Charting a global future for education in physiology

The 2005 Claude Bernard Distinguished Lecture was presented at the XXXV International Congress of Physiological Sciences (IUPS) in San Diego, CA, by Ann J. Sefton. Dr. Sefton is an Emeritus Professor of Physiology of the University of Sydney and co-Chair of the IUPS Education Committee. A full profile of Dr. Sefton is included in this issue's The Physiology Teacher.     

Claude Bernard: primer of the second biomedical revolution

Claude Bernard, the son of a Beaujolais winegrower, moved to Paris to pursue his literary ambitions and went on to become one of the fathers of modern life sciences. What did Bernard do to earn universal renown? And are his teachings relevant to modern science?     

Contribution of physiologists to the identification of the humoral component of immunity in the 19th century

The history of antimicrobial humoral immunity usually focuses on the works of the German school at the end of the 19th century, born in the tradition of chemistry and disinfection. Starting from an old quarrel of priority about serotherapy between Emil von Behring (1854–1917) and the French physiologists Charles Richet (1850–1935) and Jules Héricourt (1850–1938), we first confirm that the latter stated the principle of serotherapy in 1888 and put it into practice before the seminal Behring's article in 1890, observing several adverse effects of this new immunotherapy. We also find that researchers who can be considered heirs of the French school of Physiology founded by Claude Bernard (1813–1878) also investigated the field of humoral immunity in the 1870–1880s. Maurice Raynaud (1834–1881), Auguste Chauveau (1827–1917), and eventually Charles Richet applied the experimental method of Claude Bernard to the young field of microbiology, illustrating a movement called by Jacques Léonard “physiologization of the pasteurism.” However, the contribution of physiologists in this field started before Louis Pasteur, leading to the conclusion that physiologists and chemists synergistically contributed to the birth of bacteriology and immunology.     

Tallow and the time capsule: Claude Bernard's discovery of the pancreatic digestion of fat

In 1848, Claude Bernard discovered that pancreatic secretion could emulsify and saponify fatty substances. He would eventually attribute these reactions to an enzyme that was later named 'pancreatic lipase'. This essay has three goals: 1) to examine Bernard's previously overlooked research on the pancreas; 2) to explore the equally ignored history of lipid digestion and metabolism; 3) to reconstruct Bernard's discovery of pancreatic lipase through a parallel analysis of his laboratory notebooks and his publications. This method reveals a discrepancy between the sequence and motivation of events as they were reported by Bernard in his publications and as they appear in his laboratory notebooks.     

Isolation of two morphologically distinct cell lines from rat arterial smooth muscle expressing high tumorigenic potentials

Summary Smooth muscle cell proliferation is an important feature of atherogenesis. Some works have hypothesized that a transformation of smooth muscle cells could arise during this pathological process. The present paper describes two spontaneously transformed cell lines of arterial smooth muscle cells (SMC) established from aortic media of adult rat. The cell lines have been designated V6 and V8; some of their morphologic, growth, and metabolic characteristics are described and compared to their parent cells. The two cell lines appeared distinct by their morphology and by their degree of transformation. V6 cells appeared as elongated spindle-shaped cells whereas V8 cells were spread cells with a cobblestone pattern. Karyotypes of both cell lines showed a high polyploidy level. V6 and V8 cell lines were immortalized and showed growth characteristics of transformed cells: low requirement of serum to grow, ability to form colonies in soft agar and tumorigenicity in nude mice; V8 cells presented a higher malignancy than V6 cells. Both V6 and V8 cells exhibited characteristics of cultured arterial SMC: ultrastructure, alpha actin expression at the protein and mRNA level, prostacyclin production. The remarkably different morphologies of the V6 and V8 lines and their transformed phenotype suggest that these cell lines could be useful models to study SMC differentiation and proliferation with respect to atherosclerotic or hypertensive vascular diseases. Electron microscopy was performed in the Center of Electron Microscopy Applied to Biology and Geology (CEMABG), Claude Bernard University, Lyon I. Flow cytofluorometry was performed in the Center of Fluorometry, Department of Human Biology, Claude Bernard University, Lyon I and funded by ARC N^o 6055-80. This work was supported by INSERM, by MRT grant 86-C-0301 and by ARC grant 415-87.     

