Medical Physiology, 3rd Edition

CHAPTER 1. Foundations of Physiology

Emile L. Boulpaep, Walter F. Boron

What is physiology?

Physiology is the dynamic study of life. Physiology describes the “vital” functions of living organisms and their organs, cells, and molecules. For centuries, the discipline of physiology has been closely intertwined with medicine. Although physiology is not primarily concerned with structure—as is the case for anatomy, histology, and structural biology—structure and function are inextricably linked because the living structures perform the functions.

For some, physiology is the function of the whole person (e.g., exercise physiology). For many practicing clinicians, physiology may be the function of an individual organ system, such as the cardiovascular, respiratory, or gastrointestinal system. For still others, physiology may focus on the cellular principles that are common to the function of all organs and tissues. This last field has traditionally been called general physiology, a term that is now supplanted by cellular and molecular physiology. Although one can divide physiology according to varying degrees of reductionism, it is also possible to define a branch of physiology—for example, comparative physiology—that focuses on differences and similarities among different species. Indeed, comparative physiology may deal with all degrees of reductionism, from molecule to whole organism. In a similar way, medical physiology deals with how the human body functions, which depends on how the individual organ systems function, which depends on how the component cells function, which in turn depends on the interactions among subcellular organelles and countless molecules. Thus, medical physiology takes a global view of the human body; but in doing so, it requires an integrated understanding of events at the level of molecules, cells, and organs.

Physiology is the mother of several biological sciences, having given birth to the disciplines of biochemistry, biophysics, and neuroscience, as well as their corresponding scientific societies and journals. Thus, it should come as no surprise that the boundaries of physiology are not sharply delineated. Conversely, physiology has its unique attributes. For example, physiology has evolved over the centuries from a more qualitative to a more quantitative science. Indeed, many of the leading physiologists were—and still are—trained as chemists, physicists, mathematicians, or engineers.

Physiological genomics is the link between the organ and the gene

The life of the human body requires not only that individual organ systems do their jobs but also that these organ systems work “hand in hand” with each other. They must share information. Their actions must be interdependent. The cells within an organ or a tissue often share information, and certainly the individual cells must act in concert to perform the proper function of the organ or tissue. In fact, cells in one organ must often share information with cells in another organ and make decisions that are appropriate for the health of the individual cell as well as for the health of the whole person.

In most cases, the sharing of information between organs and between cells takes place at the level of atoms or molecules. Cell-to-cell messengers or intracellular messengers may be as simple as H+ or K+ or Ca2+. The messengers may also be more complex chemicals. A cell may release a molecule that acts on a neighboring cell or that enters the bloodstream and acts on other cells a great distance away. In other cases, a neuron may send an axon a centimeter or even a meter away and rapidly modulate, through a neurotransmitter molecule, the activity of another cell or another organ. Cells and organs must interact with one another, and the method of communication is almost always molecular.

The grand organizer—the master that controls the molecules, the cells, and the organs and the way they interact—is the genome with its epigenetic modifications. Traditionally, the discipline of physiology has, in its reductionistic journey, always stopped at about the level of cells and certain subcellular organelles as well as their component and controlling molecules. The discipline of physiology left to molecular biology and molecular genetics the business of how the cell controls itself through its DNA. The modern discipline of physiology has become closely intertwined with molecular biology, however, because DNA encodes the proteins in which physiologists are most interested. Very often, physiologists painstakingly develop elegant strategies for cloning the genes relevant to physiology. Sometimes brute-force approaches, such as the Human Genome Project in the United States, hand the physiologist a candidate gene, homologous to one of known function, on a silver platter. In still other cases, molecular biologists may clone a gene with no known function. In this case, it may be up to the physiologist to determine the function of the gene product; that is, to determine its physiology.

Physiological genomics (or functional genomics) is a new branch of physiology devoted to the understanding of the roles that genes play in physiology. Traditionally, physiologists have moved in a reductionistic direction from organ to cell to molecule to gene. One of the most fascinating aspects of physiological genomics is that it has closed the circle and linked organ physiology directly with molecular biology. Perhaps one of the most striking examples is the knockout mouse. Knocking out the gene encoding a protein that, according to conventional wisdom, is very important will sometimes have no obvious effect or sometimes unexpected effects. It is up to the physiologist, at least in part, to figure out why. It is perhaps rather sobering to consider that to truly understand the impact of a transgene or a knockout on the physiology of a mouse, one would have to carefully re-evaluate the totality of mouse physiology. To grasp the function of a gene product, the physiologist must retrace the steps up the reductionistic road and achieve an integrated understanding of that gene's function at the level of the cells, organs, and whole body. Physiology is unique among the basic medical sciences in that it is both broad in its scope (i.e., it deals with multiple systems) and integrative in its outlook.

