By far the most important type of movement that occurs in the body is that of the muscle cells in skeletal,  cardiac, and smooth muscle, which constitute almost 50 per cent of the entire body mass. The specialized functions of these cells are discussed in Chapters 6 through 9. Two other types of movement ameboid locomotion and ciliary movement occur in other cells.

Ameboid movement is movement of an entire cell in relation to its surroundings, such as movement of white blood cells through tissues. It receives its name from the fact that amebae move in this manner and have provided an excellent tool for studying the phenomenon. Typically, ameboid locomotion begins with protrusion of a pseudopodium from one end of the cell. The pseudopodium projects far out, away from the cell body, and partially secures itself in a new tissue area. Then the remainder of the cell is pulled toward the pseudopodium. Figure 2–16 demonstrates this process, showing an elongated cell, the right-hand end of which is a protruding pseudopodium. The membrane of this end of the cell is continually moving forward, and the membrane at the left-hand end of the cell is continually following along as the cell moves.

Mechanism of Ameboid Locomotion. Figure 2–16 shows the general principle of ameboid motion. Basically, it results from continual formation of new cell membrane at the leading edge of the pseudopodium and continual absorption of the membrane in mid and rear portions of the cell. Also, two other effects are essential for forward movement of the cell. The first effect is attachment of the pseudopodium to surrounding tissues so that it becomes fixed in its leading position, while the

remainder of the cell body is pulled forward toward the point of attachment. This attachment is effected by receptor proteins that line the insides of exocytotic vesicles. When the vesicles become part of the pseudopodial membrane, they open so that their insides evert to the outside, and the receptors now protrude to the outside and attach to ligands in the surrounding tissues. At the opposite end of the cell, the receptors pull away from their ligands and form new endocytotic vesicles. Then, inside the cell, these vesicles stream toward the pseudopodial end of the cell, where they are used to form still new membrane for the pseudopodium. The second essential effect for locomotion is to provide the energy required to pull the cell body in the direction of the pseudopodium. Experiments suggest the following as an explanation: In the cytoplasm of all cells is a moderate to large amount of the protein actin. Much of the actin is in the form of single molecules that do not provide any motive power; however, these polymerize to form a filamentous network, and the network contracts when it binds with an actin-binding protein such as myosin. The whole process is energized by the high-energy compound ATP. This is what happens in the pseudopodium of a moving cell, where such a network of actin filaments forms anew inside the enlarging pseudopodium. Contraction also occurs in the ectoplasm of the cell body, where a preexisting actin network is already present beneath the cell membrane.

Types of Cells That Exhibit Ameboid Locomotion. The most common cells to exhibit ameboid locomotion in the human body are the white blood cells when they move out of the blood into the tissues in the form of tissue macrophages. Other types of cells can also move by ameboid locomotion under certain circumstances. For instance, fibroblasts move into a damaged area to help repair the damage, and even the germinal cells of the skin, though ordinarily completely sessile cells, move toward a cut area to repair the rent. Finally, cell locomotion is especially important in development of the embryo and fetus after fertilization of an ovum. For instance, embryonic cells often must migrate long distances from their sites of origin to new areas during development of special structures.

Control of Ameboid Locomotion—Chemotaxis. The most important initiator of ameboid locomotion is the

process called chemotaxis. This results from the appearance of certain chemical substances in the tissues. Any chemical substance that causes chemotaxis to occur is called a chemotactic substance. Most cells that exhibit ameboid locomotion move toward the source of a chemotactic substance that is, from an area of lower concentration toward an area of higher concentration which is called positive chemotaxis. Some cells move away from the source, which is called negative chemotaxis. But how does chemotaxis control the direction of ameboid locomotion? Although the answer is not certain, it is known that the side of the cell most exposed to the chemotactic substance develops membrane changes that cause pseudopodial protrusion.

A second type of cellular motion, ciliary movement, is a whiplike movement of cilia on the surfaces of cells.This

occurs in only two places in the human body: on the sufaces of the respiratory airways and on the inside surfaces of the uterine tubes (fallopian tubes) of the reproductive tract. In the nasal cavity and lower respiratory airways, the whiplike motion of cilia causes a layer of mucus to move at a rate of about 1 cm/min toward the pharynx, in this way continually clearing these passageways of mucus and particles that have become trapped in the mucus. In the uterine tubes, the cilia cause slow movement of fluid from the ostium of the uterine tube toward the uterus cavity; this movement of fluid transports the ovum from the ovary to the uterus. As shown in Figure 2–17, a cilium has the appearance of a sharp-pointed straight or curved hair that projects 2 to 4 micrometers from the surface of the cell. Many cilia often project from a single cell—for instance, as many as 200 cilia on the surface of each epithelial cell inside the respiratory passageways. The cilium is covered by an outcropping of the cell membrane, and it is supported by 11 microtubules—9 double tubules located around the periphery of the cilium, and 2 single tubules down the center, as demonstrated in the cross section shown in Figure 2–17. Each cilium is an outgrowth of a structure that lies immediately beneath the cell membrane, called the basal body of the cilium.

