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The Concept of the Organism in Physiology
Theory Biosci. (2000) 119: 174±186 Ó Urban & Fischer Verlag http://www.urbanfischer.de/journals/theorybiosc
The Concept of the Organism in Physiology Robert L. Perlman Department of Pediatrics, The University of Chicago, Chicago, IL 60637 USA Address for Correspondence: Robert L. Perlman, Department of Pediatrics (MC 5058), The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637 USA, Phone: 7 73-7 02-64 25, Fax: 7 73-7 02-92 34, E-mail: [email protected] Received: April 12, 2000; accepted: May, 4, 2000 Key words: Claude Bernard, development, environment, homeostasis, internal environment
Summary: The growth of physiology in the 19th and 20th centuries was accompanied by the development of disciplinary boundaries between physiology and other biological sciences. Physiology became the study of the mechanisms that underlie the functions of organisms and their component parts. Concern with the internal workings of organisms has led physiologists to focus on the maintenance of homeostasis in the internal environment rather than on the interactions of organisms with their external environments. Moreover, interest in the cellular or biochemical mechanisms that underlie organismal function has resulted in the use of inbred populations of laboratory animals in which these mechanisms can be most rigorously studied. Finally, emphasis on the function of fully developed or adult organisms has been accompanied by a relative neglect of developmental processes. Disregard for the environment, for variation, and for development has made possible major advances in our knowledge of physiological mechanisms but has led to an impoverished concept of organisms. Incorporation of evolutionary, ecological, and developmental perspectives into the study of organisms might help to unite physiology more closely with the other biological sciences and lead to a richer and fuller understanding of organisms.
1. Introduction Organisms occupy a central place in biology. As individuals, organisms are organized; they comprise parts or organs whose integrated function enables the organisms to survive and reproduce. As members of populations, organisms interact with one another and with their environments, and their success or failure in these interactions results in the evolution of the populations of which they are a part. These inward-looking and outwardlooking faces of organisms should be complementary. After all, the internal structure and function of organisms have been shaped by evolution by natural selection, and conversely the adaptation of organisms to their en-
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vironment, their ability to survive and reproduce, depends upon their internal organization and regulation. Historically, however, these two aspects of organisms have been the subjects of different disciplines, with different assumptions and biases. Physiology and other disciplines of functional or mechanistic biology have been concerned with the properties of individual organisms, and especially with the cellular and molecular mechanisms that underlie the integrated function and survival of organisms. Evolutionary biology and ecology, on the other hand, have been concerned with organisms as members of populations, and with the adaptations that have promoted the survival and reproduction of organisms in the environments in which they evolved. Because these different disciplines developed separately, the inward-looking orientation of physiology and the outward-looking orientation of evolutionary biology have not been well integrated. The lack of integration of these complementary perspectives has impeded our understanding of living organisms. In the following discussion, I shall focus on the work of Claude Bernard. Bernard, one of the most influential physiologists of the 19th century, was professor of physiology at the Sorbonne and the ColleÁge de France, and a member of the AcadeÂmie FrancËaise. In addition to being an outstanding scientist, he was especially interested in epistemological and methodological questions, and in establishing physiology as an independent discipline.
2. Claude Bernard In 1865, six years after Darwin published On the Origin of Species, Bernard published his most influential work, An Introduction to the Study of Experimental Medicine (Bernard, 1865; hereafter referred to as the Introduction). In this book, Bernard mentions Darwin only once: We must doubtless admire those great horizons dimly seen by the genius of a Goethe [or] a Darwin, in which a general conception shows us all living beings as the expression of types ceaselessly transformed in the evolution of organisms and species, -types in which every living being individually disappears like a reflection of the whole to which it belongs (p. 91). But Bernard then goes on to say: But if we gave ourselves up exclusively to hypothetical contemplation, we should soon turn our backs on reality; and in my opinion, we should misunderstand true scientific philosophy (p. 92). [For the record, it seems that Darwin was more generous in his treatment of Bernard. In The Expression of the Emotions in Man and Animals (1872), Darwin comments:
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The great physiologist Claude Bernard has shown how the least excitement of a sensitive nerve reacts on the heart; even when a nerve is touched so slightly that no pain can possibly be felt by the animal under experiment . . . Claude Bernard also repeatedly insists, and this deserves especial notice, that when the heart is affected it reacts on the brain; and the state of the brain again reacts . . . on the heart; so that under any excitement there will be much mutual action and reaction between these, the two most important organs of the body. Later, Darwin refers to Bernard, along with MuÈller, Virchow, and others, as ªthe greatest physiologists.º Nevertheless, physiology has followed the path of Bernard in downplaying if not dismissing evolutionary thought.] Bernard's dismissal of Goethe and Darwin may have been motivated in part by French nationalism. More importantly, however, the Introduction was part of what William Coleman (1985) has called Bernard's campaign for ªdisciplinary justification,º a campaign to establish experimental physiology as an autonomous discipline, freed from its historical roots and separate both from physics and chemistry and from the other biological sciences (see also Schiller, 1968, Roll-Hansen, 1976). French physiology was still heavily influenced by the vitalism of Bichat and his school, who believed that physiological processes were fundamentally different from physical ones and that life resulted from a vital force that opposed the physical and chemical forces which would otherwise lead to death. In contrast, Bernard argued that: [T]he science of vital phenomena must have the same foundations as the science of the phenomena of inorganic bodies . . . there is no difference in this respect between the principles of biological science and those of physico-chemical science . . . [T]he goal which the experimental method sets itself is everywhere the same; it consists in connecting natural phenomena with their necessary conditions or with their immediate causes (p. 60). Physiological phenomena, like physical and chemical phenomena, are subject to regular laws; they are produced whenever the ªnecessary conditionsº or ªimmediate causesº exist: In living bodies, as in inorganic bodies, laws are immutable, and the phenomena governed by these laws are bound to the conditions on which they exist, by a necessary and absolute determinism (p. 69). The goal of physiological research is to identify the conditions or causes that bring about or determine physiological phenomena. In its insistence that vital phenomena are fully determined by the conditions under which they appear, Bernard's physiology rejected Bichat's form of vitalism.
