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The philosophical natural history that comprised the physiology of the Greeks has little in common with modern physiology. Many ideas important in the development of physiology, however, were formulated in the books of the Hippocratic school of medicine (before 350 bc), especially the humoral theory of disease in the treatise De natura hominis (“On the Nature of Man”). Other contributions were made by Aristotle (Lykaion, about 325 bc) and Galen of Pergamum (c. ad 130–c. 200). Significant in the history of physiology was the teleology of Aristotle, who assumed that every part of the body is formed for a purpose and that function, therefore, can be deduced from structure. The work of Aristotle was the basis for Galen’s De usu partium (“On the Use of Parts”) and a source for many early misconceptions in physiology. The tidal concept of blood flow, the humoral theory of disease, and Aristotle’s teleology, for example, led Galen into a basic misunderstanding of the movements of blood that was not corrected until William Harvey’s work on blood circulation in the 17th century.
The publication in 1628 of Harvey’s Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (An Anatomical Dissertation Upon the Movement of the Heart and Blood in Animals) usually is identified as the beginning of modern experimental physiology. Harvey’s study was based only on anatomical experiments; despite increased knowledge in physics and chemistry during the 17th century, physiology remained closely tied to anatomy and medicine. In 1747 in Berne, Switzerland, Albrecht von Haller, eminent as anatomist, physiologist, and botanist, published the first manual for physiology. Between 1757 and 1766 he published eight volumes entitled Elementa Physiologiae Corporis Humani (Elements of Human Physiology); all were in Latin and characterized his definition of physiology as anatomy in motion. At the end of the 18th century, Antoine Lavoisier wrote about the physiological problems of respiration and the production of heat by animals in a series of memoirs that still serve as a foundation for understanding these subjects.
Physiology as a distinct discipline utilizing chemical, physical, and anatomical methods began to develop in the 19th century. Claude Bernard in France; Johannes Müller, Justus von Liebig, and Carl Ludwig in Germany; and Sir Michael Foster in England may be numbered among the founders of physiology as it now is known. At the beginning of the 19th century, German physiology was under the influence of the romantic school of Naturphilosophie. In France, on the other hand, romantic elements were opposed by rational and skeptical viewpoints. Bernard’s teacher, François Magendie, the pioneer of experimental physiology, was one of the first men to perform experiments on living animals. Both Müller and Bernard, however, recognized that the results of observations and experiments must be incorporated into a body of scientific knowledge, and that the theories of natural philosophers must be tested by experimentation. Many important ideas in physiology were investigated experimentally by Bernard, who also wrote books on the subject. He recognized cells as functional units of life and developed the concept of blood and body fluids as the internal environment (milieu intérieur) in which cells carry out their activities. This concept of physiological regulation of the internal environment occupies an important position in physiology and medicine; Bernard’s work had a profound influence on succeeding generations of physiologists in France, Russia, Italy, England, and the United States.
Müller’s interests were anatomical and zoological, whereas Bernard’s were chemical and medical, but both men sought a broad biological viewpoint in physiology rather than one limited to human functions. Although Müller did not perform many experiments, his textbook Handbuch der Physiologie des Menschen für Vorlesungen and his personal influence determined the course of animal biology in Germany during the 19th century.
It has been said that, if Müller provided the enthusiasm and Bernard the ideas for modern physiology, Carl Ludwig provided the methods. During his medical studies at the University of Marburg in Germany, Ludwig applied new ideas and methods of the physical sciences to physiology. In 1847 he invented the kymograph, a cylindrical drum that still is used to record muscular motion, changes in blood pressure, and other physiological phenomena. He also made significant contributions to the physiology of circulation and urine secretion. His textbook of physiology, published in two volumes in 1852 and 1856, was the first to stress physical instead of anatomical orientation in physiology. In 1869 at Leipzig, Ludwig founded the Physiological Institute (neue physiologische Anstalt), which served as a model for research institutes in medical schools all over the world. The chemical approach to physiological problems, developed first in France by Lavoisier, was expanded in Germany by Justus von Liebig, whose books on Organic Chemistry and its Applications to Agriculture and Physiology (1840) and Animal Chemistry (1842) created new areas of study both in medical physiology and agriculture. German schools devoted to the study of physiological chemistry evolved from Liebig’s laboratory at Giessen.