The flagellum of a sperm is similar to a cilium; in fact, it has much the same type of structure and same type of contractile mechanism. The flagellum, however, is much longer and moves in quasi-sinusoidal waves instead of whiplike movements. In the inset of Figure 2–17, movement of the cilium is shown. The cilium moves forward with a sudden, rapid whiplike stroke 10 to 20 times per second, bending sharply where it projects from the surface of the cell. Then it moves backward slowly to its initial position. The rapid forward-thrusting, whiplike movement pushes the fluid lying adjacent to the cell in the direction that the cilium moves; the slow, dragging movement in the backward direction has almost no effect on fluid movement.As a result, the fluid is continually propelled in the direction of the fast-forward stroke. Because most ciliated cells have large numbers of cilia on their surfaces and because all the cilia are oriented in the same direction, this is an effective means for moving fluids from one part of the surface to another.

Mechanism of Ciliary Movement. Although not all aspects of ciliary movement are clear, we do know the following: First, the nine double tubules and the two single tubules are all linked to one another by a complex of protein cross-linkages; this total complex of tubules and crosslinkages is called the axoneme. Second, even after removal of the membrane and destruction of other elements of the cilium besides the axoneme, the cilium can still beat under appropriate conditions. Third, there are two necessary conditions for continued beating of the axoneme after removal of the other structures of the cilium: (1) the availability of ATP and (2) appropriate

ionic conditions, especially appropriate concentrations of magnesium and calcium. Fourth, during forward motion of the cilium, the double tubules on the front edge of the cilium slide outward toward the tip of the cilium, while those on the back edge remain in place. Fifth, multiple protein arms composed of the protein dynein, which has ATPase enzymatic activity, project from each double tubule toward an adjacent double tubule. Given this basic information, it has been determined that the release of energy from ATP in contact with the ATPase dynein arms causes the heads of these arms to “crawl” rapidly along the surface of the adjacent double tubule. If the front tubules crawl outward while the back tubules remain stationary, this will cause bending. The way in which cilia contraction is controlled is not understood.The cilia of some genetically abnormal cells do not have the two central single tubules, and these cilia fail to beat. Therefore, it is presumed that some signal, perhaps an electrochemical signal, is transmitted along these two central tubules to activate the dynein arms.

In the remainder of this chapter, we discuss several representative functional systems of the cell that make it a living organism.

If a cell is to live and grow and reproduce, it must obtain nutrients and other substances from the surrounding fluids. Most substances pass through the cell membrane by diffusion and active transport. Diffusion involves simple movement through the membrane caused by the random motion of the molecules of the substance; substances move either through cell membrane pores or, in the case of lipidsoluble substances, through the lipid matrix of the membrane. Active transport involves the actual carrying of a substance through the membrane by a physical protein structure that penetrates all the way through the membrane. These active transport mechanisms are so important to cell function that they are presented in detail in Chapter 4. Very large particles enter the cell by a specialized function of the cell membrane called endocytosis. The principal forms of endocytosis are pinocytosis and phagocytosis. Pinocytosis means ingestion of minute particles that form vesicles of extracellular fluid and particulate constituents inside the cell cytoplasm. Phagocytosis means ingestion of large particles, such as bacteria, whole cells, or portions of degenerating tissue.

