Look at physiological
integration
ADOLPH, E. F. Look atphysiological integration. Am. J. Physiol. 237(5): R255-R259,1979 or Am. J. Physiol.: Regulatory Integrative Comp. Physiol. 6( 3): R255-R259, 1979.-Physiological integration results from cooperating processes at work within an individual. Two chief types of study are a) empirical experiments and generalizations, and b) predictive relations derived from models. In this essay the empirical type is illustrated. For example, heart rates and other circulatory properties are modified in response to messages from specific muscles, viscera, glands. In those tissues, augmented blood flow increases the supplies of oxygen and other substances at active local sites. Because specialized actions are segregated among tissues and organs, each performer evidently informs cooperating tissues of its state. Messages are transmitted at various kinds of junctions and chemical receptors. In this essay the results or actions are emphasized: in what ways do the compounded processes promote survival and advantage? Messages are sorted as they travel, certain powers of decision residing at cellular junctions. Because selected processes are coordinated, each compound action represents an accomplishment. Thermoregulation serves as an example of relations by which several parameters yield a complex result. The multiple correlations and the intricate timing and switching are recognized. coordinated
It is this union of passionate interest equal devotion to abstract generalization
processes; specialized
in the detailed facts which forms novelty. A. N. Whitehead
actions
with (1925)
IS A CONCEPT of what organisms do. It signifies cooperative actions within individuals. How does one study it? The empiricist starts with examples of integrative action. Which examples he chooses will depend on his own researches. How many examples will be needed to formulate a helpful generalization? How many ways? An infinite number of ways can neither be listed nor comprehended. But insights are often found-from observations of what happens in what circumstances, and from experiments planned thereon. The individual scientist then draws tentative abstractions. The biotheorist, in contrast, starts with predictions. The predictions too are numerous. Some seem unacceptable to other persons whose imaginations are just as active. All predictionsneed to be tested in the crucible of laboratory examination. Every living individual has means of unifying its own activities. How does an animal manage to act as a whole individual? The animal in physiological laboratories is sometimes reduced to one receptor organ and one responder organ. In that circums tance the responses are reproducible, and the conclusions drawn are almost unexceptional. But most animals are not that stereotyped. INTEGRATION
0363-6119/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
In the mind of Aristotle (l), and later in the mind of Galen (6)) the question framed was, What is the usefulness of the actions seen in an animal’s body? What good is each one? Galen declared, “All parts of the body are in sympathy with one another; all cooperate in producing one effect .” Can the physiologist now comprehend both the oneto-one response and the inclusive situation? Obviously the science of physiology needs concepts derived from all kinds of investigation. Heart Rates First, an example of one organ acting in the midst of competing influences. An observer can watch a heart beating outside the body of a frog. The fact that beating can continue for hours under favorable conditions cannot fail to impress him. When the heart is within the frog’s body, the observer can readily ascertain that the rate of beating varies in accord with extrinsic influences, such as exercise of the frog’s legs, manipulation of the viscera, removal of oxygen from the atmosphere. Now the heart is being studied as a responder to varied influences. The observer sees the heart as a cooperating unit in an extensive array of actions. What a surprise it was when the brothers Weber (10) discovered that impulses in vagal nerves could temporarily stop the heart! Gradually, physiologists learned that the heart receives two kinds of messages through two Society
R255
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 12, 2019.
R256
E. F. ADOLPH
sets of nerves-sympathetic and parasympathetic. Further, that two kinds of chemical influence-adrenergic and cholinergiccould initiate the nerve impulses. And, that during development of the individual, at least in mammalian fetus, adrenergic hormones did not affect the rate of heartbeat in early stages, but gradually gained this power while developing. A hundred years of discovery could then be formalized into a logical story of governance. Today one can say that the heart is beating not for the sake of beating, but for the sake of bodily actions “demanding” more or less blood flow. Therefore, one studies not only the heart rate but the blood vessel calibers, the arterial pressures and other factors that may be interrelated, in order to understand what the flow of blood is accomplishing. What good is more blood flow? In most tissues the blood coming to them is carrying oxygen in a quantity that meets a demand. To this day, no one knows how the demand is accurately conveyed to the heart and to the arterioles that divert the flow hither and thither. Without a ready means of demand, however, the work that depends on oxygen supply would not get done. The fact of integration of oxygen supply and blood flow cannot be ignored. It can be measured as a combined response to an arousal. Scientists are well aware that the answers one obtains in an investigation usually depend on the questions asked. Inquire about variations of heart rates and one learns about the heart’s services to body. Reciprocally, one learns the degree of dependence on the blood flow by the several effector organs, such as brain and kidney. Division
of Labor
Milne-Edwards stated in 1827 (7) the principle of physiological division of labor. He noted that “the physiological instruments with which an animal is provided are specialized, and the diverse capabilities are localized.” The fact was so obvious that anyone could have stated it. Even so, decades were required before most physiologists realized that specialized and localized “instruments” could be of use only if they communicated one with another. Up to the close of the 19th century, just one means of communication was widely known: impulses in nerve. Nerves seemed plentiful and sufficient and all-powerful. There were sensory and motor nerves, sense organs, reflexes, voluntary controls, and much more. That era of discovery was capped by the amazing researches of Sherrington (9) reported in Integrative Action of the Nervous System. Today the physiologist has a whole list of means by which tissues communicate with one another: nerve impulse, hormone, neurohumor, decremental neuron, electrical junction, gap junction, gene, operon, allosterism, molecular receptor. The ingenuity of selective message conveyance among subcellular units is being revealed in terms of integrative actions between and among particles and membranes. But integrative actions require more than pathways for messages. Somewhere messages are processed, and decisions are made. In the case of central nervous actions the nature of those decisions is partly understood. Thus,
