to be achieved and maintained for as long as the animal continues its free and independent life. On this view, it is not difficult to see disease as a loss of this integrity, a loss of freedom and independence. Finally, for Bernard, there has to be an overall conductor (or orchestrator): ‘‘in the perfected animal, whose existence is independent, the nervous system is called upon to regulate the harmony which exists between all these conditions’’ (all translations from Fulton, 1966). Here we have two key notions in Bernard’s thinking: ‘‘regulation’’ and ‘‘harmonious whole.’’ Only the nervous system (alone of all the body’s organ systems) is in a position to assume overall control of the body’s many vital functions. At times, many organ systems have to work together in a concerted, integrated way to achieve a particular goal or to serve a common function; at other times, there are competing demands to be dealt with, and the nervous system exercises its executive authority to order priorities or to activate one function while holding back another. Bernard lived and wrote before the discovery of hormones and the endocrine system but twentieth-century physiologists quickly perceived the parallel between the two systems. For Bernard and his contemporaries the nervous system alone exercised a highly centralized control, promulgating and enforcing the rules which govern vital processes (i.e. regulation), to ensure harmony (i.e. lack of conflict and factionalism) in the body’s economy. Like many

scientists and thinkers before and since, Bernard imagined what has been termed a ‘body politic’: a striking parallel could be drawn between the organization and control of the state and the physiological organization of the whole living body. Any breakdown in regulatory activities (i.e. compliance with rules), or dissolution of harmonious co-operation among bodily systems, would inevitably lead to disease. This view of Bernard’s underlay his insistence that the experimental investigations of physiological functions in the normal state were a necessary prerequisite for the clinical study of pathological states, and for devising effective therapies. Haldane and Henderson: philosophical physiologists Two eminent physiologists led a transplantation to British and American soil of Bernard’s insights concerning internal regulation, autonomy and stability: the Scotsman John Scott Haldane (1860– 1936), who trained and worked at Oxford, and the American Lawrence Joseph Henderson (1878–1942), who trained and worked at Harvard. Allen (1967) endorsed a view that ‘‘Bernard’s work served less as a paradigm for guiding physiological research than as a convenient principle for bringing together results of diverse studies on organic control’’ (p. 412). As I see it, this view underplays Bernard’s impact on physiologists like Haldane and Henderson. In fact, Haldane and Henderson disagreed quite strongly in their interpretation of Bernard’s concept of a milieu inte´rieur. This should alert us to some deeper role that the idea played in advancing physiological thought. Both Haldane and Henderson, in addition to being highly adept experimental physiologists, were very interested in conceptual thinking with wide-ranging implications. In 1916, Haldane delivered the Silliman Memorial Lectures at Yale University (Haldane, 1917) and went on to prepare a fuller account of his work under the title Respiration (Haldane, 1922). These studies of the human physiology of breathing were carried out under normal conditions and at extreme atmospheric pressures, both high (in deep-sea diving and in deep mineshafts) and low (at high altitudes, in ballooning and mountaineering). In the final chapter of the book, Haldane refers to Claude Bernard’s dictum that ‘‘all the vital mechanisms, varied as they are, have only one object, that of preserving constant the conditions of life in the internal environment’’ (Haldane, 1922, p. 383). Haldane comments, ‘‘No more pregnant sentence was ever framed by a physiologist, and the long series of investigations described in the present book may be regarded as an attempt to follow out in regard to blood reaction and oxygen supply the line which Bernard indicated.’’ Haldane goes on to say that, ‘‘In another sense, however, physiological activity is constantly disturbing the internal environment. What is actually maintained is a dynamic balance between the disturbing and restorative activities’’ (Haldane, 1922, p. 383). Haldane was not simply patting Bernard on the head for having got it right. Instead, he himself had reached the point where he could appreciate the deeper significance of Bernard’s conceptual insight. Henderson’s (1928) classic work, Blood: a Study in General Physiology, summarised his research on buffering in the blood. His early scientific work had been on the theory of buffer solutions (Parascandola, 1971). Henderson (1906) pointed out that solutions containing both monosodium dihydrogen phosphate and disodium monohydrogen phosphate should be approximately neutral between acidity and alkalinity. If either an acid or a base is added to such a solution, its effect will be countered (buffered), maintaining neutrality. Since living cells contain large quantities of phosphates, they possess a physico-chemical mechanism for maintaining neutrality. Henderson extended the quantitative theory from

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chemically simple buffers to the much more heterogeneous buffer systems of the body, involving bicarbonates as well as phosphates (Henderson, 1908). Bodily fluids are normally prevented from becoming too acidic or too alkaline by the buffering actions of their principal ionised constituents. Thus Henderson’s approach to biological problems was to apply physical chemistry to them. His 1928 book went on to claim that buffering accounted for Bernard’s principle of stabilisation of the internal environment. Haldane (1929) protested strongly that ‘‘L.J. Henderson treats the constancy of reaction in the living body as if it depended on the physico-chemical properties of blood . . . He refers to the authority of Claude Bernard in justification of his procedure; but in so doing he seems to me to have altogether misunderstood Bernard’s conclusion’’ (p. 453). According to Haldane, Bernard’s conception of the milieu inte´rieur requires ‘‘the coordinated activity of organs by which the conditions of the blood are kept constant. Henderson leaves this coordinated activity out of account, thus turning blood in the living body into what for a physiologist is a mere artefact, and completely disregarding Bernard’s principle . . . taking a step backwards’’ (Haldane, 1929, pp. 453–454). Indeed, Haldane claimed himself to be Bernard’s true heir, ‘‘as one who has been closely connected during the last thirty years with the development of Bernard’s conception, as well as with the development of knowledge as to the physical chemistry of blood . . .’’ (p. 454). Henderson’s foreword to An Introduction (Bernard, 1927), however, makes clearer how Henderson actually regarded Bernard’s contribution. In characteristic style, he writes: ‘‘The theory of the constancy of the internal environment . . . we owe almost wholly to Claude Bernard himself. . . . A few scattered observations on the composition of the blood sufficed to justify, in his opinion, the assertion that the constancy of the internal environment (milieu inte´rieur) is the condition of free and independent life’’ (Henderson, 1927, p. viii). Henderson continues, ‘‘General physiology, according to [Bernard], includes the study of the physico-chemical properties of the environment of the cell, a similar study of the cell itself, and beyond this of the physicochemical relations between cell and environment. . . . Today, with the aid of a physical chemistry unknown to the contemporaries of Claude Bernard, it is fulfilling the promise which he alone could clearly see’’ (pp. viii–ix). Leaving aside the unlikely prophetic powers of Bernard, these comments of Henderson clearly assert the ascendancy of physical chemistry in solving biological problems. He was free to imply Bernard’s posthumous endorsement but equally Haldane was at liberty to accuse Henderson of misrepresentation and distortion of Bernard’s legacy. We shall leave Haldane with the last word here. ‘‘The reason why the physical or chemical method of treatment is so unsatisfactory in biology is that in connection with living organisms the properties of parts show peculiarities which we do not meet with in what we distinguish as the inorganic world’’ (Haldane, 1922, p. 392). Paraphrasing Bernard, Haldane claims, ‘‘Biology must take as its fundamental working hypothesis the assumption that the organic identity of a living organism actively maintains itself in the midst of changing external appearances’’ (Haldane, 1922, p. 391). We now move beyond this impasse, and consider the metamorphosis of Bernard’s constant internal environment into something more resilient and lasting. Cannon’s achievements and legacy From digestive movements to fear and rage Walter B. Cannon belonged to a generation of American physiologists who did not travel to Europe to train in leading