Paul Bert, scientist and politician

Paul Bert worked with Claude Bernard, one of the leading physiologists of the 19th century. In his laboratory at the Collège de France in Paris, Paul Bert carried out fascinating experiments in particular on respiratory processes, leading him to publish "La pression barométrique" in 1878. In this book are recalled his discovery of oxygen pressure decrease with altitude, divers diseases, the improved safety protocols in hyperbaric conditions, and the first development of gas anaesthetics for surgery. He was the third President of the Société de Biologie. Paul Bert was also a politician with strong convictions. Minister of Education under Gambetta's short term government, he initiated the fight for social equality and secular education and became one of the most prestigious figures of the developing socialist party. He received many distinctions and was given a state funeral.     

Psychosomatic Principles

There are four lines of development that might be called psychosomatic principles. The first represents the work initiated by Claude Bernard, Cannon, and others, in neurophysiology and endocrinology in relationship to stress. The second is the application of psychoanalytic formulations to the understanding of illness. The third is in the development of the social sciences, particularly anthropology, social psychology and sociology with respect to the emotional life of man, and, fourth, there is an increased application of epidemiological techniques to the understanding and incidence of disease and its causes. These principles can be applied to the concepts of comprehensive medicine and they bid fair to be unifying and helpful in its study. This means that future practitioners, as well as those working in the field of psychosomatic medicine, are going to have to have a much more precise knowledge of the influence of emotions on bodily processes.     

Charles-Edouard Brown-Séquard: an eventful life and a significant contribution to the study of the nervous system

This is an account of the life of a 19th-century physiologist who was born in 1817 in Port-Louis (Mauritius Island, formerly 'Ile de France') and died in Paris in 1894. His mother tongue, education and medical training were French, but as the 'Ile de France' had become British a few years before his birth, he was a British citizen and therefore ineligible for a permanent position in a French institution. This explains, partly at least, his eventful life, during which he restlessly wandered during several decades between France, the United States, Great Britain and Mauritius, without ever finding a position that would satisfy him. This difficult period lasted until 1879 when, having finally acquired French nationality, he succeeded Claude Bernard in the chair of experimental medicine at the 'Collège de France'. Some of his contributions to the physiology of the nervous system are analysed: sensory pathways in the spinal cord, vasoconstrictor innervation, nervous inhibition and experimental epilepsy.     

Hexosamines, insulin resistance, and the complications of diabetes: current status

Glycogen is the storage form of carbohydrate for virtually every organism from yeast to primates. Most mammalian tissues store glucose as glycogen, with the major depots located in muscle and liver. The French physiologist Claude Bernard first identified a starch-like substance in liver and muscle and coined the term glycogen, or "sugar former," in the 1850s. During the 150 years since its identification, researchers in the field of glycogen metabolism have made numerous discoveries that are now recognized as significant milestones in biochemistry and cell signaling. Even so, more questions remain, and studies continue to demonstrate the complexity of the regulation of glycogen metabolism. Under classical definitions, the functions of glycogen seem clear: muscle glycogen is degraded to generate ATP during increased energy demand, whereas hepatic glycogen is broken down for release of glucose into the bloodstream to supply other tissues. However, recent findings demonstrate that the roles of glycogen metabolism in energy sensing, integration of metabolic pathways, and coordination of cellular responses to hormonal stimuli are far more complex.     