a muscle does not both contract and relax at the same instant. The information coming to particular nervous junctions obviously is scanned in predetermined ways, so that the amount of each muscle’s contraction will be decided. Priorities are fixed, as, in the stretch reflex for the maintenance of standing posture. Integrative physiology consists partly in the formulation of such rules of decisions, and of their exceptions. Given the fact that means of transmission are many and varied, the student of integrative actions need not wait for more understanding of how the messages travel. He can focus his attention on the accomplishments that issue from cooperative actions. For example, the muscles serving locomotion “anticipate” that their demand for oxygen will be met by augmented blood flow. In severe exercise a given leg muscle can consume oxygen at 40-60 times the resting rate. The heart, lungs, breathing, vasculatures, autonomies, adrenal medulIas, spinal synapses, and many more functional units respond to this one demand for action. All the phenomena known about muscular exercise thus constitute a vast scenario-cooperation, order, aim, integration. In spite of the usual neat division of functions into 10 or 20 textbook categories, actions continuously cross-collaborate with one another. Thermoregulation Regulation, and therefore integration, typically deals with cooperation among two or more different processes. Thus, body content of heat is equilibrated by approach to equality of two overall processes, gain and loss-so much heat production and so much heat output. Integration exists in that these two counteractions respond to disturbances, and that they restore a normative result. The particular combination of heat flows is generally the one combination that will maintain the body’s heat content. So, integration depends on a choice within the available patterns of actions. Accordingly, in heat regulation, the most general links are between a) heat content of body and parts (or net temperature), b) heat additions, and c) heat dissipations. The subsidiary choices among diverse paths and sites of heat flow serve to distribute the operations. Emphasis on accomplishment reveals that the organism’s advantages are reaped from the cooperations among chosen kinds of processes. Two general results can be observed: steadiness of temperatures and patterned distribution of them. “In the organism, all the phenomena of cooling alone and heating alone are not produced in an anarchic and disordered manner. Life would be impossible in such conditions. The phenomena are, on the contrary, associated and maintained in reciprocally harmonious relations, in order to furnish the animal with conditions that are fixed and indispensable for accomplishment of its functions” (Claude Bernard, Ref. 3). In the last century the actions involved in thermoregulation could be listed simply as: heat production by oxidations, and heat losses by radiation, conduction, and convection. Today it is universally recognized that these processes are both locally and integrally controlled in a complex manner, and many sensory and central factors are intricately interrelated (5). Thus, multiple sensations
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 12, 2019.
INVITED
R257
OPINION
from skin, hypothalamus, spinal cord, abdominal cavity, and respiratory passages have been shown to converge in the central nervous system; impulses in many single nerve fibers have been sampled. Pathways and scannings of inputs are at every moment coordinated into resultant outputs. For example, skin sensations are prepotent in arousing a) extra heat production (through shivering and nonshivering), and b) vasoconstriction in superficial tissues. But sensory information from deeper organs predomi nantly arouses sweating or panting. In quantitative detail, however, the weighted ingredients of integrative action are still unpredictable. For the body as a whole, each response to temperature sensations appears to recognize a threshold. This threshold can be conveniently imagined to contribute to a socalled set point. The set point, however, is not fixed under all conditions. In addition to the physiological responses of heat production and vasoconstriction, a group of other actions may be labeled behaviors-such as hunching, huddling, sprawling. Even in newborn individuals such postures go into action. Activations of responses employ numerous portions of the central nervous system from cerebral cortex to spinal synapses, and lead to shivering, panting, and so forth. Sympathetic nervous system is almost autonomous in signaling special heat losses (vasomotor, sweating) and extra hea t production. Because muscles an ,d blood vessels are effecters of heat exchanges, large body masses are involved. Fever represents a form of heat integration. Pyrogen that escapes from a parasitic organism gives rise to outputs of norepinephrine and prostaglandin E. These hormones influence hypothalamic neurons to command extra heat production and at the same time to diminish heat loss. Thus fever, a general concom itant of illness in individuals, teaches a lesson in integration. Regulation requires both activation of processes and limitation (usually by feedback) of the processes and their speeds. Every regulation-of metabolism, movement, energy, repair- involves integration among actions. For, the regulati on can be interrupted and can be dissected. It therefore furnish .es controls over actions of parts, whether the parts be chemical, structural, or particulate. Thus, as noted, regulation of body heat depends on shifts of heat production and of heat dissipation. One can conclude that integration of body heat depends on detailed regulations in-oxidations, blood flows, and the like. There is no boundary or distinction between regulation and integration. No one process by itself yields a resultant called integra tion; but a knowledge of several constituent movements of (for example) heat as a molecular motion, does yield a picture of coordination. Integration resides not only in some lever or switch, but in the complex of interacting “decisions.” Regulation also includes shifts to new patterns, when, for example muscular exercise begins. The transition shows that order and sequence are predetermined, at the ready. Ontogeny Another
transition
is observed during ontogeny.