The British tradition of physiology is distinct from that of the continental schools. In 1869 Sir Michael Foster became Professor of Practical Physiology at University College in London, where he taught the first laboratory course ever offered as a regular part of instruction in medicine. The pattern Foster established still is followed in medical schools in Great Britain and the United States. In 1870 Foster transferred his activities to Trinity College at Cambridge, England, and a postgraduate medical school emerged from his physiology laboratory there. Although Foster did not distinguish himself in research, his laboratory produced many of the leading physiologists of the late 19th century in Great Britain and the United States. In 1877 Foster wrote a major book (Textbook of Physiology), which passed through seven editions and was translated into German, Italian, and Russian. He also published Lectures on the History of Physiology (1901). In 1876, partly in response to increased opposition in England to experimentation with animals, Foster was instrumental in founding the Physiological Society, the first organization of professional physiologists. In 1878, again due largely to Foster’s activities, the Journal of Physiology, which was the first journal devoted exclusively to the publication of research results in physiology, was initiated.
Foster’s teaching methods in physiology and a new evolutionary approach to zoology were transferred to the United States. in 1876 by Henry Newell Martin, a professor of biology at Johns Hopkins University in Baltimore, Md. The American tradition drew also on the continental schools. S. Weir Mitchell, who studied under Claude Bernard, and Henry P. Bowditch, who worked with Carl Ludwig, joined Martin to organize the American Physiological Society in 1887, and in 1898 the society sponsored publication of the American Journal of Physiology. In 1868 Eduard Pflüger, professor at the Institute of Physiology at Bonn, founded the Archiv für die gesammte Physiologie, which became the most important journal of physiology in Germany.
Physiological chemistry followed a course partly independent of physiology. Müller and Liebig provided a stronger relationship between physical and chemical approaches to physiology in Germany than prevailed elsewhere. Felix Hoppe-Seyler, who founded his Zeitschrift für physiologische Chemie in 1877, gave identity to the chemical approach to physiology. The American tradition in physiological chemistry initially followed that in Germany; in England, however, it developed from a Cambridge laboratory founded in 1898 to complement the physical approach started earlier by Foster.
Physiology in the 20th century is a mature science; during a century of growth, physiology became the parent of a number of related disciplines, of which biochemistry, biophysics, general physiology, and molecular biology are the most vigorous examples. Physiology, however, retains an important position among the functional sciences that are closely related to the field of medicine. Although many research areas, especially in mammalian physiology, have been fully exploited from a classical-organ and organ-system point of view, comparative studies in physiology may be expected to continue. The solution of the major unsolved problems of physiology will require technical and expensive research by teams of specialized investigators. Unsolved problems include the unravelling of the ultimate bases of the phenomena of life. Research in physiology also is aimed at the integration of the varied activities of cells, tissues, and organs at the level of the intact organism. Both analytical and integrative approaches uncover new problems that also must be solved. In many instances, the solution is of practical value in medicine or helps to improve the understanding of both human beings and other animals.
The anatomical and medical origins of physiology still are reflected in university courses and textbooks that concentrate on functional organ systems of animals; e.g., frog, dog, cat, and rat. The trend in physiology, however, is to emphasize function rather than structure; i.e., comprehensive functional specializations such as nutrition, transport, metabolism, and information have replaced earlier structural studies of organ systems. This trend can be explained in part by the fact that the analysis of an organ system typically involves studies at the levels of cells and molecules, and functional emphasis accommodates such studies better than the organ-system approach.