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Bernard's physiology was an experimental science that differed fundamentally from the observational or descriptive natural sciences. In the opening pages of the Introduction, Bernard sets out this distinction: Only within very narrow boundaries can man observe the phenomena which surround him; most of them naturally escape his senses, and mere observation is not enough . . . But man does not limit himself to seeing; he . . . reasons, compares facts, puts questions to them, and by the answers which he extracts, tests one by another. This sort of control, by means of reasoning and facts, is what constitutes experiment, properly speaking; and it is the only process that we have for teaching ourselves about the nature of things outside us. In the philosophic sense, observation shows, and experiment teaches (p. 5). Experimental sciences not only differed from, but were superior to, observational sciences: Naturalists, physiologists and physicians have wholly different problems in view . . . hence we cannot, for instance, exactly superpose a physiological scale on the geological scale. Physiologists and physicians delve much more deeply than zooÈlogists into the problem of biology (p. 92). Bernard recognized the distinction we now make between proximate and ultimate causes (Mayr, 1961), and was clear about the appropriate scope of physiology: The nature of our mind leads us to seek the essence or the why of things. Thus we aim beyond the goal that is given us to reach; for experience soon teaches us that we cannot get beyond the how, i. e., beyond the immediate cause or the necessary conditions of phenomena. In this respect the limits of our knowledge are the same in biological as in physico-chemical sciences (p. 80). As noted by Roll-Hansen (1976), ªBernard . . . did not accept the origin of species as a scientific problem.º In his quest to establish physiology as a distinct discipline, then, Bernard ignored, if not disparaged, other approaches to the study of organisms.
3. The milieu inteÂrieur Bernard recognized the importance of the environment in determining physiological, as well as physical and chemical phenomena. This recognition led to what is perhaps Bernard's most lasting scientific contribution, his definition of the milieu inteÂrieur, or internal environment, as the environment in which the cells (or tissue elements) of living organisms reside
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and in which these cells carry out their physiological functions. Bernard described the relationship between the outer and inner environments as follows: The phenomena of life, as well as those of inorganic bodies, are thus doubly conditioned. On the one hand, we have the organism in which vital phenomena come to pass; on the other hand, the cosmic environment in which living bodies, like inorganic bodies, find the conditions essential to the appearance of their phenomena . . . Ancient science was able to conceive only the outer environment; but to establish the science of experimental biology we must also conceive an inner environment . . . Only by passing into the inner, can the influence of the outer environment reach us, whence it follows that knowing the outer environment cannot teach us the actions born in, and proper to, the inner environment. The general cosmic environment is common to living and to inorganic bodies; but the inner environment created by an organism is special to each living being. Now, here is the true physiological environment; this it is which physiologists and physicians should study and know, for by its means they can act on the histological units which are the only effective agents in vital phenomena (pp. 74±76). And again: [V]ital phenomena are the result of contact between the organic units of the body with the inner physiological environment (p. 66, emphasis in original); and We must therefore seek the true foundation of animal physics and chemistry in the physico-chemical properties of the inner environment (p. 99). It is the internal environment that determines the functions of cells and organs. Bernard embraced a scale of nature, based on the degree to which organisms were free or independent of the external environment. In his later book, Phenomena of Life Common to Animals and Plants (1878), Bernard distinguished three forms of life: 1. Latent life; nonmanifest life. 2. Oscillating life; life with variable manifestations, and dependent upon the external environment. [and] 3. Constant life; life with free manifestations, and independent of the external environment. These forms of life were distinguished by the degree to which organisms were able to maintain their internal environment constant and to exhibit ªthe manifestations of lifeº in the face of changes in the external environment. Latent life was characterized by what Bernard called ªchemical indifference.º In this category, Bernard placed seeds, and animals such as ro-
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tifers, that can survive in an inactive, desiccated state. Bernard considered plants, invertebrates, ªcold-bloodedº vertebrates, and hibernating mammals as examples of oscillating life. These organisms are dormant in the cold, but their dormancy differs from the chemical indifference of latent life because they continue to carry out metabolic processes and to exchange materials with the external environment. Only homeothermic vertebrates, mammals and birds, manifest constant or free life. Because Bernard believed that this constant or free life was the highest form of life, he focused his attention on the mechanisms by which these organisms maintain their internal environment constant in the face of changes in their external environments. Again, the internal environment was critical to Bernard's determinism, because, in organisms that displayed constant or free life, physiological phenomena were determined by the conditions of the internal rather than the external environment. Thus, he wrote: The constancy of the internal environment is the condition for free and independent life . . . All the vital mechanisms, however varied they might be, have only one purpose, that of maintaining the integrity of the conditions for life within the internal environment.
4. Typological thinking Ernest Boesiger has argued that the scholastic and Cartesian heritage of the French predisposed them to accept what Mayr has called typological thinking and to reject the population thinking of evolutionary biology (Boesiger, 1980). Bernard certainly embraced Descartes' mechanical model of organisms. In the Introduction, Bernard stated: To succeed in solving these various problems, we must, as it were, analyze the organism, as we take apart a machine, to review and study all its works (p. 65). Bernard's emphasis on the constancy of the internal environment seems to have reinforced his typological thinking. Just as variations in the internal environment in individual organisms were given less attention than the maintenance of constant conditions within the organism, so variations between organisms were considered less important than the similarities or regularities between them. Although Bernard carried out quantitative experiments, he drew qualitative conclusions from them. He was interested, for example, in the conditions under which glycogen was synthesized or broken down in the liver, rather than in the rates or amounts of glycogen synthesis or breakdown. Again, Bernard was interested in the similarities between organisms rather than in the differences between them; he defined his discipline as general physiology, not comparative physiology. [When
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Bernard was appointed Professor of Physiology at the MuseÂum d'Histoire Naturelle in 1868, the name of the chair was changed from comparative physiology to general physiology (Grmek, 1973).] Bernard believed there were ideal types of ªvital phenomena,º just as there were ideal types of physico-chemical phenomena. He was skeptical of statistics and saw variations as deviations from the truth that were best ignored: [I]n physiology, we must never make average descriptions of experiments, because the true relations of phenomena disappear in the average; when dealing with complex and variable experiments, we must study their various circumstances, and then present our most perfect experiment as a type, which, however, still stands for true facts (p. 135).