What
is the young individual like before it has acquired integrative actions? In what order do the integrations become effective? Do their origins depend on inductions? Even a zygote has self-contained coordinations; it respires, forms new compounds, and differentiates. It is noteworthy a) that integrations among metabolic and growth processes in the embryo exist before nerves and hormones are differentiated, and b) that disproportions body, among diverse tissues arise in the embryonic guided by successions of contacts among - cells and cell masses. During ontogeny the various controls of heat exchanges are elaborated serially, and not all at once. In infant rat, for instance, heat productions by augmented oxidations are available before heat losses come under control. Even at 5 days after birth, heat is produced faster in air of 34OC than in air of 36°C. Yet a few hours without food will abolish this extra heat production in response to cooling. Surprisingly, decerebration at the midpons of the brain stem now restores the faster heat production at cooling in 34OC (4). The inhibition of the extra heat production thus conserves energy at the expense of body temperature maintenance. Body temperature is coupled with processes ordinarily considered to belong to other bodily systems. In guinea pig the dissection of the heat production can be accomplished in another way. If the infant individual be cooled soon after birth, heat production (largely in muscles) is increased without shivering. But if the hypothalamus is heated, or its action is blocked by an injection of pronethalol , the increase of nonshivering in response to external cooling is stopped and shivering replaces it (5). Thus, elimination of one path of heat exchange leads to substitution of an equal amount of heat thro ugh an alternative path. At this early age a system of priorities exists. Because the regional and tissue elements that govern heat gains and heat losses are so varied, the concept is inevitable that among vertebrate animals some portions of heat regulation could have arisen separately from other portions. Perhaps new thermostats were perfected in the course of animal evolution, each one bringing greater precision of heat d istribution and constancy (8). Methods
of Study
Of what use are these statements about thermointegration? Detailed illustrative data have already been contributed through investigations on many kinds of animals. Diagrams and flow sheets have abstracted the results. Equations have been generated. The lesson is, however, that no scheme has been devised to represent or to predict the specific coordinated actions that are actually displayed. We look for means of understanding and insight, but still have to trust the weather forecaster’s type of judgment as to what the animal will do. Disappointingly also, the systems hypotheses have done little more than catalog what pieces would be needed to produce a physiological action. The chasm between empirical and theoretical is real. Apparently the number of variables operating within the organism is beyond present recognition. The scientist who would bridge the
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R258 chasm may find that while he can write down his hunch in an evening, he would require a year or more to test the idea. The large pool of extant data will not generally furnish what he needs. And empirical physiologists will not devote themselves to the tests that his theory requires. Currently, physiologists use diverse terms to designate integrative actions. Wherever there is a chain or a cycle of chemical transformations, there the enzymes and substrates and energies are evidently working in an orderly fashion. Sequences, couplings, and other relations are pieces of one accomplishment or another. For example, adequate branch points among the possible metabolic transformations, seem to be the basis of much regulatory success. But the in vivo kinetics of branch point interactions are wrapped in the unknown. Timing and modulated speed are elements that make a responsive system effective. Suppose one were able to construct an organism as one would an automobile, by installations of its working parts. The parts are ready to function; but certain connections among them are necessary before they operate. When one installs the connections he has to know what activities are a.imed at. Once that has been decided, he can design ho NW the regu lating elements may be arranged. But soon he will find that each activity cannot be regulated alone; there are conflicts and interferences. Occasionally unpredicted influences will be manifested. In the end one arrangement after another must be redesigned before a satisfactory operation of the whole will be obtained. In organisms, that redesigning has been endlessly performed through variations and selections of evolution.