In some cases, important physiological parameters, such as blood pressure, may be under the control of many genes. Certain polymorphisms in several of these many genes could have a cumulative effect that produces high blood pressure. How would one identify which polymorphisms of which genes may underlie high blood pressure? This sort of complex problem does not easily lend itself to a physiologist's controlled studies. One approach would be to study a population of people, or strains of experimental animals, and use statistical tools to determine which polymorphisms correlate with high blood pressure in a population. Indeed, epidemiologists use statistical tools to study group effects in populations. However, even after the identification of variants in various genes, each of which may make a small contribution to high blood pressure, the physiologist has an important role. First, the physiologist, performing controlled experiments, must determine whether a particular genetic variant does indeed have at least the potential to modulate blood pressure. Second, the physiologist must determine the mechanism of the effect.

Cells live in a highly protected milieu intérieur

In his lectures on the phenomena of life, Claude Bernard noted in 1878 on the conditions of the constancy of life, which he considered a property of higher forms of life. According to Bernard, animals have two environments: the “milieu extérieur” that physically surrounds the whole organism; and the “milieu intérieur,” in which the tissues and cells of the organism live. This internal environment is neither the air nor the water in which an organism lives but rather—in the case of the human body—the well-controlled liquid environment that Bernard called “the organic liquid that circulates and bathes all the anatomic elements of the tissues, the lymph or the plasma.” In short, this internal environment is what we today call the extracellular fluid. He argued that physiological functions continue in a manner indifferent to the changing environment because the milieu intérieur isolates the organs and tissues of the body from the vagaries of the physical conditions of the environment. Indeed, Bernard described the milieu intérieur as if an organism had placed itself in a greenhouse.

According to Bernard's concept of milieu intérieur, some fluids contained within the body are not really inside the body at all. For example, the contents of the gastrointestinal tract, sweat ducts, and renal tubules are all outside the body. They are all continuous with the milieu extérieur.

Bernard compares a complex organism to an ensemble of anatomical elements that live together inside the milieu intérieur. Therefore, in Section II of this textbook, we examine the physiology of these cells and molecules. In Chapter 2 (“Functional Organization of the Cell”), we begin our journey through physiology with a discussion of the biology of the cells that are the individual elements of the body. Chapter 3 (“Signal Transduction”) discusses how cells communicate directly through gap junctions or indirectly by molecules released into the extracellular fluid. These released molecules can bind to receptors on the cell membrane and initiate signal-transduction cascades that can modify gene transcription (a genomic response) and a wide range of other cell functions (nongenomic responses). Alternatively, these released molecules can bind to receptors in the cytoplasm or nucleus and alter the transcription of genes. In Chapter 4 (“Regulation of Gene Expression”), we examine the response of the nucleus. Chapter 5 (“Transport of Solutes and Water”) addresses how the plasma membrane separates the cell interior from Bernard's milieu intérieur and establishes the composition of the cell interior. In the process of establishing the composition of the intracellular fluid, the plasma membrane also sets up ion and voltage gradients across itself. Excitable cells—mainly nerve and muscle cells—can exploit these gradients for the long-distance “electrical” transmission of information. The property of “excitability,” which requires both the perception of a change (a signal) and the reaction to it, is the topic of Chapters 6 to 9. In Section III, we examine how the nervous system exploits excitability to process information.

Another theme developed by Bernard was that the “fixité du milieu intérieur” (the constancy of the extracellular fluid) is the condition of “free, independent life.” He explains that organ differentiation is the exclusive property of higher organisms and that each organ contributes to “compensate and equilibrate” against changes in the external environment. In that sense, each of the systems discussed in Sections IV to VIII permits the body to live within an adverse external environment because the cardiovascular system, the respiratory system, the urinary system, the gastrointestinal system, and the endocrine system create and maintain a constant internal environment. Individual cell types in various organ systems act in concert to support the constancy of the internal milieu, and the internal milieu in turn provides these cells with a culture medium in which they can thrive.