5. Health and Disease As normal function or health became associated with constancy and with the insulation of organisms from their external environment, abnormal function or disease became associated with variation and with environmental susceptibility. Although Bernard felt strongly that experimental medicine should be based on physiology, he noted an important difference between physiology and medicine: [P]hysicians cannot content themselves with knowing that all vital phenomena occur in identical conditions among all human beings; they must go still further by studying the details of these conditions in each individual . . . Through study, then, of physico-chemical details, physicians will learn to understand individualities as special cases included in a general law, and will discover there, as everywhere, an harmonious generalization of variety in unity. But since physicians deal with variety, they must always seek to define it in their studies and to comprehend it in their generalizations (pp. 92±93). While physiology was concerned with similarity or uniformity, pathology was concerned with variation, both the variation from normal that characterized specific diseases and the variable manifestations associated with these diseases. Rudolf Virchow, Professor of Pathology at Berlin and WuÈrzburg, and one of the founders of cell theory, conceived of organisms as societies of cells and saw variation between organisms as arising from variable numbers and variable activities of their constituent cells. In Cellular Pathology (1858), he wrote: What is an organism? A society of living cells, a tiny well-ordered state . . . [T]he more the organism develops, the more its social character becomes evident. It consists of innumerable independent parts which to-
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gether form a single social body . . . The whole organism is so little a definite unit that the number of its living constituents is highly variable . . . Virchow recognized normal variation. Thus, he wrote: Man, like all other animals, has a fixed number of bones and teeth . . . But these numbers form no essential features of existence; a man with six fingers or seven toes remains a man . . . In the second half of the 19th century, some diseases were recognized as being caused by specific environmental factors, namely parasites. Virchow argued that disease was simply ªlife under altered circumstances.º Perhaps because Virchow was a pathologist, however, his views had more influence on pathology than on physiology. Thus, variation and ecology came to be seen as determinants of disease rather than as characteristics of health. Medicine's traditional concern with individual patients became focused on individual patients' specific illnesses. This may be an example of what Jared Diamond (1997) has called the ªAnna Karenina Principleº: All healthy people are alike but each unhealthy person is unhealthy in his or her own way.
6. Development Although Bernard suggested that development might eventually be understood in mechanistic or physico-chemical terms, he accepted development as the product of a vital force, and felt that physiologists had to work within the limits defined by the developing organism. In keeping with his focus on the essential role of the internal environment in physiological phenomena, he saw development as directed from within the organism: [W]hat distinguishes a living machine is not the nature of its physicochemical properties, complex as they may be, but rather the creation of the machine which develops under our eyes in conditions proper to itself and according to a definite idea which expresses the living being's nature and the very essence of life . . . In every living germ is a creative idea which develops and exhibits itself through organization. As long as a living being persists, it remains under the influence of this same creative vital force, and death comes when it can no longer express itself (p. 93). While Bernard argued vehemently against Bichat's ªclassicalº vitalism, his own thought was a complex blend of vitalism and materialism (Grmek, 1973). Bernard believed that vital processes were completely determined by physicochemical laws; there was no vital force that acted in opposition to these physicochemical forces. On the other hand, development, or ªorganic creation,º resulted from the expression of an inner force or urge.
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Bernard's vitalism was as much an epistemological as an ontological claim; physiologists had to accept development as the expression of a vital force because the process of development was inaccessible to experimental science. For Riese, ªIt adds scientific charm to the personality and work of Claude Bernard that he belongs to two agesº (Riese, 1943).
7. Physiology after Bernard Bernard's concept of the internal environment as the environment in which living processes occur and as the appropriate focus of physiological research was extended by Walter Cannon, professor of physiology at Harvard Medical School. Cannon coined the term homeostasis to signify the maintenance of constancy in the internal environment. Cannon did not fully share Bernard's faith in physico-chemical explanations of vital phenomena. In his classic essay on homeostasis, Cannon (1929) wrote: The factors which operate in the body to maintain uniformity are often so peculiarly physiological that any hint of immediate explanation in terms of relatively simple mechanics seems misleading. Cannon emphasized that homeostasis did not refer to physico-chemical mechanisms for maintaining equilibrium, but rather to: The coordinated physiological reactions which maintain most of the steady states in the body [and which] are so complex, and are so peculiar to the living organism. Cannon recognized that homeostatic mechanisms are called into play by changes in the external environment. Like Bernard, however, he believed that the proper subject of physiology was the internal mechanisms that maintain homeostasis rather than the external factors that elicit homeostatic responses. In Cannon's view: [R]egulation in the organism is the central problem of physiology (my emphasis), and therefore: [F]urther research into the operation of agencies for maintaining biological homeostasis is desirable. This sentence set the research agenda for physiologists for the rest of the 20th century. Joseph Barcroft, Professor of Physiology at Cambridge, asked why it was important for organisms to control their internal environments. His answer was that a constant internal environment made possible the precise, coordinated function of the mammalian central nervous system and that it
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was therefore a prerequisite for the higher mental functions of human beings (Barcroft, 1934). This argument, together with the close association of physiology with medicine, reinforced the focus of physiology on human or mammalian physiology and its emphasis on the internal environment. Of course, there were physiologists who did not accept the perspective of Bernard and his followers. As noted above, comparative physiology investigates differences between species that live in different environments and so is concerned with the relationships of organisms to their external environments. Comparative physiology, however, has never achieved the institutional support and prestige accorded to general physiology. One the most prominent physiologist-critics of Bernard's materialism was J. S. Haldane, of Oxford University. Haldane was a respiratory physiologist whose pioneering studies on acclimatization to high altitude revealed the effects of hypoxia on the structure and function of the cardiovascular and respiratory systems. Haldane argued that organisms could not be understood simply as machines made up of parts that functioned within a constant internal environment. Instead, organisms behave as integrated wholes that interact with and are affected by their external environment: The life of an organism is ultimately just as much bound up with its external as with its internal environment . . . Organism and external environment hang together in the specific manner which is a normal expression of the life of the organism (Haldane, 1931). Despite the fact that Haldane was a highly respected physiologist, however, his holistic view of organisms was dismissed as mysticism and did not gain wide support. The legacy of Bernard and Cannon continues to dominate teaching and research in physiology. Many contemporary textbooks of human or mammalian physiology sound remarkably like the Introduction. The goal of physiology, or of science in general, is presented as mechanistic: The mechanist view of life, the view taken by physiologists, holds that all phenomena, no matter how complex, can ultimately be described in terms of physical and chemical laws . . . In science, to explain a phenomenon is to reduce it to a causally linked sequence of physicochemical events (Vander et al., 1998). While these texts suggest that physiological processes are beneficial to organisms and have been produced by evolution, they say little or nothing about the mechanisms of evolution and natural selection. If taken literally, statements such as, ªThe simplest structural units into which a complex multicellular organism can be divided and still retain the functions characteristic of life are called cells (Silverthorn, 1998),º would seem to imply that evolution and natural selection are not ªfunctions characteristic of
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life.º Although most homeostatic mechanisms probably are adaptations, linguistic traditions may hinder recognition of the adaptive significance of physiological processes. In physiology, ªadaptationº refers to the decreased responsiveness of excitable cells to continuous or repetitive stimulation, not to a trait that has been shaped and preserved by natural selection. Ironically, most textbooks of mammalian physiology stress the physiological effects of high altitude; they discuss the work of Haldane and others in this field but do not mention Haldane's philosophical view of organisms or of organism-environmental interactions. Moreover, physiology remains largely the study of adult organisms. Except for a few special topics, such as the transition from fetal to independent life and the hormonal changes of puberty, physiology does not extend its purview to the development of physiological functions or of homeostatic regulatory mechanisms. Finally, most textbooks ignore the issue of variation and, following Bernard, present idealized conclusions as the truth. When variation is discussed, it is still treated as a nuisance that complicates physiological research: [T]here is a tremendous amount of variability within human populations . . . [T]o show significant differences between experimental and control groups in a human experiment, an investigator would, ideally, have to include large numbers of identical subjects. In human experiments, however, getting two groups of people who are identical in every respect is impossible . . . The variability inherent in even a select group of humans must be taken into account when doing experiments with human subjects, as variability may affect the researcher's ability to accurately interpret the significance of data collected on that group (Silverthorn, 1998). The goal of understanding organisms as physico-chemical machines in which reproducible conditions would lead to reproducible effects has affected research as well as teaching. In what might best be described as ªNature imitating art,º physiologists now study inbred strains of animals that are bred and raised in a controlled laboratory environment. Close (1993) has discussed the development of the Wistar Rat and the conscious promoting and marketing of these rats as ªstandard animalsº for physiological research. Having removed the variation and environmental influences that might otherwise complicate experiments, we now encounter organisms as we have constructed them and see no need to restore what has been lost.