Homeostasis and the physiological dimension of niche construction theory in ecology and evolution

Niche construction theory (NCT) has been represented as a new and comprehensive theory of evolution, one that breaks the constraints imposed by the dominant and largely gene-selectionist standard evolutionary model that is presently mischaracterized as “Darwinian.” I will argue that NCT is not so much a new theory, as it is a fruitful readmission of a venerable physiological perspective on adaptation, selection and evolution. This perspective is closer in spirit and philosophy to the original (and richer) Darwinian idea developed by Darwin himself, and that animated much of the rich late nineteenth century debate about evolution, heredity, adaptation and development, a debate that was largely eclipsed by the early twentieth century emergence of the Neodarwinian synthesis. I will argue that a full realization of the promise of NCT turns on a full understanding of another intellectual revolution of the nineteenth century, Claude Bernard’s conception of homeostasis, a profound statement of the nature of life that has, through the twentieth century, come to be widely misunderstood and trivialized.     

The programming of silk-gland development in Bombyx mori

Summary The cytological development of the silk gland has been studied by light and electron microscopy in silkworms experimentally starved at different periods of the natural feeding stage during the fifth instar. When newly molted animals are not provided with food, no sign of growth is observed. Starvation initiated early during the obligatory feeding period, stops cell growth and development of the organelles involved in protein synthesis and secretion, whereas it induces the appearance of organelles concerned with autolysis. These effects are reversible if starvation is not prolonged beyond two days. Starvation during the facultative feeding period, at the time of massive fibroin production, results in quantitative and qualitative modifications of organelles related to the decrease of fibroin production and the onset of autolysis.Rough endoplasmic reticulum, responsible for fibroin synthesis, forms transitory whorls. Fibroin transport via the Golgi apparatus and secretion of the protein into the gland lumen decrease parallel to fibroin synthesis, so that no fibroin storage can be detected in any organelle. After food deprivation, autophagosomes and secondary lysosomes rapidly develop in the cytoplasm, and if starvation continues portions of the cytoplasm are sequestered and completely destroyed. If animals are refed, fibroin production is resumed and autolysis declines.These ultrastructural alterations of the silk gland during experimental starvation are very similar to those observed during the periods of physiological starvation (molt and cocoon spinning) and generally considered to be under hormonal control. Our results raise the question of the nature of interactions between alimentary and hormonal factors which control silk-gland development.This study was supported by a grant from the Centre National de la Recherche Scientifique (A.T.P., Contract n 1472) and was partly carried out in the Centre de Microscopie Electronique, CMEABG, Université Claude Bernard, Lyon and the Laboratoire d'Histologie, Service de Quantimétrie, Faculté de Médicine, Université Claude Bernard, Lyon     

Programmed cell death: history and future of a concept

Cell death was observed and understood since the 19th century, but there was no experimental examination until the mid-20th century. Beginning in the 1960's, several laboratories demonstrated that cell death was biologically controlled (programmed) and that the morphology was common and not readily explained (apoptosis). By 1990 the genetic basis of programmed cell death had been established and the first components of the cell death machinery (caspase 3, bcl-2 and Fas) had been identified, sequenced, and recognized as highly conserved in evolution. The rapid development of the field has given us substantial understanding of how cell death is achieved. However, capitalizing on our knowledge for therapeutic purposes requires us to learn much more about how a cell commits to death, as well as recognizing that apoptosis may be the most common and efficient means of death, but that there are alternative pathways that can result in cell death even when the conventional pathway is blocked. Interestingly enough, many of the arguments and missteps in the history of the field were anticipated by Claude Bernard, and his warnings and recommendations remain valid today.     

Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

Rapamycin prolongs healthy lifespan in yeast, flies and mammals and delays age-related diseases, including cancer and atherosclerosis. Rapamycin is considered for prevention of diabetic complications, such as retinopathy and nephropathy, and acute treatment with rapamycin decreases insulin resistance. However, under certain conditions, chronic administration of rapamycin may cause glucose intolerance and even provoke type II diabetes. This does not fit logically with its potential effects against diabetic complications. This also seems puzzling, because calorie restriction (CR) can prevent type II diabetes and its complications, and rapamycin mimics CR. It was somehow forgotten that almost two centuries ago, Claude Bernard discovered “starvation diabetes,” as shown later, characterized by glucose intolerance, decreased insulin, increased lipoproteins and ketones, gluconeogenesis and hepatic resistance to insulin. This reversible condition is not true diabetes: it does not lead to diabetic complications, and CR extends healthy lifespan. If rapamycin is a CR-mimetic, no wonder it may, in certain models, induce “hunger diabetes.” But will rapamycin prevent true type II diabetes? Here are some answers.     