E. F. ADOLPH
then studied over both a range of x and a range of u (2). In a graph, three scales of Cartesian coordinates are then used to express the interrelations, which in total describe the integrating arrangements in the individual studied. The investigator may also measure more dependent variables, ( y, z, h, . . .) = f(x, u, . . .). Actually Astrand (2) reported measurements of heart rate, alveolar Pas, etc., under wide ranges of x and u. Had the several parameters the inbeen measured singly instead of simultaneously, terrelations among them would be less precise. Each study of concurrent variables reveals a pattern of regulations among processes that readjust the oxygen delivto every shift of ery, bl ood flow, and limb movement action. The number of variables that could be measured is unlimited. But the comprehension of the results is limited by man’s difficulty in grasping a large situation. In particular, any number of dependent parameters can be listed, though only two or three or four at a time will be perceived as connected. Any more than two or three independent parameters readily escape one’s attention, and nomograms expressing such results have not yet been built. Computations of correlation coefficients, multiple correlations, and so forth may be valuable in the study of integrations. They can express closeness of one parameter to other parameters. The very concept of the organism as a complex of many variables is a useful one. Possession of more processes and properties enables the animal individual, within limits, to achieve more objectives. Summary
Correlations Interactions among organs and cells of an individual can be expressed, and even evaluated, of course, by usual means of correlation analysis. One may simply write y = f(x) to designate that y changes when x changes. And certain insights are gained from this equation. Thus, one may inquire: does lung ven tilation (y) increase in proporti .on to oxygen uptak .e (x) during muscular work? The answer is no meaning that integrating fat tors quantitate the two, but not linearly. Studies of integration are more likely to inquire into multiple correlations y = f (x, u, u, . . .). Indeed, greater precision in measurements of y may force the investigator to include two or more such independent variables in his study. Here I am concerned with the algebraic or graphical descriptions of correlations derived from empirical data. The physiologist measures a value of y for each imposed value of x; as, in observations of oxygen uptake at each imposed rate of muscular work. Or, with addition of another independent variable, namely, high altitudes (u), one may use a relation y = f(x, u). A range of y is
The animal is more than a hodgepodge of processes and tools. It can be viewed as a person possessing powers and resources. Powers depend on ingenuity and timing. A perennial job of a physiologist is to unearth those powers by appropriate challenges to action. He uses his skills not only to see a conglomerate but to see an organism that extracts survival and even satisfaction from its actions. In future the physiologist’s understand ing of organismic multiplicity is bound to increase, and thus to enhance the concepts of animal wholeness. The organism is seen as an edifice, not only structurally but also biochemically and functionally. The belief that natural selection among reproducing individuals has determined what cells and organs can do, becomes plausible. Evidently, extreme differentiations among processes and their combinations, characterize in more detail those very species (mammals) that are being most studied. The specializations of animals’ properties seem to attract inquiries; those specializations turn out to be of most consequence when they act together.
HEFERENCES 1. ARISTOTLE. Parts ofAnimals, translated by A. L. Peck, Cambridge, MA: Harvard Univ. Press, 1945, book 1, para. 1, 640a, 35, p. 63. 2. &STRAND, P. 0. The respiratory activity in man exposed to prolonged hypoxia. Acta Physiol. Stand. 30: 343-368, 1954. 3. BERNARD, C. Leqons SW la Chaleur AnimaZe. Paris: Bailhere, 1876, p. 327.
4. BIGNALL, K. E., F. W. neonatal decerebration cold exposure in the rat. 5. BR~~cK, K. Thermoregulation: esses. In: Temperature Newborn, edited by J.
HEGGENESS, AND 3. E. PALMER. Effect of on thermogenesis during starvation and Exp. Neural. 49: 174-188, 1975. control mechanisms and neural procRegulation and Energy Metabolism in the C. Sinclair. New York: Grune & Stratton,
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INVITED
OPINION
1978, p. 157-185. 6. GALEN, C. Galen on the Usefulness of the Parts of the Body, translated by M. T. May. Ithaca, NY: Cornell Univ. Press, 1968, book 1, para. 13, p. 76. 7. MILNE-EDWARDS, H. Leqons sur la Physiologic et I’Anatomie Cornparke (1881 ed.). Paris: Masson, vol. 14, p. 280. 8. SATINOFF, E. Neural organization and evolution of thermal regulation in mammals. Science 201: 16-22, 1978.
R259 9. SHERRINGTON, C. S. The Integrative Action of the Nervous System. New York: Scribner, 1906. 10. WEBER, E. F., AND E. H. WEBER. In: Selected Headings in the History of Physiology, translated by J. F. Fulton (1930). Springfield, IL: Thomas, 1845, p. 278. 11. WHITEHEAD, A. N. Science and the Modern World. New York: Macmillan, 1925, p. 3.
