Connective Tissue

Connective tissue is characterized by large amounts of extracellular material in the spaces between the connective tissue cells. This extracellular material may be of various types and arrangements and, on this basis, several types of connective tissues are recognized: (1) connective tissue proper, (2) cartilage, (3) bone, and (4) blood. Blood is usually classified as connective tissue because about half its volume is composed of an extracellular fluid known as plasma.
Connective tissue proper includes a variety of subtypes. An example of loose connective tissue (or areolar tissue) is the dermis of the skin. This connective tissue consists of scattered fibrous proteins, called collagen, and tissue fluid, which provides abundant space for the entry of blood and lymphatic vessels and nerve fibers. Another type of connective tissue proper, dense fibrous connective tissue, contains densely packed fibers of collagen that may be irregularly or regularly arranged. Dense irregular connective tissue contains a meshwork of randomly oriented collagen fibers that resist forces applied from many directions. This tissue forms the tough capsules and sheaths surrounding organs. Tendons, which connect muscle to bone, and ligaments, which connect bones together at joints, are examples of dense regular connective tissue. The collagen fibers of this tissue are oriented in the same direction.

A photomicrograph of dense irregular connective tissue. Notice the tightly packed, irregularly arranged collagen proteins.

Dense regular connective tissue. (a) Labeled diagram and (b) photomicrograph of a tendon. Notice the dense regular arrangement of collagenous fibers.

Exocrine Glands

Exocrine glands are derived from cells of epithelial membranes. The secretions of these cells are passed to the outside of the epithelial membranes (and hence to the surface of the body) through ducts. This is in contrast to endocrine glands, which lack ducts and which therefore secrete into capillaries within the body.

The formation of exocrine and endocrine glands from epithelial membranes. Note that exocrine glands retain a duct that can carry their secretion to the surface of the epithelial membrane, whereas endocrine glands are ductless.

The secretory units of exocrine glands may be simple tubes, or they may be modified to form clusters of units around branched ducts. These clusters, or acini, are often surrounded by tentacle-like extensions of myoepithelial cells that contract and squeeze the secretions through the ducts. The rate of secretion and the action of myoepithelial cells are subject to neural and endocrine regulation.

The structure of exocrine glands. Exocrine glands may be simple invaginations of epithelial membranes, or they may be more complex derivatives.

Examples of exocrine glands in the skin include the lacrimal (tear) glands, sebaceous glands (which secrete oily sebum into hair follicles), and sweat glands. There are two types of sweat glands. The more numerous, the eccrine (or merocrine) sweat glands, secrete a dilute salt solution that serves in thermoregulation (evaporation cools the skin). The apocrine sweat glands, located in the axillae (underarms) and pubic region, secrete a protein-rich fluid. This provides nourishment for bacteria that produce the characteristic odor of this type of sweat.
All of the glands that secrete into the digestive tract are also exocrine. This is because the lumen of the digestive tract is a part of the external environment, and secretions of these glands go to the outside of the membrane that lines this tract. Mucous glands are located throughout the length of the digestive tract. Other relatively simple glands of the tract include salivary glands, gastric glands, and simple tubular glands in the intestine.
The liver and pancreas are exocrine (as well as endocrine) glands, derived embryologically from the digestive tract. The exocrine secretion of the pancreas—pancreatic juice—contains digestive enzymes and bicarbonate and is secreted into the small intestine via the pancreatic duct. The liver produces and secretes bile (an emulsifier of fat) into the small intestine via the gallbladder and bile duct.
Exocrine glands are also prominent in the reproductive system. The female reproductive tract contains numerous mucussecreting exocrine glands. The male accessory sex organs—the prostate and seminal vesicles—are exocrine glands that contribute to semen. The testes and ovaries (the gonads) are both endocrine and exocrine glands. They are endocrine because they secrete sex steroid hormones into the blood; they are exocrine because they release gametes (ova and sperm) into the reproductive tracts.