Claude Fortier: the great history of neuroendocrinology

The work of Claude Fortier is linked to the history of neuroendocrinology. Through him and his pioneer work in Montreal with Hans Selye, the < Man of stress >, and at Laval University in Quebec City in his own laboratory, where all researchers involved in the study of the hypothalamo-hypophysial adrenal axis have been through, it is the whole saga of the search for the neuropeptide CRH (corticotropin releasing factor), and the harsh fight for the Nobel distinction that can be related. Among Claude Fortier's scientific discoveries, the feedback mechanisms of glucocorticoid hormones on brain and pituitary function, the presence of both mineralo and glucocorticoid receptors in some brain structures, and the introduction of computer science in biomedical research, can be cited. The consequences of these discoveries are illustrated in the pathologies linked to stress (anxiety, depression, addiction). Claude Fortier was not only a great figure in biomedical science, honored by several distinctions, but also an important personality in the policy of research in which he played a prominent role in Quebec medical research and allowed it to rank among the best in the world.     

The basic importance of the physiological approach in clinical medicine: the experience in the area of hypertension

Since Claude Bernard the physiological approach has dramatically contributed to the unprecedented progress that clinical medicine has seen during the second half of the 19th and throughout the 20th century. If I go back to about fifty years ago, when I started as a medical student and investigator under the guidance of Giuseppe Moruzzi and Cesare Bartorelli our understanding of arterial hypertension was very small and our therapeutic abilities close to nothing, but progressive knowledge of the physiology of the sympathetic nervous system, of the kidney, of the renin-angiotensin system, etc, led to a progressive understanding of the mechanisms of elevated blood pressure and to the development of an array of effective blood pressure lowering drugs, thanks to which hypertension is now a controllable disease. The supremacy of the physiological approach to clinical medicine has been recently endangered by the rising of two new approaches, whose worshippers consider the ultimate ones promising solid conclusions and unforeseen progress. These are the large randomized therapeutics trials, that are often arrogantly defined as evidence-based medicine (as if they were to provide the only real "evidence") and molecular and genetic medicine. Needless to say, both are important new tools in medicine, but neither can make the physiological method obsolete. The risk of the pretended superiority of the new approaches (and the new fashions) is that these claims are unbalancing research activity and its financial support, thus weakening the very basis upon which these new methodologies are founded and have developed.     

French Roots of French Neo-Lamarckisms, 1879–1985

This essay attempts to describe the neo-Lamarckian atmosphere that was dominant in French biology for more than a century. Firstly, we demonstrate that there were not one but at least two French neo-Lamarckian traditions. This implies, therefore, that it is possible to propose a clear definition of a (neo)Lamarckian conception, and by using it, to distinguish these two traditions. We will see that these two conceptions were not dominant at the same time. The first French neo-Lamarckism (1879–1931) was structured by a very mechanic view of natural processes. The main representatives of this first period were scientists such as Alfred Giard (1846–1908), Gaston Bonnier (1853–1922) and Félix Le Dantec (1869–1917). The second Lamarckism – much more vitalist in its inspiration – started to develop under the supervision of people such as Albert Vandel (1894–1980) and Pierre-Paul Grassé (1895–1985). Secondly, this essay suggests that the philosophical inclinations of these neo-Lamarckisms reactivated a very ancient and strong dichotomy of French thought. One part of this dichotomy is a material, physicalist tradition, which started with René Descartes but developed extensively during the 18th and 19th centuries. The other is a spiritual and vitalist reaction to the first one, which also had a very long history, though it is most closely associated with the work of Henri Bergson. Through Claude Bernard, the first neo-Lamarckians tried to construct a mechanical and determinist form of evolutionary theory which was, in effect, a Cartesian theory. The second wave of neo-Lamarckians wanted to reconsider the autonomy and reactivity of life forms, in contrast to purely physical systems.     