E. F. Adolph Department of Physiology University of Rochester Rochester, New York 14642
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integration
ADOLPH, E. F. Look atphysiological integration. Am. J. Physiol. 237(5): R255-R259,1979 or Am. J. Physiol.: Regulatory Integrative Comp. Physiol. 6( 3): R255-R259, 1979.-Physiological integration results from cooperating processes at work within an individual. Two chief types of study are a) empirical experiments and generalizations, and b) predictive relations derived from models. In this essay the empirical type is illustrated. For example, heart rates and other circulatory properties are modified in response to messages from specific muscles, viscera, glands. In those tissues, augmented blood flow increases the supplies of oxygen and other substances at active local sites. Because specialized actions are segregated among tissues and organs, each performer evidently informs cooperating tissues of its state. Messages are transmitted at various kinds of junctions and chemical receptors. In this essay the results or actions are emphasized: in what ways do the compounded processes promote survival and advantage? Messages are sorted as they travel, certain powers of decision residing at cellular junctions. Because selected processes are coordinated, each compound action represents an accomplishment. Thermoregulation serves as an example of relations by which several parameters yield a complex result. The multiple correlations and the intricate timing and switching are recognized. coordinated
It is this union of passionate interest equal devotion to abstract generalization
processes; specialized
in the detailed facts which forms novelty. A. N. Whitehead
actions
with (1925)
IS A CONCEPT of what organisms do. It signifies cooperative actions within individuals. How does one study it? The empiricist starts with examples of integrative action. Which examples he chooses will depend on his own researches. How many examples will be needed to formulate a helpful generalization? How many ways? An infinite number of ways can neither be listed nor comprehended. But insights are often found-from observations of what happens in what circumstances, and from experiments planned thereon. The individual scientist then draws tentative abstractions. The biotheorist, in contrast, starts with predictions. The predictions too are numerous. Some seem unacceptable to other persons whose imaginations are just as active. All predictionsneed to be tested in the crucible of laboratory examination. Every living individual has means of unifying its own activities. How does an animal manage to act as a whole individual? The animal in physiological laboratories is sometimes reduced to one receptor organ and one responder organ. In that circums tance the responses are reproducible, and the conclusions drawn are almost unexceptional. But most animals are not that stereotyped. INTEGRATION
0363-6119/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
In the mind of Aristotle (l), and later in the mind of Galen (6)) the question framed was, What is the usefulness of the actions seen in an animal’s body? What good is each one? Galen declared, “All parts of the body are in sympathy with one another; all cooperate in producing one effect .” Can the physiologist now comprehend both the oneto-one response and the inclusive situation? Obviously the science of physiology needs concepts derived from all kinds of investigation. Heart Rates First, an example of one organ acting in the midst of competing influences. An observer can watch a heart beating outside the body of a frog. The fact that beating can continue for hours under favorable conditions cannot fail to impress him. When the heart is within the frog’s body, the observer can readily ascertain that the rate of beating varies in accord with extrinsic influences, such as exercise of the frog’s legs, manipulation of the viscera, removal of oxygen from the atmosphere. Now the heart is being studied as a responder to varied influences. The observer sees the heart as a cooperating unit in an extensive array of actions. What a surprise it was when the brothers Weber (10) discovered that impulses in vagal nerves could temporarily stop the heart! Gradually, physiologists learned that the heart receives two kinds of messages through two Society
R255
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 12, 2019.
R256
E. F. ADOLPH
sets of nerves-sympathetic and parasympathetic. Further, that two kinds of chemical influence-adrenergic and cholinergiccould initiate the nerve impulses. And, that during development of the individual, at least in mammalian fetus, adrenergic hormones did not affect the rate of heartbeat in early stages, but gradually gained this power while developing. A hundred years of discovery could then be formalized into a logical story of governance. Today one can say that the heart is beating not for the sake of beating, but for the sake of bodily actions “demanding” more or less blood flow. Therefore, one studies not only the heart rate but the blood vessel calibers, the arterial pressures and other factors that may be interrelated, in order to understand what the flow of blood is accomplishing. What good is more blood flow? In most tissues the blood coming to them is carrying oxygen in a quantity that meets a demand. To this day, no one knows how the demand is accurately conveyed to the heart and to the arterioles that divert the flow hither and thither. Without a ready means of demand, however, the work that depends on oxygen supply would not get done. The fact of integration of oxygen supply and blood flow cannot be ignored. It can be measured as a combined response to an arousal. Scientists are well aware that the answers one obtains in an investigation usually depend on the questions asked. Inquire about variations of heart rates and one learns about the heart’s services to body. Reciprocally, one learns the degree of dependence on the blood flow by the several effector organs, such as brain and kidney. Division
of Labor
Milne-Edwards stated in 1827 (7) the principle of physiological division of labor. He noted that “the physiological instruments with which an animal is provided are specialized, and the diverse capabilities are localized.” The fact was so obvious that anyone could have stated it. Even so, decades were required before most physiologists realized that specialized and localized “instruments” could be of use only if they communicated one with another. Up to the close of the 19th century, just one means of communication was widely known: impulses in nerve. Nerves seemed plentiful and sufficient and all-powerful. There were sensory and motor nerves, sense organs, reflexes, voluntary controls, and much more. That era of discovery was capped by the amazing researches of Sherrington (9) reported in Integrative Action of the Nervous System. Today the physiologist has a whole list of means by which tissues communicate with one another: nerve impulse, hormone, neurohumor, decremental neuron, electrical junction, gap junction, gene, operon, allosterism, molecular receptor. The ingenuity of selective message conveyance among subcellular units is being revealed in terms of integrative actions between and among particles and membranes. But integrative actions require more than pathways for messages. Somewhere messages are processed, and decisions are made. In the case of central nervous actions the nature of those decisions is partly understood. Thus,