Epithelial Tissue

Epithelial tissue consists of cells that form membranes, which cover and line the body surfaces, and of glands, which are derived from these membranes. There are two categories of glands. Exocrine glands (exo = outside) secrete chemicals through a duct that leads to the outside of a membrane, and thus to the outside of a body surface. Endocrine glands (from the Greek endon = within) secrete chemicals called hormones into the blood.
Epithelial Membranes
Epithelial membranes are classified according to the number of their layers and the shape of the cells in the upper layer. Epithelial cells that are flattened in shape are squamous; thosethat are taller than they are wide are columnar; and those that are as wide as they are tall are cuboidal. Those epithelial membranes that are only one cell layer thick are known as simple membranes; those that are composed of a number of layers are stratified membranes.

Different types of simple epithelial membranes. (a) Simple squamous, (b) simple cuboidal, and (c) simple columnar epithelial membranes. The tissue beneath each membrane is connective tissue.

Epithelial membranes cover all body surfaces and line the cavity (lumen) of every hollow organ. Thus, epithelial membranes provide a barrier between the external environment and the internal environment of the body. Stratified epithelial membranes are specialized to provide protection. Simple epithelial membranes, in contrast, provide little protection; instead, they are specialized for transport of substances between the internal and external environments. In order for a substance to get into the body, it must pass through an epithelial membrane, and simple epithelia are specialized for this function For example, a simple squamous epithelium in the lungs allows the rapid passage of oxygen and carbon dioxide between the air (external environment) and blood (internal environment). A simple columnar epithelium in the small intestine, as another example, allows digestion products to pass from the intestinal lumen (external environment) to the blood (internal environment).
Dispersed among the columnar epithelial cells are specialized unicellular glands called goblet cells that secrete mucus. The columnar epithelial cells in the uterine (fallopian) tubes of females and in the respiratory passages contain numerous ciliathat can move in a coordinated fashion and aid the functions of these organs.

The epithelial lining of the esophagus and vagina that provides protection for these organs is a stratified squamous epithelium. This is a nonkeratinized membrane, and all layers consist of living cells. The epidermis of the skin, by contrast, is keratinized, or cornified. Since the epidermis is dry and exposed to the potentially desiccating effects of the air, the surface is covered with dead cells that are filled with a water-resistant protein known as keratin. This protective layer is constantly flaked off from the surface of the skin and therefore must be constantly replaced by the division of cells in the deeper layers of the epidermis.

A stratified squamous nonkeratinized epithelial membrane. This is a photomicrograph (a) and illustration (b) of the epithelial lining of the vagina.

The epidermis is a stratified, squamous keratinized epithelium. Notice the loose connective tissue dermis beneath the cornified epidermis. Loose connective tissue contains scattered collagen fibers in a matrix of protein-rich fluid. The intercellular spaces also contain cells and blood vessels.

The constant loss and renewal of cells is characteristic of epithelial membranes. The entire epidermis is completely replaced every 2 weeks; the stomach lining is renewed every 2 to 3 days. Examination of the cells that are lost, or “exfoliated,” from the outer layer of epithelium lining the female reproductive tract is a common procedure in gynecology (as in the Pap smear).
In order to form a strong membrane that is effective as a barrier at the body surfaces, epithelial cells are very closely packed and are joined together by structures collectively called junctional complexes. There is no room for blood vessels between adjacent epithelial cells. The epithelium must therefore receive nourishment from the tissue beneath, which has large intercellular spaces that can accommodate blood vessels and nerves. This underlying tissue is called connective tissue. Epithelial membranes are attached to the underlying connective tissue by a layer of proteins and polysaccharides known as the basement membrane. This layer can be observed only under the microscope using specialized staining techniques.

Nervous Tissue

Nervous tissue consists of nerve cells, or neurons, which are specialized for the generation and conduction of electrical events, and of supporting cells, which provide the neurons with anatomical and functional support. Supporting cells in the brain and spinal cord are referred to as neuroglial cells, or often simply as glial cells.
Each neuron consists of three parts: (1) a cell body, (2) dendrites,
and (3) an axon. The cell body contains the nucleus and serves as the metabolic center of the cell. The dendrites (literally, “branches”) are highly branched cytoplasmic extensions of the cell body that receive input from other neurons or from receptor cells. The axon is a single cytoplasmic extension of the cell body that can be quite long (up to a few feet in length). It is specialized for conducting nerve impulses from the cell body to another neuron or to an effector (muscle or gland) cell.