Pinocytosis. Pinocytosis occurs continually in the cell membranes of most cells, but it is especially rapid in some cells. For instance, it occurs so rapidly in macrophages that about 3 per cent of the total macrophage membrane is engulfed in the form of vesicles each minute. Even so, the pinocytotic vesicles are so smal usually only 100 to 200 nanometers in diameter that most of them can be seen only with the electron microscope. Pinocytosis is the only means by which most large macromolecules, such as most protein molecules, can enter cells. In fact, the rate at which pinocytotic vesicles form is usually enhanced when such macromolecules attach to the cell membrane. Figure 2–11 demonstrates the successive steps of pinocytosis, showing three molecules of protein attaching to the membrane. These molecules usually attach to specialized protein receptors on the surface of the membrane that are specific for the type of protein that is to be absorbed.The receptors generally are concentrated in small pits on the outer surface of the cell membrane, called coated pits. On the inside of the cell membrane beneath these pits is a latticework of fibrillar protein called clathrin, as well as other proteins, perhaps including contractile filaments of actin and myosin. Once the protein molecules have bound with the receptors, the surface properties of the local

membrane change in such a way that the entire pit invaginates inward, and the fibrillar proteins surrounding the invaginating pit cause its borders to close over the attached proteins as well as over a small amount of extracellular fluid. Immediately thereafter, the invaginated portion of the membrane breaks away from the surface of the cell, forming a pinocytotic vesicle inside the cytoplasm of the cell. What causes the cell membrane to go through the necessary contortions to form pinocytotic vesicles remains mainly a mystery.This process requires energy from within the cell; this is supplied by ATP, a highenergy substance discussed later in the chapter. Also, it requires the presence of calcium ions in the extracellular fluid, which probably react with contractile protein filaments beneath the coated pits to provide the force for pinching the vesicles away from the cell membrane.

Phagocytosis. Phagocytosis occurs in much the same way as pinocytosis, except that it involves large particles rather than molecules. Only certain cells have the capability of phagocytosis, most notably the tissue macrophages and some of the white blood cells. Phagocytosis is initiated when a particle such as a bacterium, a dead cell, or tissue debris binds with receptors on the surface of the phagocyte. In the case of bacteria, each bacterium usually is already attached to a specific antibody, and it is the antibody that attaches to the phagocyte receptors, dragging the bacterium along with it.This intermediation of antibodies is called opsonization, which is discussed in Chapters 33 and 34. Phagocytosis occurs in the following steps: 

1. The cell membrane receptors attach to the surface ligands of the particle. 

2. The edges of the membrane around the points of attachment evaginate outward within a fraction of a second to surround the entire particle; then, progressively more and more membrane receptor sattach to the particle ligands. All this occurs suddenly in a zipper-like manner to form a closed phagocytic vesicle. 

3. Actin and other contractile fibrils in the cytoplasm surround the phagocytic vesicle and contract around its outer edge, pushing the vesicle to the interior. 

4. The contractile proteins then pinch the stem of the vesicle so completely that the vesicle separates from the cell membrane, leaving the vesicle in the cell interior in the same way that pinocytotic vesicles are formed.

Almost immediately after a pinocytotic or phagocytic vesicle appears inside a cell, one or more lysosomes become attached to the vesicle and empty their acid hydrolases to the inside of the vesicle, as shown in Figure 2–12. Thus, a digestive vesicle is formed inside the cell cytoplasm in which the vesicular hydrolases begin hydrolyzing the proteins, carbohydrates, lipids, and other substances in the vesicle. The products of digestion are small molecules of amino acids, glucose, phosphates, and so forth that can diffuse through the membrane of the vesicle into the cytoplasm. What is left of the digestive vesicle, called the residual body, represents indigestible substances. In most instances, this is finally excreted through the cell membrane by a process called exocytosis, which is essentially the opposite of endocytosis. Thus, the pinocytotic and phagocytic vesicles containing lysosomes can be called the digestive organs of the cells.

Regression of Tissues and Autolysis of Cells. Tissues of the body often regress to a smaller size. For instance, this

occurs in the uterus after pregnancy, in muscles during long periods of inactivity, and in mammary glands at the end of lactation. Lysosomes are responsible for much of this regression.The mechanism by which lack of activity in a tissue causes the lysosomes to increase their activity is unknown. Another special role of the lysosomes is removal of damaged cells or damaged portions of cells from tissues. Damage to the cell caused by heat, cold, trauma, chemicals, or any other factor induces lysosomes to rupture. The released hydrolases immediately begin to digest the surrounding organic substances. If the damage is slight, only a portion of the cell is removed, followed by repair of the cell. If the damage is severe, the entire cell is digested, a process called autolysis. In this way, the cell is completely removed, and a new cell of the same type ordinarily is formed by mitotic reproduction of an adjacent cell to take the place of the old one. The lysosomes also contain bactericidal agents that can kill phagocytized bacteria before they can cause cellular damage. These agents include (1) lysozyme, which dissolves the bacterial cell membrane; (2) lysoferrin, which binds iron and other substances before they can promote bacterial growth; and (3) acid at a pH of about 5.0, which activates the hydrolases and inactivates bacterial metabolic systems.