a muscle does not both contract and relax at the same instant. The information coming to particular nervous junctions obviously is scanned in predetermined ways, so that the amount of each muscle’s contraction will be decided. Priorities are fixed, as, in the stretch reflex for the maintenance of standing posture. Integrative physiology consists partly in the formulation of such rules of decisions, and of their exceptions. Given the fact that means of transmission are many and varied, the student of integrative actions need not wait for more understanding of how the messages travel. He can focus his attention on the accomplishments that issue from cooperative actions. For example, the muscles serving locomotion “anticipate” that their demand for oxygen will be met by augmented blood flow. In severe exercise a given leg muscle can consume oxygen at 40-60 times the resting rate. The heart, lungs, breathing, vasculatures, autonomies, adrenal medulIas, spinal synapses, and many more functional units respond to this one demand for action. All the phenomena known about muscular exercise thus constitute a vast scenario-cooperation, order, aim, integration. In spite of the usual neat division of functions into 10 or 20 textbook categories, actions continuously cross-collaborate with one another. Thermoregulation Regulation, and therefore integration, typically deals with cooperation among two or more different processes. Thus, body content of heat is equilibrated by approach to equality of two overall processes, gain and loss-so much heat production and so much heat output. Integration exists in that these two counteractions respond to disturbances, and that they restore a normative result. The particular combination of heat flows is generally the one combination that will maintain the body’s heat content. So, integration depends on a choice within the available patterns of actions. Accordingly, in heat regulation, the most general links are between a) heat content of body and parts (or net temperature), b) heat additions, and c) heat dissipations. The subsidiary choices among diverse paths and sites of heat flow serve to distribute the operations. Emphasis on accomplishment reveals that the organism’s advantages are reaped from the cooperations among chosen kinds of processes. Two general results can be observed: steadiness of temperatures and patterned distribution of them. “In the organism, all the phenomena of cooling alone and heating alone are not produced in an anarchic and disordered manner. Life would be impossible in such conditions. The phenomena are, on the contrary, associated and maintained in reciprocally harmonious relations, in order to furnish the animal with conditions that are fixed and indispensable for accomplishment of its functions” (Claude Bernard, Ref. 3). In the last century the actions involved in thermoregulation could be listed simply as: heat production by oxidations, and heat losses by radiation, conduction, and convection. Today it is universally recognized that these processes are both locally and integrally controlled in a complex manner, and many sensory and central factors are intricately interrelated (5). Thus, multiple sensations
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 12, 2019.
INVITED
R257
OPINION
from skin, hypothalamus, spinal cord, abdominal cavity, and respiratory passages have been shown to converge in the central nervous system; impulses in many single nerve fibers have been sampled. Pathways and scannings of inputs are at every moment coordinated into resultant outputs. For example, skin sensations are prepotent in arousing a) extra heat production (through shivering and nonshivering), and b) vasoconstriction in superficial tissues. But sensory information from deeper organs predomi nantly arouses sweating or panting. In quantitative detail, however, the weighted ingredients of integrative action are still unpredictable. For the body as a whole, each response to temperature sensations appears to recognize a threshold. This threshold can be conveniently imagined to contribute to a socalled set point. The set point, however, is not fixed under all conditions. In addition to the physiological responses of heat production and vasoconstriction, a group of other actions may be labeled behaviors-such as hunching, huddling, sprawling. Even in newborn individuals such postures go into action. Activations of responses employ numerous portions of the central nervous system from cerebral cortex to spinal synapses, and lead to shivering, panting, and so forth. Sympathetic nervous system is almost autonomous in signaling special heat losses (vasomotor, sweating) and extra hea t production. Because muscles an ,d blood vessels are effecters of heat exchanges, large body masses are involved. Fever represents a form of heat integration. Pyrogen that escapes from a parasitic organism gives rise to outputs of norepinephrine and prostaglandin E. These hormones influence hypothalamic neurons to command extra heat production and at the same time to diminish heat loss. Thus fever, a general concom itant of illness in individuals, teaches a lesson in integration. Regulation requires both activation of processes and limitation (usually by feedback) of the processes and their speeds. Every regulation-of metabolism, movement, energy, repair- involves integration among actions. For, the regulati on can be interrupted and can be dissected. It therefore furnish .es controls over actions of parts, whether the parts be chemical, structural, or particulate. Thus, as noted, regulation of body heat depends on shifts of heat production and of heat dissipation. One can conclude that integration of body heat depends on detailed regulations in-oxidations, blood flows, and the like. There is no boundary or distinction between regulation and integration. No one process by itself yields a resultant called integra tion; but a knowledge of several constituent movements of (for example) heat as a molecular motion, does yield a picture of coordination. Integration resides not only in some lever or switch, but in the complex of interacting “decisions.” Regulation also includes shifts to new patterns, when, for example muscular exercise begins. The transition shows that order and sequence are predetermined, at the ready. Ontogeny Another
transition
is observed during ontogeny.