Early in the 20th century, the emphasis on cells as units of function resulted in a view that all physiology is essentially cell physiology and that all teaching therefore should pivot around the properties of cells. In later years successful analyses of cellular mechanisms involving synthesis, control, and inheritance led to similar emphasis at a new and more fundamental level, the molecules that comprise cells. The study of physiology now encompasses molecules, cells, organs, and many types of animals, including man. The comparisons resulting from such studies not only strengthen human physiology but also generate new problems that extend into evolution and ecology. Much of the impetus for comparative physiology has resulted from the economic or medical importance to man of parasites, insects, and fishes.
Most of the physiology of microorganisms and plants developed independently of animal physiology. The concept of comparative biochemistry provided the foundations for a physiology of microorganisms that extended beyond the parasitic forms that are of medical importance and resulted in recognition of the fundamental roles of microorganisms in the biosphere. Botanists and agriculturists explore the physiology of higher plants, but fundamental differences in the modes of life of animals and plants leave little common ground above the molecular and cellular levels. In a little-known textbook, Claude Bernard stated that there is only one way to live, only one physiology of all living things. The goal of general physiology is to abstract this single physiology from the physiologies of all types of organisms. Although common or general features usually are found at the cellular and molecular levels of organization, multicellular structures also are studied. Processes that underlie cell function are emphasized in an approach based on analyses in terms of physical and chemical principles.
Areas of study
In the late 19th century the principle of conservation of energy was derived in part from observations that fermentation and muscle contraction are essentially problems in energetics. Biological energetics began with studies that established the basic equation of respiration as:
Fuel + oxygen → carbon dioxide + water + heat.
It was realized that the heat produced in fermentation and the work performed during muscle contraction must originate in similar processes, and that fuel in the equation above is a source of potential energy. Early in the 20th century studies of animal calorimetry verified these concepts in man and other animals. Calorimetry studies showed that the energy produced by the metabolism of foodstuffs in an animal equals that produced by the combustion of these foodstuffs outside the body. After these studies, measurement of the basal metabolic rate (BMR) was used in the diagnosis of certain diseases, and data relating the composition of foodstuffs to their value as sources of metabolic energy were obtained.
Early in the 20th century it was established that measurable amounts of the carbohydrate glycogen are converted to lactic acid in frog muscles contracting in the absence of oxygen. This observation and studies of alcoholic fermentation confirmed that the energy for fermentation or muscle contraction depends on a series of reactions now known as glycolysis. In order to show that the conversion of glycogen to lactic acid could provide the necessary energy for muscular contraction, extremely delicate measurements of the heat produced by contracting muscles were required. As a result of glycolysis studies, adenosine triphosphate (ATP) was recognized as an important molecule in cellular energy transfer and utilization; e.g., movement, generation of electricity, transport of materials across cell membranes, and production of light by cells. Soon it was discovered that a muscle protein called myosin acts as an enzyme (organic catalyst) by liberating the energy stored in ATP and that ATP in turn can modify the physical properties of myosin molecules. It was also shown that a muscle fibre has an elaborate and ordered structure, which is based on a precise arrangement of myosin and another muscle protein called actin.
Glycolysis is an anaerobic process (i.e., it does not require oxygen) and may represent one of the oldest mechanisms for cellular energy transfer, since the process could have evolved before there was free oxygen in the Earth’s atmosphere. Most cells, however, derive their energy from a series of reactions involving oxygen and called the Krebs tricarboxylic acid cycle. The enzymes for the cycle are part of the structure of a mitochondrion, which is an elaborate cellular component filled with membranes and often shaped like a very small bean. In the course of the oxidation, three molecules of energy-rich ATP are generated for each oxygen atom used to form a molecule of water. The mitochondrion, therefore, is the cellular site of respiratory combustion first clearly demonstrated in whole animals by Lavoisier.