Many of us think of the cell as the lowest level of life.However, the cell is a very complicated organism that required many hundreds of millions of years to develop after the earliest form of life, an organism similar to the present-day virus, first appeared on earth. Figure 2–10 shows the relative sizes of (1) the smallest known virus, (2) a large virus, (3) a rickettsia,

(4) a bacterium, and (5) a nucleated cell, demonstrating that the cell has a diameter about 1000 times that of the smallest virus and, therefore, a volume about 1billion times that of the smallest virus. Correspondingly, the functions and anatomical organization of the cell are also far more complex than those of the virus. The essential life-giving constituent of the small virus is a nucleic acid embedded in a coat of protein. This nucleic acid is composed of the same basic nucleic acid constituents (DNA or RNA) found in mammalian cells, and it is capable of reproducing itself under appropriate conditions. Thus, the virus propagates its lineage from generation to generation and is therefore a living structure in the same way that the cell and the human being are living structures. As life evolved, other chemicals besides nucleic acid and simple proteins became integral parts of the organism, and specialized functions began to develop in different parts of the virus. A membrane formed around the virus, and inside the membrane, a fluid matrix appeared. Specialized chemicals then developed inside the fluid to perform special functions; many protein enzymes appeared that were capable of catalyzing chemical reactions and, therefore, determining the organism’s activities. In still later stages of life, particularly in the rickettsial and bacterial stages, organelles developed inside the organism, representing physical structures of chemical aggregates that perform functions in a more efficient manner than can be achieved by dispersed chemicals throughout the fluid matrix. Finally, in the nucleated cell, still more complex organelles developed, the most important of which is the nucleus itself. The nucleus distinguishes this type of cell from all lower forms of life; the nucleus provides a control center for all cellular activities, and it provides for exact reproduction of new cells generation after generation, each new cell having almost exactly the same structure as its progenitor.

The cell is not merely a bag of fluid, enzymes, and chemicals; it also contains highly organized physical structures, called intracellular organelles. The physical nature of each organelle is as important as the cell’s chemical constituents for cell function. For instance, without one of the organelles, the mitochondria, more than 95 per cent of the cell’s energy release from nutrients would cease immediately. The most important organelles and other structures of the cell are shown in Figure 2–2.

Most organelles of the cell are covered by membranes composed primarily of lipids and proteins.These membranes include the cell membrane, nuclear membrane, membrane of the endoplasmic reticulum, and membranes of the mitochondria, lysosomes, and Golgi apparatus. The lipids of the membranes provide a barrier that impedes the movement of water and water-soluble substances from one cell compartment to another because water is not soluble in lipids. However, protein molecules in the membrane often do penetrate all the way through the membrane, thus providing specialized pathways, often organized into actual pores, for passage of specific substances through the membrane. Also, many other membrane proteins are enzymes that catalyze a multitude of different chemical reactions, discussed here and in subsequent chapters.

The cell membrane (also called the plasma membrane), which envelops the cell, is a thin, pliable, elastic structure only 7.5 to 10 nanometers thick. It is composed almost entirely of proteins and lipids. The approximate composition is proteins, 55 per cent; phospholipids, 25 per cent; cholesterol, 13 per cent; other lipids, 4 per cent; and carbohydrates, 3 per cent.

Figure 2–3 shows the structure of the cell membrane. Its basic structure is a lipid bilayer, which is a thin, double-layered film of lipids each layer only one molecule thick—that is continuous over the entire cell surface. Interspersed in this lipid film are large globular protein molecules. The basic lipid bilayer is composed of phospholipid molecules. One end of each phospholipid molecule is soluble in water; that is, it is hydrophilic. The other end is soluble only in fats; that is, it is hydrophobic. The

phosphate end of the phospholipid is hydrophilic, and the fatty acid portion is hydrophobic. Because the hydrophobic portions of the phospholipid molecules are repelled by water but are mutually attracted to one another, they have a natural tendency to attach to one another in the middle of the membrane, as shown in Figure 2–3. The hydrophilic phosphate portions then constitute the two surfaces of the complete cell membrane, in contact with intracellular water on the inside of the membrane and extracellular water on the outside surface. The lipid layer in the middle of the membrane is impermeable to the usual water-soluble substances, such as ions, glucose, and urea. Conversely, fat-soluble substances, such as oxygen, carbon dioxide, and alcohol, can penetrate this portion of the membrane with ease. The cholesterol molecules in the membrane are also lipid in nature because their steroid nucleus is highly fat soluble. These molecules, in a sense, are dissolved in the bilayer of the membrane. They mainly help determine the degree of permeability (or impermeability) of the bilayer to water-soluble constituents of body fluids. Cholesterol controls much of the fluidity of the membrane as well.