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8. Conclusions My purpose is not to fault Bernard, Cannon, or other physiologists who have followed the trail they blazed. Their work has led to a deep understanding of the wondrous complexity and harmony of biological regulatory mechanisms. The focus of physiology on the internal workings of organisms, rather than on their relationships with the external environment, was probably essential for the progress this discipline has made. Nonetheless, it may now be time to integrate a physiological view of organisms with the complementary views of evolutionary and developmental biology, and ecology. The abstraction of organisms from their ecological contexts provides only a partial and misleading view of organisms. The focus on idealized or ªtypicalº organisms and the treatment of variation as a nuisance obscures the important realization that variation is a defining characteristic of biological species. Perhaps most problematic, however, is the focus of mechanistic biology on internal causes of physiological phenomena. The current emphasis of physiology on genes and gene expression, together with the neglect of the external environment and of developmental processes, presents a misleading view of organisms as simply the products of their genes. A richer account of organisms would integrate their internal and external faces and would present an understanding of development as a development of the interaction between the organism and its environment. A closing anecdote emphasizes the similarities between biomedical research in Claude Bernard's day and in our own. Bernard, like most productive scientists, had an insatiable appetite for research facilities and research support. When he moved from the ColleÁge de France to the MuseÂum d'Histoire Naturelle, Bernard hoped to build a suitable laboratory for his work at the MuseÂum. But upon hearing how much this new laboratory would cost, the Emperor Napoleon the Third is alleged to have exclaimed, ªFour hundred thousand francs! This physiology ± will it be as costly as the artillery?º (Halberg, 1967).
Acknowledgments Jason Robert and Bill Wimsatt provided valuable feedback on earlier drafts of this manuscript. John Beatty alerted me to the Coleman (1985) paper.
References Barcroft, J. (1934) Features in the Architecture of Physiological Function, Cambridge, Cambridge University Press. Bernard, C. (1865) Introduction a l'EÂtude de la MeÂdecine ExpeÂrimentale, Paris, J.-B. BaillieÂre. English translation: An Introduction to the Study of Experimental Medicine (Green, H. C., tr.), New York, Dover, 1957
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Bernard, C. (1878) LecËons sur les PheÂnomeÁnes de la Vie communs aux Animaux et aux Vegetaux, Paris, J.-B. BaillieÂre. English translation: Lectures on the Phenomena of Life Common to Animals and Plants (Hoff, H. E., Guillemin, R., and Guillemin, L., tr.), Springfield, IL, Thomas, 1974. Boesiger, E. (1980) Evolutionary biology in France at the time of the evolutionary synthesis. In The Evolutionary Synthesis (Mayr, E., and Provine, W. B., eds.), Cambridge, MA, Harvard, pp. 309±321. Cannon, W. B. (1929) Organization for physiological homeostasis. Physiol. Rev. 9, 399±431. Close, B. T. (1993) The Wistar Rat as a right choice: Establishing mammalian standards and the ideal of a standardized mammal. J. Hist. Biol. 26, 329±349. Coleman, W. (1985): The cognitive basis of the discipline: Claude Bernard on physiology. Isis 76, 49±70. Darwin, C. (1872) The Expression of the Emotions in Man and Animals, London, Appleton. Diamond, J. (1997) Guns, Germs, and Steel, New York, Norton. Grmek, M. (1973) Bernard, Claude. In Dictionary of Scientific Biography (Gillespie, C. C., ed.), New York, Scribners, vol. 2, pp. 24±34. Halberg, F. (1967) Claude Bernard and the ªextreme variability of the internal milieu.º In Claude Bernard and Experimental Medicine (Grande, F., and Visscher, M. B., eds.), Cambridge, MA, Schenkman. Haldane, J. S. (1931) The Philosophical Basis of Biology, Garden City, NY, Doubleday, Doran & Co. Mayr, E. (1961) Cause and effect in biology. Science 134, 1501±1506. Riese, W. (1943) Claude Bernard in the light of modern science. Bull. Hist. Med. 14, 281±294. Roll-Hansen (1976) Critical teleology: Immanuel Kant and Claude Bernard on the limitations of experimental biology. J. Hist. Biol. 9, 59±91. Schiller, J. (1968) Physiology's struggle for independence in the first half of the nineteenth century. Hist. Sci. 7, 64±89. Silverthorn, D.U. (1998) Human Physiology: An Integrated Approach, Upper Saddle River, NJ, Prentice Hall. Vander, A., Sherman, J., and Luciano, D. (1998) Human Physiology, 7th Ed., Boston, WCB/ McGraw-Hill. Virchow, R. (1858) Die Cellularpathologie, Berlin, Hirschwald. English translation: Cellular Pathology (Chance, F., tr.), New York, Dover, 1971.