The ultimate source of foodstuffs used by animals is plants. Early 19th-century studies of photosynthesis were closely related to those of respiration and began with Joseph Priestley’s demonstration that plants could restore the air used during respiration or combustion. The most important equations for living things therefore, are mutually inverse. In respiration:
(CH2O)n + nO2 → nCO2 + nH2O + heat.carbo-oxygen carbon waterhydrate dioxide
nCO2 + nH2O + light → (CH2O)n + nO2.
In the 1930s, it was shown that photosynthesis involves splitting hydrogen from water and that the oxygen liberated in photosynthesis comes from water. During the light reactions, light energy is captured by a green pigment called chlorophyll and used to generate reactive hydrogen and ATP that are used during dark reactions in which carbohydrates and other cell constituents are synthesized.
The classical fields of organ-system physiology have a role subsidiary to that of cellular metabolism. Feeding and digestion, for example, become a means for the enzyme-catalyzed breakdown of organic compounds into relatively small molecules that can be transported readily; nutrition, therefore, is a way to supply animals with sufficient sources of energy and specific substances that they cannot synthesize. Comparative animal studies, which were of practical importance in the discovery of some vitamins, led also to the general observation that the specific nutrient requirements of animals are consequences of a slow evolutionary deterioration in which synthetic abilities are lost through changes or mutations in hereditary material.
Nutrition and digestion, however, also have been important in obtaining information at the cellular and molecular levels. It was through studies of digestion, for example, that the existence and nature of enzymes were first disclosed clearly. In addition, early recognition of similarities between digestion and fermentation foreshadowed knowledge of the important role of fermentation in cellular metabolism. Finally, the study of vitamin nutrition was closely integrated with that of cellular oxidation, in which certain vitamins play an essential catalytic role.
In intact organisms, the chemical activities of individual cells do not interfere with the functions of the organism. Much of the study of physiology now is concerned with the ways by which cells obtain their nutrients and dispose of their waste products. Knowledge of the mechanism of protein synthesis and its connections with inheritance and cellular control mechanisms have initiated new inquiries into functions at all levels; i.e., cells, organs, and organisms.
Many important advances in surgery and medicine have been based on the physiology of circulation, which was first studied in 1628. The measurement of blood pressure, for example, was introduced on a practicable basis late in the 19th century and has become an important part of medical diagnosis. The physiology of circulation is concerned with the origin of blood pressure in the force of the heartbeat and the regulation of heart rate, blood pressure, and the flow of blood.
Variations in heart rate that led Aristotle to consider the heart as the seat of the emotions—a myth that persists even now—were among the phenomena whose explanation revealed the existence of the autonomic nervous system. Variations in heart rate are less important to the circulatory system, however, than is the ability of the heart to adjust the strength of its beat to meet certain demands of the body.
The peripheral control of blood pressure and blood flow depends upon a maze of interacting control mechanisms, most significant of which are direct control of the diameter of small arterial branches that enlarge or dilate in response to chemical products formed during metabolism. Increased metabolic activity of tissues such as muscles or the intestine, therefore, automatically induces increased blood flow through the dilated vessels. This action, which could result in a fall in blood pressure, is offset by central-reflex controls that constrict arterial branches not dilated as a result of local chemical effects. Certain regions of the skin and the intestines serve as reservoirs for blood that may be diverted to muscles or the brain if necessary. Peripheral control may break down if excessive demands are made upon it in hot weather (heat stroke), during vigorous exercise after meals (muscle cramp), and after extensive loss of blood or tissue damage (wound shock) or extreme emotion with consequent activation of the autonomic nervous system (emotional shock). A remarkable adaptation occurs in air-breathing vertebrates—reptiles, birds, and mammals—which dive for food or protection. During a dive, the flow of blood to all parts of the body except the brain and the heart is reduced substantially. The energy for muscle contraction is provided by the anaerobic process of glycolysis because the oxygen in the blood goes to the brain and heart, which cannot function without a constant supply of oxygen.