The discipline of physiology also deals with those characteristics that are the property of a living organism as opposed to a nonliving organism. Four fundamental properties distinguish the living body. First, only living organisms exchange matter and energy with the environment to continue their existence. Several organ systems of the body participate in these exchanges. Second, only living organisms can receive signals from their environment and react accordingly. The principles of sensory perception, processing by the nervous system, and reaction are discussed in the chapters on excitability and the nervous system. Third, what distinguishes a living organism is the life cycle of growth and reproduction, as discussed in the chapters on reproduction (Section IX). Finally, the living organism is able to adapt to changing circumstances. This is a theme that is developed throughout this textbook but especially in the chapters on everyday life (Section X).

Homeostatic mechanisms—operating through sophisticated feedback control mechanisms—are responsible for maintaining the constancy of the milieu intérieur

Homeostasis is the control of a vital parameter. The body carefully controls a seemingly endless list of vital parameters. Examples of tightly controlled parameters that affect nearly the whole body are arterial pressure and blood volume. At the level of the milieu intérieur, tightly regulated parameters include body core temperature and plasma levels of oxygen, glucose, potassium ions (K+), calcium ions (Ca2+), and hydrogen ions (H+). Homeostasis also occurs at the level of the single cell. Thus, cells regulate many of the same parameters that the body as a whole regulates: volume, the concentrations of many small inorganic ions (e.g., Na+, Ca2+, H+), and energy levels (e.g., ATP).

One of the most common themes in physiology is the negative-feedback mechanism responsible for homeostasis. Negative feedback requires at least four elements. First, the system must be able to sense the vital parameter (e.g., glucose level) or something related to it. Second, the system must be able to compare the input signal with some internal reference value called a set-point, thereby forming a difference signal. Third, the system must multiply the error signal by some proportionality factor (i.e., the gain) to produce some sort of output signal (e.g., release of insulin). Fourth, the output signal must be able to activate an effector mechanism (e.g., glucose uptake and metabolism) that opposes the source of the input signal and thereby brings the vital parameter closer to the set-point (e.g., decrease of blood glucose levels back to normal). imageN1-1 Sometimes the body controls a parameter, in part, by cleverly employing positive-feedback loops.

N1-1

Feedback Control

Contributed by Arthur DuBois

In proportional control, the set-point is not reached because the difference signal would disappear, and control would come to an end. Engineers devised a way around this. They took the time integral of the difference signal and used that to activate the effector mechanism to achieve integral control that would allow return to the set-point. There was another problem. Since there is a time delay in processing the input signal, there is a delay in returning to the set-point. Engineers also had a way around that. They took the time-derivative of the difference signal and added that to the corrective signal, speeding up the return toward the set-point.

Another problem turned up. If you have a heater and a cooler, each with its own thermostat, and you want the room to be 23°C to 25°C, you must set one thermostat to turn on the heater at temperatures <23°C but to shut it off at ≥23°C. The thermostat for the cooler has to turn it on >25°C but shut it off at ≤25°C to avoid running the heater and cooler both at once. If the room is cold, the heater will warm it up to 23°C, then shut off. If the room is warm, the cooler will cool it down to 25°C, then shut off. By analogy, the body has separate systems for shivering and sweating, so both do not occur at once. One can picture that anabolic and catabolic pathways should cycle separately and not simultaneously. Many body systems such as respiratory and circulatory controls oscillate between slightly above and slightly below the desired average, hunting for it rather than sitting on a single ideal value. In a case in which the control system is less precise, the swings become wider, as they do when a drunk driver wanders back and forth across the road proceeding home.

A single feedback loop often does not operate in isolation but rather as part of a larger network of controls. Thus, a complex interplay may exist among feedback loops within single cells, within a tissue, within an organ or organ system, or at the level of the whole body. After studying these individual feedback loops in isolation, the physiologist may find that two feedback loops act either synergistically or antagonistically. For example, insulin lowers blood glucose levels, whereas epinephrine and cortisol have the opposite effect. Thus, the physiologist must determine the relative weights of feedback loops in competition with one another. Finally, the physiologist must also establish hierarchy among various feedback loops. For example, the hypothalamus controls the anterior pituitary, which controls the adrenal cortex, which releases cortisol, which helps control blood glucose levels.