The Concept of the Organism in Physiology Robert L. Perlman Department of Pediatrics, The University of Chicago, Chicago, IL 60637 USA Address for Correspondence: Robert L. Perlman, Department of Pediatrics (MC 5058), The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637 USA, Phone: 7 73-7 02-64 25, Fax: 7 73-7 02-92 34, E-mail: [email protected] Received: April 12, 2000; accepted: May, 4, 2000 Key words: Claude Bernard, development, environment, homeostasis, internal environment
Summary: The growth of physiology in the 19th and 20th centuries was accompanied by the development of disciplinary boundaries between physiology and other biological sciences. Physiology became the study of the mechanisms that underlie the functions of organisms and their component parts. Concern with the internal workings of organisms has led physiologists to focus on the maintenance of homeostasis in the internal environment rather than on the interactions of organisms with their external environments. Moreover, interest in the cellular or biochemical mechanisms that underlie organismal function has resulted in the use of inbred populations of laboratory animals in which these mechanisms can be most rigorously studied. Finally, emphasis on the function of fully developed or adult organisms has been accompanied by a relative neglect of developmental processes. Disregard for the environment, for variation, and for development has made possible major advances in our knowledge of physiological mechanisms but has led to an impoverished concept of organisms. Incorporation of evolutionary, ecological, and developmental perspectives into the study of organisms might help to unite physiology more closely with the other biological sciences and lead to a richer and fuller understanding of organisms.
1. Introduction Organisms occupy a central place in biology. As individuals, organisms are organized; they comprise parts or organs whose integrated function enables the organisms to survive and reproduce. As members of populations, organisms interact with one another and with their environments, and their success or failure in these interactions results in the evolution of the populations of which they are a part. These inward-looking and outwardlooking faces of organisms should be complementary. After all, the internal structure and function of organisms have been shaped by evolution by natural selection, and conversely the adaptation of organisms to their en-
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vironment, their ability to survive and reproduce, depends upon their internal organization and regulation. Historically, however, these two aspects of organisms have been the subjects of different disciplines, with different assumptions and biases. Physiology and other disciplines of functional or mechanistic biology have been concerned with the properties of individual organisms, and especially with the cellular and molecular mechanisms that underlie the integrated function and survival of organisms. Evolutionary biology and ecology, on the other hand, have been concerned with organisms as members of populations, and with the adaptations that have promoted the survival and reproduction of organisms in the environments in which they evolved. Because these different disciplines developed separately, the inward-looking orientation of physiology and the outward-looking orientation of evolutionary biology have not been well integrated. The lack of integration of these complementary perspectives has impeded our understanding of living organisms. In the following discussion, I shall focus on the work of Claude Bernard. Bernard, one of the most influential physiologists of the 19th century, was professor of physiology at the Sorbonne and the ColleÁge de France, and a member of the AcadeÂmie FrancËaise. In addition to being an outstanding scientist, he was especially interested in epistemological and methodological questions, and in establishing physiology as an independent discipline.
2. Claude Bernard In 1865, six years after Darwin published On the Origin of Species, Bernard published his most influential work, An Introduction to the Study of Experimental Medicine (Bernard, 1865; hereafter referred to as the Introduction). In this book, Bernard mentions Darwin only once: We must doubtless admire those great horizons dimly seen by the genius of a Goethe [or] a Darwin, in which a general conception shows us all living beings as the expression of types ceaselessly transformed in the evolution of organisms and species, -types in which every living being individually disappears like a reflection of the whole to which it belongs (p. 91). But Bernard then goes on to say: But if we gave ourselves up exclusively to hypothetical contemplation, we should soon turn our backs on reality; and in my opinion, we should misunderstand true scientific philosophy (p. 92). [For the record, it seems that Darwin was more generous in his treatment of Bernard. In The Expression of the Emotions in Man and Animals (1872), Darwin comments:
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The great physiologist Claude Bernard has shown how the least excitement of a sensitive nerve reacts on the heart; even when a nerve is touched so slightly that no pain can possibly be felt by the animal under experiment . . . Claude Bernard also repeatedly insists, and this deserves especial notice, that when the heart is affected it reacts on the brain; and the state of the brain again reacts . . . on the heart; so that under any excitement there will be much mutual action and reaction between these, the two most important organs of the body. Later, Darwin refers to Bernard, along with MuÈller, Virchow, and others, as ªthe greatest physiologists.º Nevertheless, physiology has followed the path of Bernard in downplaying if not dismissing evolutionary thought.] Bernard's dismissal of Goethe and Darwin may have been motivated in part by French nationalism. More importantly, however, the Introduction was part of what William Coleman (1985) has called Bernard's campaign for ªdisciplinary justification,º a campaign to establish experimental physiology as an autonomous discipline, freed from its historical roots and separate both from physics and chemistry and from the other biological sciences (see also Schiller, 1968, Roll-Hansen, 1976). French physiology was still heavily influenced by the vitalism of Bichat and his school, who believed that physiological processes were fundamentally different from physical ones and that life resulted from a vital force that opposed the physical and chemical forces which would otherwise lead to death. In contrast, Bernard argued that: [T]he science of vital phenomena must have the same foundations as the science of the phenomena of inorganic bodies . . . there is no difference in this respect between the principles of biological science and those of physico-chemical science . . . [T]he goal which the experimental method sets itself is everywhere the same; it consists in connecting natural phenomena with their necessary conditions or with their immediate causes (p. 60). Physiological phenomena, like physical and chemical phenomena, are subject to regular laws; they are produced whenever the ªnecessary conditionsº or ªimmediate causesº exist: In living bodies, as in inorganic bodies, laws are immutable, and the phenomena governed by these laws are bound to the conditions on which they exist, by a necessary and absolute determinism (p. 69). The goal of physiological research is to identify the conditions or causes that bring about or determine physiological phenomena. In its insistence that vital phenomena are fully determined by the conditions under which they appear, Bernard's physiology rejected Bichat's form of vitalism.