Comparative studies have disclosed two major patterns in circulatory systems. Among vertebrates and a few invertebrates—notably annelid worms and cephalopod mollusks—the blood flows entirely in closed channels or vessels, never coming into direct contact with cells and tissues; blood pressure and the velocity of flow are high and relatively constant, and the volume of blood is small. In many invertebrates—especially arthropods and mollusks other than cephalopods—the blood flows for part of its course in large sinuses or lacunae and comes directly into contact with the tissues. Blood pressure and the velocity of flow are low and variable in these invertebrates, and the large volume of blood is comparable to the total volume of all body fluids in vertebrates.
Consideration of the blood as a transport system has centred especially on thetransport of oxygen andcarbon dioxide. The colour of blood changes as it passes through the lungs; venous blood is dark purple and arterial blood is bright red because of the properties of a blood pigment called hemoglobin. The complete structure of hemoglobin now has been determined, and minute variations in this structure have enabled man to study fundamental questions of heredityat the molecular level. The development of blood-banks and the techniques involved in blood transfusions depend on knowledge of the physical, chemical, and biological properties of blood. These properties include a remarkable diversity of hemoglobin, both among individuals and species and also within an individual during development. In many instances variations in protein composition better adapt a species to its circumstances.
Studies of membrane transport at the cellular level are an important part of general physiology. Although quantitative theories of diffusion and osmosis that developed around 1900 were applied to cell physiology, a number of phenomena (e.g., movement through membranes of certain ions and other compounds of biological importance) did not behave according to established physical principles. As a result of studies of osmotic and ionic regulation in freshwater animals, the concept of active transport was formulated. Crucial to the acceptance of this concept were studies with frog skin, which can transport sodium ions against chemical and electrical forces; the transport, specific for sodium ions, is dependent on a continuing input of metabolic energy. Efforts have been directed toward establishing a molecular mechanism that may involve an enzyme found in surface membranes of cells. This enzyme breaks down ATP and releases the energy in the molecule only if sodium and potassium ions are present.
The physiology of animals differs from that of plants in the rapid response of animals to stimuli. René Descartes, responsible for the concept of the reflex that dominated neurophysiology for most of its history, thought a sensory impulse was “reflected” from the brain to produce a reaction in muscles. Later studies of the effects of ions on nerves suggested that a nerve must be surrounded by a membrane and that a nerve impulse results from a change in the ability of the membrane to allow passage of potassium ions. When it was shown that nerves are made up of thousands of tiny fibres, which are processes that extend from cells located in the brain or spinal cord, the nerve impulse hypothesis was applied to individual nerve fibres rather than to whole nerves. Electronic technology provided the techniques and giant nerve fibres of squids provided the experimental material that enabled two Nobel prize winners for physiology, Alan Lloyd Hodgkin and Andrew Fielding Huxley, to extend this hypothesis into a theory of the excitation of nerve cells in which sodium ions and potassium ions play principal roles.
The reflex concept, however, was not dependent on understanding the molecular basis of excitation, conduction, and transmission. Early in the 20th century the role of interaction of nervous centres in controlling muscle contractions was established. The reflex now is conceived as a unit in which nerve impulses initiated in sensory neurons or nerve cells are conducted to a centre in the brain or spinal cord. In the centre, impulses initiated in motor neurons are conducted to muscles and induce a reflex response. Two processes can occur in the centre; one is associated with central excitatory states, the other with central inhibitory states. The net effect of any stimulus or group of stimuli, therefore, can be interpreted as an interaction of these opposing states in the centre.
After the demonstration that the effects of the vagus nerve in slowing the heart are mediated by a chemical substance, subsequently identified as acetylcholine, the concept of chemical transmission of nervous impulses was extended to the central nervous system. Typically, transmission of excitation from cell to cell is accomplished by the liberation of a chemical transmitter from a nerve ending.
The reflex concept gave rise to premature attempts to develop a psychology based on reflexes. These attempts (behaviourism) were advanced by the Russian I.P. Pavlov’s discovery of conditioned responses. Originally known as conditioned reflexes, these responses have been found in most animals with central nervous systems. More complex than simple reflexes, their mechanism has not yet been established with certainty.