Cell Membrane Proteins. Figure 2–3 also shows globular masses floating in the lipid bilayer. These are membrane proteins, most of which are glycoproteins. Two types of proteins occur: integral proteins that protrude all the way through the membrane, and peripheral proteins that are attached only to one surface of the membrane and do not penetrate all the way through. Many of the integral proteins provide structural channels (or pores) through which water molecules and water-soluble substances, especially ions, can diffuse between the extracellular and intracellular fluids.These protein channels also have selective properties that allow preferential diffusion of some substances over others. Other integral proteins act as carrier proteins for transporting substances that otherwise could not penetrate the lipid bilayer. Sometimes these even transport substances in the direction opposite to their natural direction of diffusion, which is called “active transport.” Still others act as enzymes.

Integral membrane proteins can also serve as receptors for water-soluble chemicals, such as peptide hormones, that do not easily penetrate the cell membrane. Interaction of cell membrane receptors with specific ligands that bind to the receptor causes conformational changes in the receptor protein. This, in turn,

enzymatically activates the intracellular part of the protein or induces interactions between the receptor and proteins in the cytoplasm that act as second messengers, thereby relaying the signal from the extracellular part of the receptor to the interior of the cell. In this way, integral proteins spanning the cell membrane provide a means of conveying information about the environment to the cell interior. Peripheral protein molecules are often attached to the integral proteins. These peripheral proteins function almost entirely as enzymes or as controllers of transport of substances through the cell membrane “pores.”

Membrane Carbohydrates The Cell “Glycocalyx.” Membrane carbohydrates occur almost invariably in combination with proteins or lipids in the form of glycoproteins or glycolipids. In fact, most of the integral proteins are glycoproteins, and about one tenth of the membrane lipid molecules are glycolipids.The “glyco” portions of these molecules almost invariably protrude to the outside of the cell, dangling outward from the cell surface. Many other carbohydrate compounds, called proteoglycans which are mainly carbohydrate substances bound to small protein cores are loosely attached to the outer surface of the cell as well. Thus, the entire outside surface of the cell often has a loose carbohydrate coat called the glycocalyx. The carbohydrate moieties attached to the outer surface of the cell have several important functions: (1) Many of them have a negative electrical charge, which gives most cells an overall negative surface charge that repels other negative objects. (2) The glycocalyx of some cells attaches to the glycocalyx of other cells, thus attaching cells to one another. (3) Many of the carbohydrates act as receptor substances for binding hormones, such as insulin; when bound, this combination activates attached internal proteins that, in turn, activate a cascade of intracellular enzymes. (4) Some carbohydrate moieties enter into immune reactions.

The cytoplasm is filled with both minute and large dispersed particles and organelles.The clear fluid portion of the cytoplasm in which the particles are dispersed is called cytosol; this contains mainly dissolved proteins, electrolytes, and glucose. Dispersed in the cytoplasm are neutral fat globules, glycogen granules, ribosomes, secretory vesicles, and five especially important organelles: the endoplasmic reticulum, the Golgi apparatus, mitochondria, lysosomes, and peroxisomes.

Figure 2–2 shows a network of tubular and flat vesicular structures in the cytoplasm; this is the endoplasmic reticulum. The tubules and vesicles interconnect with one another. Also, their walls are constructed of lipid bilayer membranes that contain large amounts of proteins, similar to the cell membrane. The total surface area of this structure in some cells the liver cells, for instance can be as much as 30 to 40 times the cell membrane area. The detailed structure of a small portion of endoplasmic reticulum is shown in Figure 2–4. The space inside the tubules and vesicles is filled with endoplasmic matrix, a watery medium that is different from the fluid in the cytosol outside the endoplasmic reticulum. Electron micrographs show that the space inside the endoplasmic reticulum is connected with the space between the two membrane surfaces of the nuclear membrane. Substances formed in some parts of the cell enter the space of the endoplasmic reticulum and are then conducted to other parts of the cell. Also, the vast surface area of this reticulum and the multiple enzyme

systems attached to its membranes provide machinery for a major share of the metabolic functions of the cell.