Another theme of homeostasis is redundancy. The more vital a parameter is, the more systems the body mobilizes to regulate it. If one system should fail, others are there to help maintain homeostasis. It is probably for this reason that genetic knockouts sometimes fail to have their expected deleterious effects. The result of many homeostatic systems controlling many vital parameters is a milieu intérieur with a stable composition.

Whether at the level of the milieu intérieur or the cytoplasm of a single cell, homeostasis occurs at a price: energy. When a vital parameter (e.g., the blood glucose level) is well regulated, that parameter is not in equilibrium. Equilibrium is a state that does not involve energy consumption. Instead, a well-regulated parameter is generally in a steady state. That is, its value is constant because the body or the cell carefully matches actions that lower the parameter value with other actions that raise it. The net effect is that the vital parameter is held at a constant value.

An important principle in physiology, to which we have already alluded, is that each cell plays a specialized role in the overall function of the body. In return, the body—which is the sum of all these cells—provides the milieu intérieur appropriate for the life of each cell. As part of the bargain, each cell or organ must respect the needs of the body as a whole and not run amok for its own greedy interests. For example, during exercise, the system that controls body core temperature sheds heat by elaborating sweat for evaporation. However, the production of sweat ultimately reduces blood volume. Because the body as a whole places a higher priority on the control of blood volume than on the control of body core temperature, at some point the system that controls blood volume will instruct the system that controls body core temperature to reduce the production of sweat. Unfortunately, this juggling of priorities works only if the individual stops exercising; if not, the result may be heat stroke.

The adaptability of an organism depends on its ability to alter its response. Indeed, flexible feedback loops are at the root of many forms of physiological adaptation. For instance, at sea level, experimentally lowering the level of oxygen (the sensory stimulus) in the inspired air causes an increase in breathing (the response). However, after acclimatization at high altitude to low oxygen levels, the same low level of oxygen (the same sensory stimulus) causes one to breathe much faster (a greater response). Thus, the response may depend on the previous history and therefore the “state” of the system. In addition to acclimatization, genetic factors can also contribute to the ability to respond to an environmental stress. For example, certain populations of humans who have lived for generations at high altitude withstand hypoxia better than lowlanders do, even after the lowlanders have fully acclimatized.

Medicine is the study of “physiology gone awry”

Medicine borrows its physicochemical principles from physiology. Medicine also uses physiology as a reference state: it is essential to know how organs and systems function in the healthy person to grasp which components may be malfunctioning in a patient. A large part of clinical medicine is simply dealing with the abnormal physiology brought about by a disease process. One malfunction (e.g., heart failure) can lead to a primary pathological effect (e.g., a decrease in cardiac output) that—in chain-reaction style—leads to a series of secondary effects (e.g., fluid overload) that are the appropriate responses of physiological feedback loops. Indeed, as clinician-physiologists have explored the basis of disease, they have discovered a great deal about physiology. For this reason, we have tried to illustrate physiological principles with clinical examples, some of which are displayed in clinical boxes in this text.

Physiologists have developed many tools and tests to examine normal function. A large number of functional tests—used in diagnosis of a disease, monitoring of the evolution of an illness, and evaluation of the progress of therapy—are direct transfers of technology developed in the physiology laboratory. Typical examples are cardiac monitoring, pulmonary function tests, and renal clearance tests as well as the assays used to measure plasma levels of various ions, gases, and hormones. Refinements of such technology in the hospital environment, in turn, benefit the study of physiology. Thus, the exchange of information between medicine and physiology is a two-way street. The understanding of physiology summarized in this book comes from some experiments on humans but mostly from research on other mammals and even on squids and slime molds. However, our ultimate focus is on the human body.

References

Bernard C. Leçons sur les phénomènes de la vie communs aux animaux et aux végétaux. Cours de physiologie générale du Museum d’Histoire Naturelle. Baillière et Fils: Paris; 1878.

Cannon WB. The Wisdom of the Body. WW Norton: New York; 1932.

Smith HW. From Fish to Philosopher. Doubleday: New York; 1961.


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