The analysis of sensory functions also extends to the cellular level. Sense organs are diverse in structure and sensitivity to specific stimuli. It may be that the common molecular basis for the differences in sensitivity is a change in permeability of a special region of the membrane surrounding a sensory cell. This change in permeability could allow a nerve fibre to become excited and initiate a nerve impulse. Neurophysiology has borrowed from, and contributed to, the information theory used in communications engineering. The function of sense organs is to gather information both from the environment and the organism. The central nervous system integrates this information and translates it into a program of response involving the entire organism. In addition, the brain can store information previously received (memory) and has the ability to initiate actions without obvious external stimulation (spontaneity). Some aspects of memory and integrative function have been modelled in electronic computers; in fact the development of computers was closely connected with the development of ideas about the functions of the central nervous system.
The analytical interpretation of central nervous function remains, however, a complex and difficult field, even though recent progress has brought closer together the study of behaviour in terms of nerve function and behavioral models. Considerable effort now is directed to the localization of brain function. Although specific centres for reception of sensory information and integration of motor programs are known, the integrative functions that tie them together, as well as the functions of memory, are not so well established.
The concept of internal regulations is attributed to Claude Bernard, who thought of blood as an internal environment in which cells function; according to Bernard, maintenance of the internal environment at a constant level was a major responsibility of all body functions. Bernard showed in studies of the formation and breakdown of glycogen in the liver that internal organs can secrete materials into the blood. Other investigators demonstrated such a secretion and used the word hormone to describe the substance. One classical study concerned control of the secretion of digestive fluids by the pancreas; an active substance secretin was purified, as have been a number of similar materials from the digestive tract. The field of endocrinology now is a major part of physiology.
The endocrine system complements the nervous system in control and coordination. Hormones, liberated into blood and other body fluids by endocrine glands and transported throughout the body, usually act either on specific target organs or on certain activities of many organs. Nervous coordination most often is concerned with rapid responses of short duration; endocrine coordination, however, usually is involved in slower responses of longer duration. Stationary-state regulation, or homeostasis, depends on the action of hormones at many points. The hormones insulin and glucagon, both formed in specialized endocrine tissue in the pancreas, control the level of sugar in blood. Vasopressin from the pituitary gland at the base of the brain and aldosterone from the adrenal glands near the kidneys control salt and water balance of the blood. Hormonal regulation, however, is not confined to homeostasis. The cyclic events of the female reproductive cycles in mammals, for example, are determined by a complex sequence of endocrine interactions involving hormones of the pituitary gland and the ovary.
The pervasive regulatory action of hormones is part of a large system of interactions to which the term feedback generally is applied. Hormones involved in homeostatic regulation, for example, influence their own secretion. The secretion of certain steroid hormones, which have a significant action on the conversion of amino acids to glycogen, is controlled by another hormone called the adrenocorticotropic hormone (ACTH), which is formed in the anterior pituitary gland. In turn the secretion of ACTH is controlled by a releasing factor formed in the midbrain and liberated from the stalk of the pituitary gland. ACTH liberation normally is controlled by the concentration of steroids in the blood, so that an increase in steroid concentration inhibits ACTH secretion; this negative feedback, however, may be overcome in certain conditions of intense nervous stimulation.
A similar pattern of releasing factors, by which the nervous system interacts with the endocrine system, also is known for other anterior pituitary hormones; e.g., those involved in the reproductive cycle and in responses of the thyroid gland to temperature changes. In addition, neurosecretory cells—nerve cells specialized for endocrine function—liberate hormones (e.g., vasopressin) that act directly on a specific target. Comparative studies show that neurosecretory cells are important in developmental and regulatory functions of most animals. Discrete endocrine glands, however, occur less frequently; in insects and crustaceans, cycles of growth, molting (shedding of the cuticle), and development are controlled by hormones. The identification of insect hormones may be useful in controlling pests through specific interference with processes of growth and development.