A photomicrograph of nerve tissue. A single neuron and numerous smaller supporting cells can be seen.

The supporting cells do not conduct impulses but instead serve to bind neurons together, modify the extracellular environment of the nervous system, and influence the nourishment and electrical activity of neurons. Supporting cells are about five times more abundant than neurons in the nervous system and, unlike neurons, maintain a limited ability to divide by mitosis throughout life.

Muscle Tissue

 Muscle tissue is specialized for contraction. There are three types of muscle tissue: skeletal, cardiac, and smooth. Skeletal muscle is often called voluntary muscle because its contraction is consciously controlled. Both skeletal and cardiac muscles are striated; they have striations, or stripes, that extend across the width of the muscle cell. These striations are produced by a characteristic arrangement of contractile proteins, and for this reason skeletal and cardiac muscle have similar mechanisms of contraction. Smooth muscle lacks these striations and has a different mechanism of contraction.

Three skeletal muscle fibers showing the characteristic
light and dark cross striations. Because of this feature, skeletal muscle is also called striated muscle.

Skeletal Muscle

Skeletal muscles are generally attached to bones at both ends by means of tendons; hence, contraction produces movements of the skeleton. There are exceptions to this pattern, however. The tongue, superior portion of the esophagus, anal sphincter, and diaphragm are also composed of skeletal muscle, but they do not cause movements of the skeleton.

Beginning at about the fourth week of embryonic development, separate cells called myoblasts fuse together to form skeletal muscle fibers, or myofibers (from the Greek myos, meaning “muscle”). Although myofibers are often referred to as skeletal muscle cells, each is actually a syncytium, or multinucleate mass formed from the union of separate cells. Despite their unique origin and structure, each myofiber contains mitochondria and other organelles common to all cells.

The muscle fibers within a skeletal muscle are arranged in bundles, and within these bundles the fibers extend in parallel from one end to the other of the bundle. The parallel arrangement of muscle fibers allows each fiber to be controlled individually: one can thus contract fewer or more muscle fibers and, in this way, vary the strength of contraction of the whole muscle. The ability to vary, or “grade,” the strength of skeletal muscle contraction is obviously needed for precise control of skeletal movements.

Human cardiac muscle. Notice the striated appearance and dark-staining intercalated discs

Cardiac Muscle

Although cardiac muscle is striated, it differs markedly from skeletal muscle in appearance. Cardiac muscle is found only in the heart, where the myocardial cells are short, branched, and intimately interconnected to form a continuous fabric. Special areas of contact between adjacent cells stain darkly to show intercalated discs, which are characteristic of heart muscle.

The intercalated discs couple myocardial cells together mechanically and electrically. Unlike skeletal muscles, therefore, the heart cannot produce a graded contraction by varying the number of cells stimulated to contract. Because of the way it is constructed, the stimulation of one myocardial cell results in the stimulation of all other cells in the mass and a “wholehearted” contraction.

A photomicrograph of smooth muscle cells. Notice that these cells contain single, centrally located nuclei and lack striations.

Smooth Muscle 

As implied by the name, smooth muscle cells  do not have the striations characteristic of skeletal and cardiac muscle. Smooth muscle is found in the digestive tract, blood vessels, bronchioles (small air passages in the lungs), and in the ducts of the urinary and reproductive systems. Circular arrangements of smooth muscle in these organs produce constriction of the lumen (cavity) when the muscle cells contract. The digestive tract also contains longitudinally arranged layers of smooth muscle. The series of wavelike contractions of circular and longitudinal layers of muscle known as peristalsis pushes food from one end of the digestive tract to the other.