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Bernard's physiology was an experimental science that differed fundamentally from the observational or descriptive natural sciences. In the opening pages of the Introduction, Bernard sets out this distinction: Only within very narrow boundaries can man observe the phenomena which surround him; most of them naturally escape his senses, and mere observation is not enough . . . But man does not limit himself to seeing; he . . . reasons, compares facts, puts questions to them, and by the answers which he extracts, tests one by another. This sort of control, by means of reasoning and facts, is what constitutes experiment, properly speaking; and it is the only process that we have for teaching ourselves about the nature of things outside us. In the philosophic sense, observation shows, and experiment teaches (p. 5). Experimental sciences not only differed from, but were superior to, observational sciences: Naturalists, physiologists and physicians have wholly different problems in view . . . hence we cannot, for instance, exactly superpose a physiological scale on the geological scale. Physiologists and physicians delve much more deeply than zooÈlogists into the problem of biology (p. 92). Bernard recognized the distinction we now make between proximate and ultimate causes (Mayr, 1961), and was clear about the appropriate scope of physiology: The nature of our mind leads us to seek the essence or the why of things. Thus we aim beyond the goal that is given us to reach; for experience soon teaches us that we cannot get beyond the how, i. e., beyond the immediate cause or the necessary conditions of phenomena. In this respect the limits of our knowledge are the same in biological as in physico-chemical sciences (p. 80). As noted by Roll-Hansen (1976), ªBernard . . . did not accept the origin of species as a scientific problem.º In his quest to establish physiology as a distinct discipline, then, Bernard ignored, if not disparaged, other approaches to the study of organisms.
3. The milieu inteÂrieur Bernard recognized the importance of the environment in determining physiological, as well as physical and chemical phenomena. This recognition led to what is perhaps Bernard's most lasting scientific contribution, his definition of the milieu inteÂrieur, or internal environment, as the environment in which the cells (or tissue elements) of living organisms reside
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and in which these cells carry out their physiological functions. Bernard described the relationship between the outer and inner environments as follows: The phenomena of life, as well as those of inorganic bodies, are thus doubly conditioned. On the one hand, we have the organism in which vital phenomena come to pass; on the other hand, the cosmic environment in which living bodies, like inorganic bodies, find the conditions essential to the appearance of their phenomena . . . Ancient science was able to conceive only the outer environment; but to establish the science of experimental biology we must also conceive an inner environment . . . Only by passing into the inner, can the influence of the outer environment reach us, whence it follows that knowing the outer environment cannot teach us the actions born in, and proper to, the inner environment. The general cosmic environment is common to living and to inorganic bodies; but the inner environment created by an organism is special to each living being. Now, here is the true physiological environment; this it is which physiologists and physicians should study and know, for by its means they can act on the histological units which are the only effective agents in vital phenomena (pp. 74±76). And again: [V]ital phenomena are the result of contact between the organic units of the body with the inner physiological environment (p. 66, emphasis in original); and We must therefore seek the true foundation of animal physics and chemistry in the physico-chemical properties of the inner environment (p. 99). It is the internal environment that determines the functions of cells and organs. Bernard embraced a scale of nature, based on the degree to which organisms were free or independent of the external environment. In his later book, Phenomena of Life Common to Animals and Plants (1878), Bernard distinguished three forms of life: 1. Latent life; nonmanifest life. 2. Oscillating life; life with variable manifestations, and dependent upon the external environment. [and] 3. Constant life; life with free manifestations, and independent of the external environment. These forms of life were distinguished by the degree to which organisms were able to maintain their internal environment constant and to exhibit ªthe manifestations of lifeº in the face of changes in the external environment. Latent life was characterized by what Bernard called ªchemical indifference.º In this category, Bernard placed seeds, and animals such as ro-
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tifers, that can survive in an inactive, desiccated state. Bernard considered plants, invertebrates, ªcold-bloodedº vertebrates, and hibernating mammals as examples of oscillating life. These organisms are dormant in the cold, but their dormancy differs from the chemical indifference of latent life because they continue to carry out metabolic processes and to exchange materials with the external environment. Only homeothermic vertebrates, mammals and birds, manifest constant or free life. Because Bernard believed that this constant or free life was the highest form of life, he focused his attention on the mechanisms by which these organisms maintain their internal environment constant in the face of changes in their external environments. Again, the internal environment was critical to Bernard's determinism, because, in organisms that displayed constant or free life, physiological phenomena were determined by the conditions of the internal rather than the external environment. Thus, he wrote: The constancy of the internal environment is the condition for free and independent life . . . All the vital mechanisms, however varied they might be, have only one purpose, that of maintaining the integrity of the conditions for life within the internal environment.
4. Typological thinking Ernest Boesiger has argued that the scholastic and Cartesian heritage of the French predisposed them to accept what Mayr has called typological thinking and to reject the population thinking of evolutionary biology (Boesiger, 1980). Bernard certainly embraced Descartes' mechanical model of organisms. In the Introduction, Bernard stated: To succeed in solving these various problems, we must, as it were, analyze the organism, as we take apart a machine, to review and study all its works (p. 65). Bernard's emphasis on the constancy of the internal environment seems to have reinforced his typological thinking. Just as variations in the internal environment in individual organisms were given less attention than the maintenance of constant conditions within the organism, so variations between organisms were considered less important than the similarities or regularities between them. Although Bernard carried out quantitative experiments, he drew qualitative conclusions from them. He was interested, for example, in the conditions under which glycogen was synthesized or broken down in the liver, rather than in the rates or amounts of glycogen synthesis or breakdown. Again, Bernard was interested in the similarities between organisms rather than in the differences between them; he defined his discipline as general physiology, not comparative physiology. [When
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Bernard was appointed Professor of Physiology at the MuseÂum d'Histoire Naturelle in 1868, the name of the chair was changed from comparative physiology to general physiology (Grmek, 1973).] Bernard believed there were ideal types of ªvital phenomena,º just as there were ideal types of physico-chemical phenomena. He was skeptical of statistics and saw variations as deviations from the truth that were best ignored: [I]n physiology, we must never make average descriptions of experiments, because the true relations of phenomena disappear in the average; when dealing with complex and variable experiments, we must study their various circumstances, and then present our most perfect experiment as a type, which, however, still stands for true facts (p. 135).