Vitalism and the Resistance to Experimentation on Life in the Eighteenth Century

There is a familiar opposition between a ‘Scientific Revolution’ ethos and practice of experimentation, including experimentation on life, and a ‘vitalist’ reaction to this outlook. The former is often allied with different forms of mechanism – if all of Nature obeys mechanical laws, including living bodies, ‘iatromechanism’ should encounter no obstructions in investigating the particularities of animal-machines – or with more chimiatric theories of life and matter, as in the ‘Oxford Physiologists’. The latter reaction also comes in different, perhaps irreducibly heterogeneous forms, ranging from metaphysical and ethical objections to the destruction of life, as in Margaret Cavendish, to more epistemological objections against the usage of instruments, the ‘anatomical’ outlook and experimentation, e.g. in Locke and Sydenham. But I will mainly focus on a third anti-interventionist argument, which I call ‘vitalist’ since it is often articulated in the writings of the so-called Montpellier Vitalists, including their medical articles for the Encyclopédie. The vitalist argument against experimentation on life is subtly different from the metaphysical, ethical and epistemological arguments, although at times it may borrow from any of them. It expresses a Hippocratic sensibility – understood as an artifact of early modernity, not as some atemporal trait of medical thought – in which Life resists the experimenter, or conversely, for the experimenter to grasp something about Life, it will have to be without torturing or radically intervening in it. I suggest that this view does not have to imply that Nature is something mysterious or sacred; nor does the vitalist have to attack experimentation on life in the name of some ‘vital force’ – which makes it less surprising to find a vivisectionist like Claude Bernard sounding so close to the vitalists.     

The role of the autonomic nervous liver innervation in the control of energy metabolism

Despite a longstanding research interest ever since the early work by Claude Bernard, the functional significance of autonomic liver innervation, either sympathetic or parasympathetic, is still ill defined. This scarcity of information not only holds for the brain control of hepatic metabolism, but also for the metabolic sensing function of the liver and the way in which this metabolic information from the liver affects the brain. Clinical information from the bedside suggests that successful human liver transplantation (implying a complete autonomic liver denervation) causes no life threatening metabolic derangements, at least in the absence of severe metabolic challenges such as hypoglycemia. However, from the benchside, data are accumulating that interference with the neuronal brain–liver connection does cause pronounced changes in liver metabolism. This review provides an extensive overview on how metabolic information is sensed by the liver, and how this information is processed via neuronal pathways to the brain. With this information the brain controls liver metabolism and that of other organs and tissues. We will pay special attention to the hypothalamic pathways involved in these liver–brain–liver circuits. At this stage, we still do not know the final destination and processing of the metabolic information that is transferred from the liver to the brain. On the other hand, in recent years, there has been a considerable increase in the understanding which brain areas are involved in the control of liver metabolism via its autonomic innervation. However, in view of the ever rising prevalence of type 2 diabetes, this potentially highly relevant knowledge is still by far too limited. Thus the autonomic innervation of the liver and its role in the control of metabolism needs our continued and devoted attention.     

Culture and Progress. DISTINGUISHED LECTURE-1975

This paper is the text of the sixth Distinguished Lecture, delivered in San Francisco at the 74th annual meeting of the American Anthropological Association, December 1975. The Lectureship was established in 1969 to honor outstanding scholars in the profession. Colson, a social anthropologist and ethnographer of wide experience, has worked in both the New and the Old Worlds, with American Indian and central African cultures. She is currently Fairchild Fellow, California Institute of Technology, on leave from her professorship at the University of California, Berkeley. Her interest in both the history and the future of our profession is reflected in her talk. The first five Distinguished Lectures—by Joseph H. Greenberg, Robert J. Braidwood, Georges Condominas, John W. M. Whiting, and Miguel León-Portilla—were published in the Association's Annual Reports (1970–74). The Lecture will now appear each year in the American Anthropologist.