Feedback Control of Hormone Secretion

The nature of the endocrine glands, the interaction of the nervous and endocrine systems, and the actions of hormones will be discussed in detail in later chapters. For now, it is sufficient to describe the regulation of hormone secretion very broadly, since it so superbly illustrates the principles of homeostasis and negative feedback regulation.
Hormones are secreted in response to specific chemical stimuli. A rise in the plasma glucose concentration, for example, stimulates insulin secretion from structures in the pancreas known as the pancreatic islets, or islets of Langerhans. Hormones are also secreted in response to nerve stimulation and to stimulation by other hormones.
The secretion of a hormone can be inhibited by its own effects, in a negative feedback manner. Insulin, as previously described, produces a lowering of blood glucose. Since a rise in blood glucose stimulates insulin secretion, a lowering of blood glucose caused by insulin’s action inhibits further insulin secretion. This closed-loop control system is called negative feedback inhibition.
Homeostasis of blood glucose is too important—the brain uses blood glucose as its primary source of energy—to entrust to the regulation of only one hormone, insulin. So, during fasting, when blood glucose falls, it is prevented from falling too far by several mechanisms. First, insulin secretion decreases, preventing muscle, liver, and adipose cells from taking too much glucose from the blood. Second, the secretion of a hormone antagonistic to insulin, called glucagon, increases. Glucagon stimulates processes in the liver that cause it to secrete glucose into the blood. Through these and other antagonistic negative feedback mechanisms, the blood glucose is maintained within a homeostatic range.

Negative feedback control of blood glucose.

The rise in blood glucose that occurs after eating carbohydrates is corrected by the action of insulin, which is secreted in increasing amounts (a) at that time. During fasting, when blood glucose falls, insulin secretion is inhibited and the secretion of an antagonistic hormone, glucagon, is increased (b). This stimulates the liver to secrete glucose into the blood, helping to prevent blood glucose from continuing to fall. In this way, blood glucose concentrations are maintained within a homeostatic range following eating and during fasting.

Although physiology is the study of function, it is difficult to properly understand the function of the body without some knowledge of its anatomy, particularly at a microscopic level. Microscopic anatomy constitutes a field of study known as histology. The anatomy and histology of specific organs will be discussed together with their functions in later chapters. In this section, the common “fabric” of all organs is described.
Cells are the basic units of structure and function in the body. Cells that have similar functions are grouped into categories called tissues. The entire body is composed of only four major types of tissues. These primary tissues include (1) muscle, (2) nervous, (3) epithelial, and (4) connective tissues. Groupings of these four primary tissues into anatomical and functional units are called organs. Organs, in turn, may be grouped together by common functions into systems. The systems of the body act in a coordinated fashion to maintain the entire organism.

Neural and Endocrine Regulation

Homeostasis is maintained by two general categories of regulatory mechanisms: (1) those that are intrinsic, or “built-in,” to the organs being regulated and (2) those that are extrinsic, as in regulation of an organ by the nervous and endocrine systems. The endocrine system functions closely with the nervous system in regulating and integrating body processes and maintaining homeostasis. The nervous system controls the secretion of many endocrine glands, and some hormones in turn affect the function of the nervous system. Together, the nervous and endocrine systems regulate the activities of most of the other systems of the body.
Regulation by the endocrine system is achieved by the secretion of chemical regulators called hormones into the blood. Since hormones are secreted into the blood, they are carried by the blood to all organs in the body. Only specific organs can respond to a particular hormone, however; these are known as the target organs of that hormone.
Nerve fibers are said to innervate the organs that they regulate. When stimulated, these fibers produce electrochemical nerve impulses that are conducted from the origin of the fiber to its end point in the target organ innervated by the fiber. These target organs can be muscles or glands that may function as effectors in the maintenance of homeostasis.

Positive Feedback

Constancy of the internal environment is maintained by effectors that act to compensate for the change that served as the stimulus for their activation; in short, by negative feedback loops. A thermostat, for example, maintains a constant temperature by increasing heat production when it is cold and decreasing heat production when it is warm. The opposite occurs during positive feedback—in this case, the action of effectors amplifies those changes that stimulated the effectors. A thermostat that works by positive feedback, for example, would increase heat production in response to a rise in temperature.
It is clear that homeostasis must ultimately be maintained by negative rather than by positive feedback mechanisms. The effectiveness of some negative feedback loops, however, is increased by positive feedback mechanisms that amplify the actions of a negative feedback response. Blood clotting, for example, occurs as a result of a sequential activation of clotting factors; the activation of one clotting factor results in activation of many in a positive feedback cascade. In this way, a single change is amplified to produce a blood clot. Formation of the clot, however, can prevent further loss of blood, and thus represents the completion of a negative feedback loop that restores homeostasis.