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laboratories as many of their predecessors had done. Nevertheless, he was well aware that he was heir to a European tradition in biology and physiology. When Cannon was in Paris in 1918, eager to continue his experimental investigations, he found space in the Colle`ge de France, ‘‘only a few hundred yards from the little rooms where Claude Bernard carried on his researches for more than thirty years’’ as he explained in a letter home (cited in Wolfe, Barger, & Benison, 2000, p. 26). On the wall above the fireplace in Cannon’s professorial office at Harvard Medical School were a portrait of Charles Darwin and a framed print of Claude Bernard (Benison, Barger, Wolfe, & Walter, 1987, p. 2). It is not difficult to imagine that both men were an inspiration to him. Cannon marked himself out as a scientific investigator by publishing studies while still a medical student on movements of swallowing (at the suggestion of his professor) and in the stomach wall using the recently discovered X-rays (Cannon, 1898; Cannon & Moser, 1898). He was appointed as an instructor first in zoology and then in physiology but very soon found himself running the physiology department’s laboratory, managing a large class taking a new course in physiology and editor of the recently founded American Journal of Physiology. Cannon’s research continued the use of X-rays to study movements of the stomach and the small and large intestines, and added studies of the rates of gastric emptying of various foodstuffs. In 1906, Cannon became George Higginson Professor and chairman of the department. This brought a large increase in administrative duties and committee work, at the expense of his time in the laboratory, as well as public work in the defence of animal experimentation in medical research (Benison et al., 1987). Nevertheless he was able to bring together his initial decade of research in his first book, The Mechanical Factors of Digestion (Cannon, 1911). However, Cannon’s interests had begun to shift towards roles of the autonomic nervous system (ANS) in the control of peristaltic movements and rates of gastric emptying. He was struck by the similarity between the effects of adrenal extracts and the actions of the sympathetic branch of the ANS. He became interested in the influence of emotional disturbance (distress, discomfort or pain) on the secretion of a substance later identified as adrenaline, and the physiological sequelae of the hormone’s actions. As an undergraduate at Harvard, he had been attracted to philosophy and psychology (William James was a teacher). From the British psychologist–philosopher William McDougall’s widely read book, An Introduction to Social Psychology (1908), Cannon took the idea that experience of fear as an emotion elicited an instinct to flee, whereas the experience of anger elicited an instinct to fight or attack — both responses being necessary for survival. Cannon formulated the idea that strong emotional states stimulate the secretion of adrenaline from the medulla of the adrenal gland and the hormone acts on peripheral tissues in such a way as to prepare the animal for vigorous action, either fighting or fleeing in life-threatening emergencies (Cannon, 1914). He collected his thoughts together into a book that became very widely known, Bodily changes in pain, hunger, fear and rage (Cannon, 1915). This attempt at physiological synthesis would have been entirely congenial to Bernard. It may have been coincidence, but the relevance of what Cannon was describing to the carnage inflicted in the Great War could not have been lost on his readers. As soon as the United States declared war on Germany in 1917, Cannon asked for a place in the Harvard Medical Unit and set sail for France. His war-work, like that of many other medical investigators, was concerned with the nature and treatment of surgical shock following great loss of blood in battlefield casualties (Benison, Barger, Wolfe, & Walter, 1991).