5. Health and Disease As normal function or health became associated with constancy and with the insulation of organisms from their external environment, abnormal function or disease became associated with variation and with environmental susceptibility. Although Bernard felt strongly that experimental medicine should be based on physiology, he noted an important difference between physiology and medicine: [P]hysicians cannot content themselves with knowing that all vital phenomena occur in identical conditions among all human beings; they must go still further by studying the details of these conditions in each individual . . . Through study, then, of physico-chemical details, physicians will learn to understand individualities as special cases included in a general law, and will discover there, as everywhere, an harmonious generalization of variety in unity. But since physicians deal with variety, they must always seek to define it in their studies and to comprehend it in their generalizations (pp. 92±93). While physiology was concerned with similarity or uniformity, pathology was concerned with variation, both the variation from normal that characterized specific diseases and the variable manifestations associated with these diseases. Rudolf Virchow, Professor of Pathology at Berlin and WuÈrzburg, and one of the founders of cell theory, conceived of organisms as societies of cells and saw variation between organisms as arising from variable numbers and variable activities of their constituent cells. In Cellular Pathology (1858), he wrote: What is an organism? A society of living cells, a tiny well-ordered state . . . [T]he more the organism develops, the more its social character becomes evident. It consists of innumerable independent parts which to-
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gether form a single social body . . . The whole organism is so little a definite unit that the number of its living constituents is highly variable . . . Virchow recognized normal variation. Thus, he wrote: Man, like all other animals, has a fixed number of bones and teeth . . . But these numbers form no essential features of existence; a man with six fingers or seven toes remains a man . . . In the second half of the 19th century, some diseases were recognized as being caused by specific environmental factors, namely parasites. Virchow argued that disease was simply ªlife under altered circumstances.º Perhaps because Virchow was a pathologist, however, his views had more influence on pathology than on physiology. Thus, variation and ecology came to be seen as determinants of disease rather than as characteristics of health. Medicine's traditional concern with individual patients became focused on individual patients' specific illnesses. This may be an example of what Jared Diamond (1997) has called the ªAnna Karenina Principleº: All healthy people are alike but each unhealthy person is unhealthy in his or her own way.
6. Development Although Bernard suggested that development might eventually be understood in mechanistic or physico-chemical terms, he accepted development as the product of a vital force, and felt that physiologists had to work within the limits defined by the developing organism. In keeping with his focus on the essential role of the internal environment in physiological phenomena, he saw development as directed from within the organism: [W]hat distinguishes a living machine is not the nature of its physicochemical properties, complex as they may be, but rather the creation of the machine which develops under our eyes in conditions proper to itself and according to a definite idea which expresses the living being's nature and the very essence of life . . . In every living germ is a creative idea which develops and exhibits itself through organization. As long as a living being persists, it remains under the influence of this same creative vital force, and death comes when it can no longer express itself (p. 93). While Bernard argued vehemently against Bichat's ªclassicalº vitalism, his own thought was a complex blend of vitalism and materialism (Grmek, 1973). Bernard believed that vital processes were completely determined by physicochemical laws; there was no vital force that acted in opposition to these physicochemical forces. On the other hand, development, or ªorganic creation,º resulted from the expression of an inner force or urge.
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Bernard's vitalism was as much an epistemological as an ontological claim; physiologists had to accept development as the expression of a vital force because the process of development was inaccessible to experimental science. For Riese, ªIt adds scientific charm to the personality and work of Claude Bernard that he belongs to two agesº (Riese, 1943).
7. Physiology after Bernard Bernard's concept of the internal environment as the environment in which living processes occur and as the appropriate focus of physiological research was extended by Walter Cannon, professor of physiology at Harvard Medical School. Cannon coined the term homeostasis to signify the maintenance of constancy in the internal environment. Cannon did not fully share Bernard's faith in physico-chemical explanations of vital phenomena. In his classic essay on homeostasis, Cannon (1929) wrote: The factors which operate in the body to maintain uniformity are often so peculiarly physiological that any hint of immediate explanation in terms of relatively simple mechanics seems misleading. Cannon emphasized that homeostasis did not refer to physico-chemical mechanisms for maintaining equilibrium, but rather to: The coordinated physiological reactions which maintain most of the steady states in the body [and which] are so complex, and are so peculiar to the living organism. Cannon recognized that homeostatic mechanisms are called into play by changes in the external environment. Like Bernard, however, he believed that the proper subject of physiology was the internal mechanisms that maintain homeostasis rather than the external factors that elicit homeostatic responses. In Cannon's view: [R]egulation in the organism is the central problem of physiology (my emphasis), and therefore: [F]urther research into the operation of agencies for maintaining biological homeostasis is desirable. This sentence set the research agenda for physiologists for the rest of the 20th century. Joseph Barcroft, Professor of Physiology at Cambridge, asked why it was important for organisms to control their internal environments. His answer was that a constant internal environment made possible the precise, coordinated function of the mammalian central nervous system and that it
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was therefore a prerequisite for the higher mental functions of human beings (Barcroft, 1934). This argument, together with the close association of physiology with medicine, reinforced the focus of physiology on human or mammalian physiology and its emphasis on the internal environment. Of course, there were physiologists who did not accept the perspective of Bernard and his followers. As noted above, comparative physiology investigates differences between species that live in different environments and so is concerned with the relationships of organisms to their external environments. Comparative physiology, however, has never achieved the institutional support and prestige accorded to general physiology. One the most prominent physiologist-critics of Bernard's materialism was J. S. Haldane, of Oxford University. Haldane was a respiratory physiologist whose pioneering studies on acclimatization to high altitude revealed the effects of hypoxia on the structure and function of the cardiovascular and respiratory systems. Haldane argued that organisms could not be understood simply as machines made up of parts that functioned within a constant internal environment. Instead, organisms behave as integrated wholes that interact with and are affected by their external environment: The life of an organism is ultimately just as much bound up with its external as with its internal environment . . . Organism and external environment hang together in the specific manner which is a normal expression of the life of the organism (Haldane, 1931). Despite the fact that Haldane was a highly respected physiologist, however, his holistic view of organisms was dismissed as mysticism and did not gain wide support. The legacy of Bernard and Cannon continues to dominate teaching and research in physiology. Many contemporary textbooks of human or mammalian physiology sound remarkably like the Introduction. The goal of physiology, or of science in general, is presented as mechanistic: The mechanist view of life, the view taken by physiologists, holds that all phenomena, no matter how complex, can ultimately be described in terms of physical and chemical laws . . . In science, to explain a phenomenon is to reduce it to a causally linked sequence of physicochemical events (Vander et al., 1998). While these texts suggest that physiological processes are beneficial to organisms and have been produced by evolution, they say little or nothing about the mechanisms of evolution and natural selection. If taken literally, statements such as, ªThe simplest structural units into which a complex multicellular organism can be divided and still retain the functions characteristic of life are called cells (Silverthorn, 1998),º would seem to imply that evolution and natural selection are not ªfunctions characteristic of
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life.º Although most homeostatic mechanisms probably are adaptations, linguistic traditions may hinder recognition of the adaptive significance of physiological processes. In physiology, ªadaptationº refers to the decreased responsiveness of excitable cells to continuous or repetitive stimulation, not to a trait that has been shaped and preserved by natural selection. Ironically, most textbooks of mammalian physiology stress the physiological effects of high altitude; they discuss the work of Haldane and others in this field but do not mention Haldane's philosophical view of organisms or of organism-environmental interactions. Moreover, physiology remains largely the study of adult organisms. Except for a few special topics, such as the transition from fetal to independent life and the hormonal changes of puberty, physiology does not extend its purview to the development of physiological functions or of homeostatic regulatory mechanisms. Finally, most textbooks ignore the issue of variation and, following Bernard, present idealized conclusions as the truth. When variation is discussed, it is still treated as a nuisance that complicates physiological research: [T]here is a tremendous amount of variability within human populations . . . [T]o show significant differences between experimental and control groups in a human experiment, an investigator would, ideally, have to include large numbers of identical subjects. In human experiments, however, getting two groups of people who are identical in every respect is impossible . . . The variability inherent in even a select group of humans must be taken into account when doing experiments with human subjects, as variability may affect the researcher's ability to accurately interpret the significance of data collected on that group (Silverthorn, 1998). The goal of understanding organisms as physico-chemical machines in which reproducible conditions would lead to reproducible effects has affected research as well as teaching. In what might best be described as ªNature imitating art,º physiologists now study inbred strains of animals that are bred and raised in a controlled laboratory environment. Close (1993) has discussed the development of the Wistar Rat and the conscious promoting and marketing of these rats as ªstandard animalsº for physiological research. Having removed the variation and environmental influences that might otherwise complicate experiments, we now encounter organisms as we have constructed them and see no need to restore what has been lost.