Quantitative Measurements

Normal ranges and deviations from the set point must be known quantitatively in order to study physiological mechanisms. For these and other reasons, quantitative measurements are basic to the science of physiology. One example of this, and of the actions of antagonistic mechanisms in maintaining homeostasis. Blood glucose concentrations were measured in five healthy people before and after an injection of insulin, a hormone that acts to lower the blood glucose concentration. A graph of the data reveals that the blood glucose concentration decreased rapidly but was brought back up to normal levels within 80 minutes after the injection. This demonstrates that negative feedback mechanisms acted to restore homeostasis in this experiment. These mechanisms involve the action of hormones whose effects are antagonistic to that of insulin—that is, they promote the secretion of glucose from the liver.

Homeostasis of the blood glucose concentration.

Average blood glucose concentrations of five healthy individuals are graphed before and after a rapid intravenous injection of insulin. The “0” indicates the time of the injection. Notice that, following injection of insulin, the blood glucose is brought back up to the normal range. This occurs as a result of the action of hormones antagonistic to insulin, which cause the liver to secrete glucose into the blood. In this way, homeostasis is maintained.

Antagonistic Effectors

Most factors in the internal environment are controlled by several effectors, which often have antagonistic actions. Control by antagonistic effectors is sometimes described as “push-pull,” where the increasing activity of one effector is accompanied by decreasing activity of an antagonistic effector. This affords a finer degree of control than could be achieved by simply switching one effector on and off.
Room temperature can be maintained for example, by simply turning an air conditioner on and off, or by just turning a heater on and off. A much more stable temperature, however, can be achieved if the air conditioner and heater are both controlled by a thermostat. Then the heater is turned on when the air conditioner is turned off, and vice versa. Normal body temperature is maintained about a set point of 37° C by the antagonistic effects of sweating, shivering, and other mechanisms.

How body temperature is maintained within the normal range. 

The body temperature normally has a set point of 37° C. This is maintained, in part, by two antagonistic mechanisms—shivering and sweating. Shivering is induced when the body temperature falls too low, and it gradually subsides as the temperature rises. Sweating occurs when the body temperature is too high, and it diminishes as the temperature falls. Most aspects of the internal environment are regulated by the antagonistic actions of different effector mechanisms.

The blood concentrations of glucose, calcium, and other substances are regulated by negative feedback loops involving hormones that promote opposite effects. While insulin, for example, lowers blood glucose, other hormones raise the blood glucose concentration. The heart rate, similarly, is controlled by nerve fibers that produce opposite effects: stimulation of one group of nerve fibers increases heart rate; stimulation of another group slows the heart rate.

Negative Feedback Loops

The concept of homeostasis has been of immense value in the study of physiology because it allows diverse regulatory mechanisms to be understood in terms of their “why” as well as their “how.” The concept of homeostasis also provides a major foundation for medical diagnostic procedures. When a particular measurement of the internal environment, such as a blood measurement, deviates significantly from the normal range of values, it can be concluded that homeostasis is not being maintained and that the person is sick. A number of such measurements, combined with clinical observations, may allow the particular defective mechanism to be identified.
In order for internal constancy to be maintained, the body must have sensors that are able to detect deviations from a set point. The set point is analogous to the temperature set on a house thermostat. In a similar manner, there is a set point for body temperature, blood glucose concentration, the tension on a tendon, and so on. When a sensor detects a deviation from a particular set point, it must relay this information to an integrating center, which usually receives information from many different sensors. The integrating center is often a particular region of the brain or spinal cord, but in some cases it can also be a group of cells in an endocrine gland. The relative strengths of different sensory inputs are weighed in the integrating center, which responds by either increasing or decreasing the activity of particular effectors—generally, muscles or glands.
The thermostat of a house can serve as a simple example. Suppose you set the thermostat at a set point of 70° F. If the temperature of the house rises sufficiently above the set point, a sensor within the thermostat will detect the deviation. This will then act, via the thermostat’s equivalent of an integrating center, to activate the effector. The effector in this case may be an air conditioner, which acts to reverse the deviation from the set point.