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Cannon’s formulation of homeostasis Adolph (1961) documented ideas stretching back centuries concerning physiological regulations, ‘‘controls of activities of living beings . . . self-contained and automatic’’ (p. 737). He pointed out that these regulatory controls do not have to be learned, unlike many rules of behaviour, or consciously monitored and adjusted, unlike speech or writing; they autonomously achieve stability and a condition of equilibrium within the body’s economy. Adolph reviewed developments in this concept within modern experimental physiology up to the 1940s. He considered the introduction of the term homeostasis by Cannon to be a defining moment, confirming the progress already made and pointing the way to future work. Throughout the 1920s what started as a relatively narrow view of emergency function began to take on a new and more general form. In an address given before the Congress of American Physicians in May 1925, Cannon explained, ‘‘A fairly constant or steady state, maintained in many aspects of the bodily economy even when they are beset by conditions tending to disturb them, is a most remarkable characteristic of the living organism’’ (cited in Wolfe et al., 2000, p. 152). This statement is firmly in the Bernard tradition but Cannon went on to enunciate six propositions. (1) In an open system, such as our bodies represent, complex and subject to numberless disturbances, the very existence of a poised or steady state is in itself evidence that agencies are at hand keeping the balance, or ready to act in such a way as to keep the balance. (2) If the state remains steady, there is an automatic arrangement whereby any tendency toward change is effectively met by increased action of the factor or factors which resist the change. (3) Any factor which operates to maintain a steady state by action in one direction does not act at the same point in the opposite direction. (4) Factors which may be antagonistic in one region, where they effect a balance, may be cooperative in another region. (5) The system of checks which determines a balanced state may not be constituted of only two antagonistic factors; on either side there may be two or more, brought into action at the same time or successively. (6) When a physiologic factor is known which can shift a steady state in one direction, it is reasonable to look for a physiologic factor or factors having a contrary or counter-balancing effect (Wolfe et al., 2000, pp. 152–153). A year later, in a volume honouring the Nobel Prize-winning, French physiologist, Charles Robert Richet, who had studied with Bernard, Cannon published a short paper entitled ‘‘Physiological regulation of normal states: some tentative postulates concerning biological homeostatics.’’ This was the first time that Cannon’s neologism had appeared in print (Wolfe et al., 2000, p. 154). In my view, Cannon never lost sight of Bernard’s work. Cannon’s paper draws from Bernard (1878), referring to ‘‘the conditions of life in the internal environment.’’ At the same time, Cannon was aware that the torch had to be carried a long way further. He declared, ‘‘It is clear that an examination of homeostatic conditions in the body and the agencies controlling them is of very great biological and medical interest and importance. It is a field which has been too little cultivated’’ (cited in Wolfe et al., 2000, p. 155). Three years later, Cannon published what was to become a classic paper in physiology, Organisation for physiological homeostasis (Cannon, 1929). Once again, Cannon pays homage to Bernard, crediting him with the notion of the maintained stability of the internal environment (milieu interne or inte´rieur). Like

Haldane (1922), Cannon repeats the dictum, ‘‘It is the fixity of the ‘milieu inte´rieur’ which is the condition of free and independent life’’ (Bernard, 1878). It is also clear that, in the disagreement between Haldane and Henderson on how to interpret Bernard’s meaning, Cannon sided with Haldane. ‘‘The term ‘equilibrium’ might be used to designate these constant conditions. That term, however, has come to have exact meaning as applied to relatively simple physico-chemical states in closed systems where known forces are balanced. In an exhaustive monograph L.J. Henderson (1928) has recently treated the blood from this point of view’’ (Cannon, 1929, p. 400). Cannon asserted that, in contrast, ‘‘The present discussion is concerned with the physiological rather than the physical arrangements for attaining constancy.’’ Indeed, Cannon’s new term was required to distinguish physiological systems from merely physical systems. ‘‘The coo¨rdinated physiological reactions which maintain most of the steady states in the body are so complex, and are so peculiar to the living organism, that [I have] suggested . . . that a specific designation for these states be employed — homeostasis’’ (Cannon, 1929, p. 400). The contrast between in vivo physiological processes and the in vitro reactions of the chemists was a leitmotif of Bernard’s writings. Cannon was re-affirming Bernard’s position for physiology in the twentieth century. His protracted defence of medical research against the onslaughts of the anti-vivisectionists was predicated on there being such a contrast: living processes could not be understood from studies only in the glassware of a chemistry laboratory. What did Cannon wish to convey with his new term? Living beings are open systems, continually in contact with the outer environment, responsive to changes in the environment, but also prone to large fluctuations whenever environmental conditions are grossly disturbed. However, through the agency of automatic, internal compensating adjustments, higher organisms are able to keep internal fluctuations within ‘‘narrow limits’’. Thus, a single fixed value is not attained, but the variation of physiological variables is kept within a small range of values. Hence, Cannon expressed a preference for the Greek-derived prefix ‘‘homeo’’ (meaning ‘‘like’’ or ‘‘similar’’) rather than ‘‘homo’’ (meaning ‘‘same’’ or ‘‘fixed’’). Constancy of the internal environment is therefore a relative attribute rather than an absolute one, and should be understood in its physiological sense rather than in a strictly physico-chemical way. Thus, Cannon sharpened up Bernard’s terminology, and moved from a sense of ‘‘fixed values’’ to the more realistic notion of ‘‘keeping within narrow limits.’’ (A vast amount of measurement of blood variables had taken place in the decades since Bernard’s death, and there was a much better understanding of normal variation around average values.) Yet Cannon had done more than this. He had also shifted attention away from the state of the internal environment (characterised in life by its relative constancy) to a more detailed study of those control factors which intervene to ensure the maintenance of the steady conditions of the body. His choice of term, homeostatics, for this study of biological control factors may relate to statics in physics, the branch of mechanics that deals with active forces in balance on an object. The body of Cannon’s (1929) paper amplifies on Bernard’s conditions which must be maintained at constant values, i.e. material supplies for cellular needs (carbohydrates, protein, fat, water, sodium chloride, calcium, oxygen and internal secretions) and environmental factors affecting cellular activity, i.e. osmotic pressure, temperature and hydrogen-ion concentration (acid–base balance). Cannon had decades of additional experimental data to call upon in support, but the basic scheme enunciated by Bernard

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remained much the same. He detailed how homeostasis could work through the regulation of supplies, the provision of storage facilities, the operation of hunger and thirst to meet insistent demands, the excretion of excesses and the maintenance of neutral blood pH and of body temperature. In a penultimate section, Cannon stressed the role of the autonomic nervous system in homeostasis. Having thought earlier of the ANS in terms of emergency reactions of the body to threatening external circumstances, Cannon now broadened its physiological significance. He became more ready to identify sympathetic activity, coupled with the actions of adrenal medullary secretions, with keeping constant the conditions of the internal environment. The concluding section of his article reiterated the six propositions put forward in his 1925 address but now positioned them within the context of homeostatic regulation. ‘The Wisdom of the Body’ In 1932 Cannon published a book on homeostasis for the general reader, The Wisdom of the Body, based largely on the work of the physiological laboratory at Harvard from 1906 onwards. It was an instant success, widely reviewed and praised for its accessible style, immediately finding an appreciative public audience (Wolfe et al., 2000, p. 262) like Bernard’s famous Introduction. Cannon had made ‘homeostasis’ into a household word. Cannon’s (1932) book became a classic in physiology too. There is a certain irony in the fact that Cannon made no mention of hormones or the endocrine system in Wisdom, apart from an account of his work on extracts of adrenal glands. It seems that the book’s title was a tribute to Ernest Henry Starling, Foulerton Research Professor of the Royal Society, who died unexpectedly in1927, and had discovered secretin (Bayliss & Starling, 1904), introduced the term ‘hormones’ for the chemical messengers of the body (Starling, 1905) and contributed greatly to the development of endocrinology (Starling, 1923b). Cannon took his title from that of an address given before the Royal College of Physicians of London (Starling, 1923a). In turn, Starling’s title was drawn from William Harvey, ‘‘Who hath put wisdom in the inward parts? Or who hath given understanding to the heart?’’ However, the book was not all physiological science: an ‘‘Epilogue’’ dealt with relations between biological and social homeostasis. Like many before him, including Bernard, Cannon drew ‘‘analogies between the body physiologic and the body politic’’ (Cannon, 1932, p. 287). He held up a Utopian vision of society, which greatly appealed to his reading public. ‘‘Lack of stability in the social organism’’ leads to the ‘‘sufferings of human creatures’’ (p. 302). ‘‘Just as social stabilisation would foster the stability, both physical and mental, of the members of the social organism, so likewise it would foster their higher freedom, giving them serenity and leisure . . . for the discovery of a satisfactory and invigorating social milieu, and for the discipline and enjoyment of individual aptitudes’’ (p. 306). Negative feedback: a mechanism for homeostasis Cannon, I have suggested, shifted the argument in regulatory physiology away from the steady state of the internal environment, as emphasised by Bernard, towards the processes of control that help to stabilise conditions in the body. This idea of control has implications that Cannon did not make explicit but Starling had started to develop as early as 1908. In a lecture given that year to the Harvey Society in New York, published under the title The Chemical Control of the Body, Starling promoted the idea of an

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alternative to the neural control of physiological functions. He used the term ‘‘chemical messengers’’ for hormones. The notion of a ‘message’ is familiar today in terms of communication of information from one site to another. Bringing the concepts of control and communication together considerably broadens the scope of physiological enquiry. A defining difference between late nineteenth century physiology and the science of the latter part of the twentieth century (including, most importantly, neuroscience) is the transition from consideration of biological controls alone to an understanding of the transmission of information through systems of control. The engineers of the 1920s and 1930s were the first to formulate the issues clearly (Mindell, 2002). Mindell’s account begins with the U.S. Navy’s development of gunnery control systems in the First World War. It was notoriously difficult for gunfire to hit a moving target, especially at long range. Engineers recognised that, to optimise firing performance, it was necessary to include ‘‘feedback’’ circuitry that corrected errors. Feedback can be understood as the updating of information, in this case about the distance between the position of the target and the position hit by the gunfire. A problem intrinsic to the use of feedback is that heavy machinery (e.g. a naval gun turret) moves slowly whereas signals can be high in frequency. This can set up oscillations, known as ‘‘hunting.’’ Such instability in the system could seriously compromise the accuracy of firing. ‘‘By the end of the 1920s nearly one in five graduates of MIT’s electrical engineering program addressed stability-related issues in their theses’’ (Mindell, 2002, p. 147). This is a remarkable echo of Bernard’s abiding concern for control of the stability of the internal environment in living systems. By 1940, the problems of gunnery control had become more difficult because aircraft move in three dimensions, whereas (large) ships move only in two. The US National Defense Research Committee asked the eminent mathematician at MIT, Norbert Wiener (1894–1964) to work on predictive control of anti-aircraft guns. Wiener’s report in 1942 was not taken up by the NDRC (Mindell, 2002, pp. 277–280) but the ideas he had developed prefigured his introduction of cybernetics after the war (Heims, 1980). Back in 1930, Cannon had been joined by an extremely able research physician on a Guggenheim Fellowship from Mexico, Arturo Rosenblueth, who had studied in Berlin and then in Paris under Richet. Rosenblueth formed a close personal and working relationship with Cannon (Wolfe et al., 2000) and an equally close relationship with Wiener at MIT, providing the intellectual bridge between Cannon’s homeostatic physiology and Wiener’s vision of cybernetics. A paper in 1943 by Rosenblueth, Wiener and Bigelow, with the title Behavior, Purpose and Teleology, was an historic landmark. After the strenuous efforts of nineteenth-century physiologists to rid their fledgling science of teleology, it was back but in a mechanistic form in terms of signalled messages. They identified a form of active behaviour as goal-directed (or purposeful), which could be with or without information ‘fed back’ from the target to the controller. The ‘feedback’ that they had in mind was negative feedback — information that brings the output into closer proximity to the designated goal. They stated that ‘‘All purposeful behavior may be considered to require negative feedback’’ (p. 19) and that ‘‘the behavior of some machines and some reactions of living organisms involve a continuous feed-back from the goal that modifies and guides the behaving object’’ (p. 20). Rosenblueth, Wiener and Bigelow (1943) divided feedback in purposeful behaviour into predictive and non-predictive, pointing out that ‘‘predictive animal behavior . . . is a commonplace’’ (p. 20) and that it is the level of the organization of the central nervous system which determines ‘‘the complexity of predictive behavior’’ that a mammal is able to demonstrate.