What
is the young individual like before it has acquired integrative actions? In what order do the integrations become effective? Do their origins depend on inductions? Even a zygote has self-contained coordinations; it respires, forms new compounds, and differentiates. It is noteworthy a) that integrations among metabolic and growth processes in the embryo exist before nerves and hormones are differentiated, and b) that disproportions body, among diverse tissues arise in the embryonic guided by successions of contacts among - cells and cell masses. During ontogeny the various controls of heat exchanges are elaborated serially, and not all at once. In infant rat, for instance, heat productions by augmented oxidations are available before heat losses come under control. Even at 5 days after birth, heat is produced faster in air of 34OC than in air of 36°C. Yet a few hours without food will abolish this extra heat production in response to cooling. Surprisingly, decerebration at the midpons of the brain stem now restores the faster heat production at cooling in 34OC (4). The inhibition of the extra heat production thus conserves energy at the expense of body temperature maintenance. Body temperature is coupled with processes ordinarily considered to belong to other bodily systems. In guinea pig the dissection of the heat production can be accomplished in another way. If the infant individual be cooled soon after birth, heat production (largely in muscles) is increased without shivering. But if the hypothalamus is heated, or its action is blocked by an injection of pronethalol , the increase of nonshivering in response to external cooling is stopped and shivering replaces it (5). Thus, elimination of one path of heat exchange leads to substitution of an equal amount of heat thro ugh an alternative path. At this early age a system of priorities exists. Because the regional and tissue elements that govern heat gains and heat losses are so varied, the concept is inevitable that among vertebrate animals some portions of heat regulation could have arisen separately from other portions. Perhaps new thermostats were perfected in the course of animal evolution, each one bringing greater precision of heat d istribution and constancy (8). Methods
of Study
Of what use are these statements about thermointegration? Detailed illustrative data have already been contributed through investigations on many kinds of animals. Diagrams and flow sheets have abstracted the results. Equations have been generated. The lesson is, however, that no scheme has been devised to represent or to predict the specific coordinated actions that are actually displayed. We look for means of understanding and insight, but still have to trust the weather forecaster’s type of judgment as to what the animal will do. Disappointingly also, the systems hypotheses have done little more than catalog what pieces would be needed to produce a physiological action. The chasm between empirical and theoretical is real. Apparently the number of variables operating within the organism is beyond present recognition. The scientist who would bridge the
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R258 chasm may find that while he can write down his hunch in an evening, he would require a year or more to test the idea. The large pool of extant data will not generally furnish what he needs. And empirical physiologists will not devote themselves to the tests that his theory requires. Currently, physiologists use diverse terms to designate integrative actions. Wherever there is a chain or a cycle of chemical transformations, there the enzymes and substrates and energies are evidently working in an orderly fashion. Sequences, couplings, and other relations are pieces of one accomplishment or another. For example, adequate branch points among the possible metabolic transformations, seem to be the basis of much regulatory success. But the in vivo kinetics of branch point interactions are wrapped in the unknown. Timing and modulated speed are elements that make a responsive system effective. Suppose one were able to construct an organism as one would an automobile, by installations of its working parts. The parts are ready to function; but certain connections among them are necessary before they operate. When one installs the connections he has to know what activities are a.imed at. Once that has been decided, he can design ho NW the regu lating elements may be arranged. But soon he will find that each activity cannot be regulated alone; there are conflicts and interferences. Occasionally unpredicted influences will be manifested. In the end one arrangement after another must be redesigned before a satisfactory operation of the whole will be obtained. In organisms, that redesigning has been endlessly performed through variations and selections of evolution.