If the body temperature exceeds the set point of 37° C, sensors in a part of the brain detect this deviation and, acting via an integrating center (also in the brain), stimulate activities of effectors (including sweat glands) that lower the temperature. If, as another example, the blood glucose concentration falls below normal, the effectors act to increase the blood glucose. One can think of the effectors as “defending” the set points against deviations. Since the activity of the effectors is influenced by the effects they produce, and since this regulation is in a negative, or reverse, direction, this type of control system is known as a negative feedback loop.

A rise in some factor of the internal environment (⇑X) is detected by a sensor. 

This information is relayed to an integrating center, which causes an effector to produce a change in the opposite direction (⇓X). The initial deviation is thus reversed, completing a negative feedback loop (shown by the dashed arrow and negative sign). The numbers indicate the sequence of changes.

The nature of the negative feedback loop can be understood by again referring to the analogy of the thermostat and air conditioner. After the air conditioner has been on for some time, the room temperature may fall significantly below the set point of the thermostat. When this occurs, the air conditioner will be turned off. The effector (air conditioner) is turned on by a high temperature and, when activated, produces a negative change (lowering of the temperature) that ultimately causes the effector to be turned off. In this way, constancy is maintained.
It is important to realize that these negative feedback loops are continuous, ongoing processes. Thus, a particular nerve fiber that is part of an effector mechanism may always display some activity, and a particular hormone, which is part of another effector mechanism, may always be present in the blood. The nerve activity and hormone concentration may decrease in response to deviations of the internal environment in one direction, or they may increase in response to deviations in the opposite direction. Changes from the normal range in either direction are thus compensated for by reverse changes in effector activity.
Since negative feedback loops respond after deviations from the set point have stimulated sensors, the internal environment is never absolutely constant. Homeostasis is best conceived as a state of dynamic constancy, in which conditions are stabilized above and below the set point. These conditions can be measured quantitatively, in degrees Celsius for body temperature, for example, or in milligrams per deciliter (one-tenth of a liter) for blood glucose. The set point can be taken as the average value within the normal range of measurements.

A fall in some factor of the internal environment (⇓X) is detected by a sensor.

Negative feedback loops maintain a state of dynamic constancy within the internal environment. The completion of the negative feedback loop is indicated by negative signs.

History of Physiology

The Greek philosopher Aristotle (384–322 B.C.) speculated on the function of the human body, but another ancient Greek, Erasistratus (304–250? B.C.), is considered the father of physiology because he attempted to apply physical laws to the study of human function. Galen (A.D. 130–201) wrote widely on the subject and was considered the supreme authority until the advent of the Renaissance. Physiology became a fully experimental science with the revolutionary work of the English physician William Harvey (1578–1657), who demonstrated that the heart pumps blood through a closed system of vessels.
However, the father of modern physiology is the French physiologist Claude Bernard (1813–1878), who observed that the milieu interieur (“internal environment”) remains remarkably constant despite changing conditions in the external environment. In a book entitled The Wisdom of the Body, published in 1932, the American physiologist Walter Cannon (1871–1945) coined the term homeostasis to describe this internal constancy. Cannon further suggested that the many mechanisms of physiological regulation have but one purpose—the maintenance of internal constancy.
Most of our present knowledge of human physiology has been gained in the twentieth century. Further, new knowledge is being added at an ever more rapid pace, fueled in more recent decades by the revolutionary growth of molecular genetics and its associated biotechnology, and by the availability of ever more powerful computers and other equipment. A very brief history of twentieth-century physiology, limited by space to only two citations per decade.