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Negative feedback was also the mechanism adopted to make homeostasis work. Feedback signals can be used to maintain stability against externally imposed fluctuations. In addition, negative feedback can be used to ‘home in’ on an end state — that is, to approach a stable condition and, once achieved, to maintain it. Wiener sub-titled his influential book on cybernetics, ‘‘control and communication in the animal and the machine’’ (Wiener, 1948, 2nd ed., 1961). His aim was to launch an interdisciplinary programme including both control systems and communicating systems. Wiener recognised that negative feedback underpins homeostasis and that this is an essential condition for the continuation of life (p. 114, 2nd ed.). Ross Ashby, in his book Design for a Brain (1952), elaborated on many of these ideas. Nowadays, negative feedback loops to achieve homeostatic control of essential physiological variables are familiar from textbook diagrams. Concluding perspective Bernard had trained and developed as an analytical experimentalist, reducing complex phenomena to simpler problems that could be tackled in the laboratory (compare, for drinking and eating, Cannon, 1919, and Cannon & Washburn, 1912). As Medawar (1967) wrote, ‘‘research is surely the art of the soluble.’’ Bernard was fully aware that physiology faced a much bigger issue than the other sciences of his day: how to explain the complex, highly organized and goal-oriented systems on which life itself depended? There were no means at his disposal, or indeed for his generation, to attempt to answer these great questions. Bernard’s vision did not take root initially. Following his death, physiology began to develop its strengths in Britain and the United States but Haldane and Henderson disagreed on what exactly Bernard had bequeathed to their discipline. In my view, it was Cannon who grasped the full significance of Bernard’s message, although relatively late in his career. Out of his early work, Cannon formulated an idea of how a variety of bodily systems might work co-operatively in times of emergency. Later he realised that integration drawing upon the resources of multiple psychological and physiological systems was a central feature also of normal conditions. Then Cannon could dovetail his insights with those of Bernard. The milieu inte´rieur remains stable provided that all bodily systems function in harmony to provide active stabilisation. The ‘‘normal’’ state is not a ‘‘resting’’ state. Cannon’s last major co-worker, Rosenblueth, working with Wiener at the same time, saw how homeostasis could be operationalised by introducing the engineering principle of negative feedback. Homeostasis was lifted from an updating of Bernard’s concept to a working proposition. Development of the concept has continued through the second half of the twentieth century. Other accounts must be provided of the work since Cannon’s time. I expect that the strengths and limitations of homeostasis as an explanatory tool will be seen to depend entirely on how the concept is interpreted in the circumstances to which it is applied. Acknowledgements After Professor Cooper retired, his PA while Head of Department, Mrs Anne Halliwell, kindly produced a photographically illustrated monograph he had written with the title, ‘‘From Claude Bernard to Walter Cannon: the emergence of the concept of homeostasis in 19th and 20th century experimental physiology and medicine.’’ This abbreviated version for publication has been prepared (and introduced) by David Booth and reviewed by Gerry Smith. While

terminally ill, Steve Cooper approved the proposal to publish such an abridgement but unexpectedly died before a draft could be shown to him. From the start of work on the monograph, he had regarded the history of further developments as a separate project and was glad to learn that others would take up that task in their own way alongside this paper. References Adolph, E. F. (1961). Concepts of physiological regulations. Physiological Reviews, 41, 737–770. Allen, G. E. (1967). J.S. Haldane: the development of the idea of control mechanisms in respiration. Journal of History of Medicine, 22, 392–412. Bayliss, W. M., & Starling, E. H. (1904). The chemical regulation of the secretory process. Proceedings of the Royal Society, 73, 310–322. Benison, S., Barger, A. C., Wolfe, E. L., & Walter, B. (1987). Cannon: the life and times of a young scientist. Cambridge, MA: Belknap Press. Benison, S., Barger, A. D., Wolfe, E. L., & Walter, B. (1991). 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