E. F. ADOLPH
then studied over both a range of x and a range of u (2). In a graph, three scales of Cartesian coordinates are then used to express the interrelations, which in total describe the integrating arrangements in the individual studied. The investigator may also measure more dependent variables, ( y, z, h, . . .) = f(x, u, . . .). Actually Astrand (2) reported measurements of heart rate, alveolar Pas, etc., under wide ranges of x and u. Had the several parameters the inbeen measured singly instead of simultaneously, terrelations among them would be less precise. Each study of concurrent variables reveals a pattern of regulations among processes that readjust the oxygen delivto every shift of ery, bl ood flow, and limb movement action. The number of variables that could be measured is unlimited. But the comprehension of the results is limited by man’s difficulty in grasping a large situation. In particular, any number of dependent parameters can be listed, though only two or three or four at a time will be perceived as connected. Any more than two or three independent parameters readily escape one’s attention, and nomograms expressing such results have not yet been built. Computations of correlation coefficients, multiple correlations, and so forth may be valuable in the study of integrations. They can express closeness of one parameter to other parameters. The very concept of the organism as a complex of many variables is a useful one. Possession of more processes and properties enables the animal individual, within limits, to achieve more objectives. Summary
Correlations Interactions among organs and cells of an individual can be expressed, and even evaluated, of course, by usual means of correlation analysis. One may simply write y = f(x) to designate that y changes when x changes. And certain insights are gained from this equation. Thus, one may inquire: does lung ven tilation (y) increase in proporti .on to oxygen uptak .e (x) during muscular work? The answer is no meaning that integrating fat tors quantitate the two, but not linearly. Studies of integration are more likely to inquire into multiple correlations y = f (x, u, u, . . .). Indeed, greater precision in measurements of y may force the investigator to include two or more such independent variables in his study. Here I am concerned with the algebraic or graphical descriptions of correlations derived from empirical data. The physiologist measures a value of y for each imposed value of x; as, in observations of oxygen uptake at each imposed rate of muscular work. Or, with addition of another independent variable, namely, high altitudes (u), one may use a relation y = f(x, u). A range of y is
The animal is more than a hodgepodge of processes and tools. It can be viewed as a person possessing powers and resources. Powers depend on ingenuity and timing. A perennial job of a physiologist is to unearth those powers by appropriate challenges to action. He uses his skills not only to see a conglomerate but to see an organism that extracts survival and even satisfaction from its actions. In future the physiologist’s understand ing of organismic multiplicity is bound to increase, and thus to enhance the concepts of animal wholeness. The organism is seen as an edifice, not only structurally but also biochemically and functionally. The belief that natural selection among reproducing individuals has determined what cells and organs can do, becomes plausible. Evidently, extreme differentiations among processes and their combinations, characterize in more detail those very species (mammals) that are being most studied. The specializations of animals’ properties seem to attract inquiries; those specializations turn out to be of most consequence when they act together.
HEFERENCES 1. ARISTOTLE. Parts ofAnimals, translated by A. L. Peck, Cambridge, MA: Harvard Univ. Press, 1945, book 1, para. 1, 640a, 35, p. 63. 2. &STRAND, P. 0. The respiratory activity in man exposed to prolonged hypoxia. Acta Physiol. Stand. 30: 343-368, 1954. 3. BERNARD, C. Leqons SW la Chaleur AnimaZe. Paris: Bailhere, 1876, p. 327.
4. BIGNALL, K. E., F. W. neonatal decerebration cold exposure in the rat. 5. BR~~cK, K. Thermoregulation: esses. In: Temperature Newborn, edited by J.
HEGGENESS, AND 3. E. PALMER. Effect of on thermogenesis during starvation and Exp. Neural. 49: 174-188, 1975. control mechanisms and neural procRegulation and Energy Metabolism in the C. Sinclair. New York: Grune & Stratton,
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INVITED
OPINION
1978, p. 157-185. 6. GALEN, C. Galen on the Usefulness of the Parts of the Body, translated by M. T. May. Ithaca, NY: Cornell Univ. Press, 1968, book 1, para. 13, p. 76. 7. MILNE-EDWARDS, H. Leqons sur la Physiologic et I’Anatomie Cornparke (1881 ed.). Paris: Masson, vol. 14, p. 280. 8. SATINOFF, E. Neural organization and evolution of thermal regulation in mammals. Science 201: 16-22, 1978.
R259 9. SHERRINGTON, C. S. The Integrative Action of the Nervous System. New York: Scribner, 1906. 10. WEBER, E. F., AND E. H. WEBER. In: Selected Headings in the History of Physiology, translated by J. F. Fulton (1930). Springfield, IL: Thomas, 1845, p. 278. 11. WHITEHEAD, A. N. Science and the Modern World. New York: Macmillan, 1925, p. 3.
E. F. Adolph Department of Physiology University of Rochester Rochester, New York 14642
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