Development of Pharmaceutical Drugs

The development of new pharmaceutical drugs can serve as an example of how the scientific method is used in physiology and its health applications. The process usually starts with basic physiological research, often at cellular and molecular levels. Perhaps a new family of drugs is developed using cells in tissue culture (in vitro, or outside the body). For example, cell physiologists, studying membrane transport, may discover that a particular family of compounds blocks membrane channels for calcium ions (Ca2+). Because of their knowledge of physiology, other scientists may predict that a drug of this nature might be useful in the treatment of hypertension (high blood pressure). This drug may then be tried in experimental animals.
If a drug is effective at extremely low concentrations in vitro, (in cells cultured outside of the body), there is a chance that it may work in vivo (in the body) at concentrations low enough not to be toxic (poisonous). This possibility must be thoroughly tested utilizing experimental animals, primarily rats and mice. More than 90% of drugs tested in experimental animals are too toxic for further development.
Only in those rare cases when the toxicity is low enough may development progress to human/clinical trials.
Biomedical research is often aided by animal models of particular diseases. These are strains of laboratory rats and mice that are genetically susceptible to particular diseases that resemble human diseases. Research utilizing laboratory animals typically takes several years and always precedes human (clinical) trials of promising drugs. It should be noted that this length of time does not include all of the years of “basic” physiological research (involving laboratory animals) that provided the scientific foundation for the specific medical application.
In phase I clinical trials, the drug is tested on healthy human volunteers. This is done to test its toxicity in humans and to study how the drug is “handled” by the body: how it is metabolized, how rapidly it is removed from the blood by the liver and kidneys, how it can be most effectively administered, and so on. If no toxic effects are observed, the drug can proceed to the next stage. In phase II clinical trials, the drug is tested on the target human population (for example, those with hypertension). Only in those exceptional cases where the drug seems to be effective but has minimal toxicity does testing move to the next phase. Phase III trials occur in many research centers across the country to maximize the number of test participants. At this point, the test population must include a sufficient number of subjects of both sexes, as well as people of different ethnic groups. In addition,
people are tested who have other health problems besides the one that the drug is intended to benefit. For example, those who have diabetes in addition to hypertension would be included in this phase. If the drug passes phase III trials, it goes to the Food and Drug Administration (FDA) for approval. Phase IV trials test other potential uses of the drug.
The percentage of drugs that make it all the way through these trials to eventually become approved and marketed is very low. Notice the crucial role of basic research, using experimental animals, in this process. Virtually every prescription drug on the market owes its existence to such research.

Use of Measurements, Controls, and Statistics

Suppose you wanted to test the hypothesis that a regular exercise program causes people to have a lower resting heart rate. First, you would have to decide on the nature of the exercise program. Then, you would have to decide how the heart rate (or pulse rate) would be measured. This is a typical problem in physiology research, because the testing of most physiological hypotheses requires quantitative measurements.
The group that is subject to the testing condition—in this case, exercise—is called the experimental group. A measurement of the heart rate for this group would only be meaningful if it is compared to that of another group, known as the control group. How shall this control group be chosen? Perhaps the subjects could serve as their own controls—that is, a person’s resting heart rate could be measured before and after the exercise regimen. If this isn’t possible, a control group could be other people who do not follow the exercise program. The choice of control groups is often a controversial aspect of physiology studies. In this example, did the people in the control group really refrain from any exercise? Were they comparable to the people in the experimental group with regard to age, sex, ethnicity, body weight, health status, and so on? You can see how difficult it could be in practice to get a control group that could satisfy any potential criticism.
Another potential criticism could be bias in the way that the scientists perform the measurements. This bias could be completely unintentional; scientists are human, after all, and they may have invested months or years in this project! Thus, the person doing the measurements often does not know if a subject is part of the experimental or the control group. This is known as a blind measurement.
Now suppose the data are in, and it looks like the experimental group indeed has a lower average resting heart rate than the control group. But there is overlap—some people in the control group have measurements that are lower than some people in the experimental group. Now, is the difference in the average measurements of the groups due to a real, physiological difference, or is it due to chance variations in the measurements? Scientists attempt to test the null hypothesis (the hypothesis that the difference is due to chance) by employing the mathematical tools of statistics. If the statistical results so warrant, the null hypothesis can be rejected and the experimental hypothesis can be deemed to be supported by this study.
The statistical test chosen will depend upon the design of the experiment, and it can also be a source of contention among scientists in evaluating the validity of the results. Because of the nature of the scientific method, “proof” in science is always provisional. Some other researchers, employing the scientific method in a different way (with different measuring techniques, experimental procedures, choice of control groups, statistical tests, and so on) may later obtain different results. The scientific method is thus an ongoing enterprise.
The results of the scientific enterprise are written up as research articles, and these must be reviewed by other scientists who work in the same field before they can be published in peer-reviewed journals. More often than not, the reviewers will suggest that certain changes be made in the articles before they can be accepted for publication.