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8. Conclusions My purpose is not to fault Bernard, Cannon, or other physiologists who have followed the trail they blazed. Their work has led to a deep understanding of the wondrous complexity and harmony of biological regulatory mechanisms. The focus of physiology on the internal workings of organisms, rather than on their relationships with the external environment, was probably essential for the progress this discipline has made. Nonetheless, it may now be time to integrate a physiological view of organisms with the complementary views of evolutionary and developmental biology, and ecology. The abstraction of organisms from their ecological contexts provides only a partial and misleading view of organisms. The focus on idealized or ªtypicalº organisms and the treatment of variation as a nuisance obscures the important realization that variation is a defining characteristic of biological species. Perhaps most problematic, however, is the focus of mechanistic biology on internal causes of physiological phenomena. The current emphasis of physiology on genes and gene expression, together with the neglect of the external environment and of developmental processes, presents a misleading view of organisms as simply the products of their genes. A richer account of organisms would integrate their internal and external faces and would present an understanding of development as a development of the interaction between the organism and its environment. A closing anecdote emphasizes the similarities between biomedical research in Claude Bernard's day and in our own. Bernard, like most productive scientists, had an insatiable appetite for research facilities and research support. When he moved from the ColleÁge de France to the MuseÂum d'Histoire Naturelle, Bernard hoped to build a suitable laboratory for his work at the MuseÂum. But upon hearing how much this new laboratory would cost, the Emperor Napoleon the Third is alleged to have exclaimed, ªFour hundred thousand francs! This physiology ± will it be as costly as the artillery?º (Halberg, 1967).
Acknowledgments Jason Robert and Bill Wimsatt provided valuable feedback on earlier drafts of this manuscript. John Beatty alerted me to the Coleman (1985) paper.
References Barcroft, J. (1934) Features in the Architecture of Physiological Function, Cambridge, Cambridge University Press. Bernard, C. (1865) Introduction a l'EÂtude de la MeÂdecine ExpeÂrimentale, Paris, J.-B. BaillieÂre. English translation: An Introduction to the Study of Experimental Medicine (Green, H. C., tr.), New York, Dover, 1957
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Bernard, C. (1878) LecËons sur les PheÂnomeÁnes de la Vie communs aux Animaux et aux Vegetaux, Paris, J.-B. BaillieÂre. English translation: Lectures on the Phenomena of Life Common to Animals and Plants (Hoff, H. E., Guillemin, R., and Guillemin, L., tr.), Springfield, IL, Thomas, 1974. Boesiger, E. (1980) Evolutionary biology in France at the time of the evolutionary synthesis. In The Evolutionary Synthesis (Mayr, E., and Provine, W. B., eds.), Cambridge, MA, Harvard, pp. 309±321. Cannon, W. B. (1929) Organization for physiological homeostasis. Physiol. Rev. 9, 399±431. Close, B. T. (1993) The Wistar Rat as a right choice: Establishing mammalian standards and the ideal of a standardized mammal. J. Hist. Biol. 26, 329±349. Coleman, W. (1985): The cognitive basis of the discipline: Claude Bernard on physiology. Isis 76, 49±70. Darwin, C. (1872) The Expression of the Emotions in Man and Animals, London, Appleton. Diamond, J. (1997) Guns, Germs, and Steel, New York, Norton. Grmek, M. (1973) Bernard, Claude. In Dictionary of Scientific Biography (Gillespie, C. C., ed.), New York, Scribners, vol. 2, pp. 24±34. Halberg, F. (1967) Claude Bernard and the ªextreme variability of the internal milieu.º In Claude Bernard and Experimental Medicine (Grande, F., and Visscher, M. B., eds.), Cambridge, MA, Schenkman. Haldane, J. S. (1931) The Philosophical Basis of Biology, Garden City, NY, Doubleday, Doran & Co. Mayr, E. (1961) Cause and effect in biology. Science 134, 1501±1506. Riese, W. (1943) Claude Bernard in the light of modern science. Bull. Hist. Med. 14, 281±294. Roll-Hansen (1976) Critical teleology: Immanuel Kant and Claude Bernard on the limitations of experimental biology. J. Hist. Biol. 9, 59±91. Schiller, J. (1968) Physiology's struggle for independence in the first half of the nineteenth century. Hist. Sci. 7, 64±89. Silverthorn, D.U. (1998) Human Physiology: An Integrated Approach, Upper Saddle River, NJ, Prentice Hall. Vander, A., Sherman, J., and Luciano, D. (1998) Human Physiology, 7th Ed., Boston, WCB/ McGraw-Hill. Virchow, R. (1858) Die Cellularpathologie, Berlin, Hirschwald. English translation: Cellular Pathology (Chance, F., tr.), New York, Dover, 1971.