Scientific Method

All of the information in this text has been gained by application of the scientific method. Although many different techniques are involved in the scientific method, all share three attributes:
(1) confidence that the natural world, including ourselves, is ultimately explainable in terms we can understand;
(2) descriptions and explanations of the natural world that are honestly based on observations and that could be modified or refuted by other observations;
(3) humility, or the willingness to accept the fact that we could be wrong. If further study should yield conclusions that refuted all or part of an idea, the idea would have to be modified accordingly. In short, the scientific method is based on a confidence in our rational ability, honesty, and humility. Practicing scientists may not always display these attributes, but the validity of the large body of scientific knowledge that has been accumulated—as shown by the technological applications and the predictive value of scientific hypotheses—are ample testimony to the fact that the scientific method works.
The scientific method involves specific steps. After making certain observations regarding the natural world, a hypothesis is formulated. In order for this hypothesis to be scientific, it must be capable of being refuted by experiments or other observations of the natural world. For example, one might hypothesize that people who exercise regularly have a lower resting pulse rate than other people. Experiments are conducted, or other observations are made, and the results are analyzed. Conclusions are then drawn as to whether the new data either refute or support the hypothesis. If the hypothesis survives such testing, it might be incorporated into a more general theory. Scientific theories are statements about the natural world that incorporate a number of proven hypotheses. They serve as a logical framework by which these hypotheses can be interrelated and provide the basis for predictions that may as yet be untested.
The hypothesis in the preceding example is scientific because it is testable; the pulse rates of 100 athletes and 100 sedentary people could be measured, for example, to see if there were statistically significant differences. If there were, the statement that athletes, on the average, have lower resting pulse rates than other people would be justified based on these data. One must still be open to the fact that this conclusion could be wrong. Before the discovery could become generally accepted as fact, other scientists would have to consistently replicate the results. Scientific theories are based on reproducible data.
It is quite possible that when others attempt to replicate the experiment their results will be slightly different. They may then construct scientific hypotheses that the differences in resting pulse rate also depend on other factors—for example, the nature of the exercise performed. When scientists attempt to test these hypotheses, they will likely encounter new problems, requiring new explanatory hypotheses, which then must be tested by additional experiments.
In this way, a large body of highly specialized information is gradually accumulated, and a more generalized explanation (a scientific theory) can be formulated. This explanation will almost always be different from preconceived notions. People who follow the scientific method will then appropriately modify their concepts, realizing that their new ideas will probably have to be changed again in the future as additional experiments are performed.

Introduction to Physiology

Physiology (from the Greek physis = nature; logos = study) is the study of biological function—of how the body works, from cell to tissue, tissue to organ, organ to system, and of how the organism as a whole accomplishes particular tasks essential for life. In the study of physiology, the emphasis is on  mechanisms—with questions that begin with the word how and answers that involve cause-and-effect sequences. These sequences can be woven into larger and larger stories that include descriptions of the structures involved (anatomy) and that overlap with the sciences of chemistry and physics.
The separate facts and relationships of these cause-andeffect sequences are derived empirically from experimental evidence. Explanations that seem logical are not necessarily true; they are only as valid as the data on which they are based, and they can change as new techniques are developed and further experiments are performed. The ultimate objective of physiological research is to understand the normal functioning of cells, organs, and systems. A related science—pathophysiology—is concerned with how physiological processes are altered in disease or injury.
Pathophysiology and the study of normal physiology complement one another. For example, a standard technique for investigating the functioning of an organ is to observe what happens when it is surgically removed from an experimental animal or when its function is altered in a specific way. This study is often aided by “experiments of nature”—diseases—that involve specific damage to the functioning of an organ. The study of disease processes has thus aided our understanding of normal functioning, and the study of normal physiology has provided much of the scientific basis of modern medicine. This relationship is recognized by the Nobel Prize committee, whose members award prizes in the category “Physiology or Medicine.”
The physiology of invertebrates and of different vertebrate groups is studied in the science of comparative physiology. Much of the knowledge gained from comparative physiology has benefited the study of human physiology. This is because animals, including humans, are more alike than they are different. This is especially true when comparing humans with other mammals. The small differences in physiology between humans and other mammals can be of crucial importance in the development of pharmaceutical drugs (discussed later in this section), but these differences are relatively slight in the overall study of physiology.