Attached to the outer surfaces of many parts of the endoplasmic reticulum are large numbers of minute granular particles called ribosomes. Where these are present, the reticulum is called the granular endoplasmic reticulum. The ribosomes are composed of a mixture of RNA and proteins, and they function to synthesize new protein molecules in the cell.

Agranular Endoplasmic Reticulum. Part of the endoplasmic reticulum has no attached ribosomes. This part is called the agranular, or smooth, endoplasmic reticulum. The agranular reticulum functions for the synthesis of lipid substances and for other processes of the cells promoted by intrareticular enzymes.

The Golgi apparatus, shown in Figure 2–5, is closely related to the endoplasmic reticulum. It has membranes similar to those of the agranular endoplasmic reticulum. It usually is composed of four or more stacked layers of thin, flat, enclosed vesicles lying near one side of the nucleus. This apparatus is prominent in secretory cells, where it is located on the side of the cell from which the secretory substances are extruded. The Golgi apparatus functions in association with the endoplasmic reticulum. As shown in Figure 2–5, small “transport vesicles” (also called endoplasmic reticulum vesicles, or ER vesicles) continually pinch off from the endoplasmic reticulum and shortly thereafter fuse with the Golgi apparatus. In this way, substances entrapped in the ER vesicles are transported from the endoplasmic reticulum to the Golgi apparatus. The transported substances are then processed in the Golgi apparatus to form lysosomes, secretory vesicles, and other cytoplasmic components.

Lysosomes, shown in Figure 2–2, are vesicular organelles that form by breaking off from the Golgi apparatus and then dispersing throughout the cytoplasm. The lysosomes provide an intracellular digestive system that allows the cell to digest (1) damaged cellular structures, (2) food particles that have been ingested by the cell, and (3) unwanted matter such as bacteria. The lysosome is quite different in different types of cells, but it is usually 250 to 750 nanometers in diameter. It is surrounded by a typical lipid bilayer membrane and is filled with large numbers of small granules 5 to 8 nanometers in diameter, which are protein aggregates of as many as 40 different hydrolase (digestive) enzymes. A hydrolytic enzyme is capable of splitting an organic compound into two or more parts by combining hydrogen from a water molecule with one part of the compound and combining the hydroxyl portion of the water molecule with the other part of the compound. For instance, protein is hydrolyzed to form amino acids, glycogen is hydrolyzed to form glucose, and lipids are hydrolyzed to form fatty acids and glycerol. Ordinarily, the membrane surrounding the lysosome prevents the enclosed hydrolytic enzymes from coming in contact with other substances in the cell and, therefore, prevents their digestive actions. However, some conditions of the cell break the membranes of some of the lysosomes, allowing release of the digestive enzymes. These enzymes then split the organic substances with which they come in contact into small, highly diffusible substances such as amino acids and glucose. Some of the more specific functions of lysosomes.

Peroxisomes are similar physically to lysosomes, but they are different in two important ways. First, they are believed to be formed by self-replication (or perhaps by budding off from the smooth endoplasmic reticulum) rather than from the Golgi apparatus. Second, they contain oxidases rather than hydrolases. Several of the oxidases are capable of combining oxygen with hydrogen ions derived from different intracellular chemicals to form hydrogen peroxide (H2O2). Hydrogen peroxide is a highly oxidizing substance and is used in association with catalase, another oxidase enzyme present in large quantities in peroxisomes, to oxidize many substances that might otherwise be poisonous to the cell. For instance, about half the alcohol a person drinks is detoxified by the peroxisomes of the liver cells in this manner.

One of the important functions of many cells is secretion of special chemical substances. Almost all such secretory substances are formed by the endoplasmic reticulum–Golgi apparatus system and are then released from the Golgi apparatus into the cytoplasm in the form of storage vesicles called secretory vesicles or secretory granules. Figure 2–6 shows typical secretory vesicles inside pancreatic acinar cells; these 

vesicles store protein proenzymes (enzymes that are not yet activated). The proenzymes are secreted later through the outer cell membrane into the pancreatic duct and thence into the duodenum, where they become activated and perform digestive functions on the food in the intestinal tract.

The mitochondria, shown in Figures 2–2 and 2–7, are called the “powerhouses” of the cell. Without them, cells would be unable to extract enough energy from the nutrients, and essentially all cellular functions would cease. Mitochondria are present in all areas of each cell’s cytoplasm, but the total number per cell varies from

less than a hundred up to several thousand, depending on the amount of energy required by the cell. Further, the mitochondria are concentrated in those portions of the cell that are responsible for the major share of its energy metabolism. They are also variable in size and shape. Some are only a few hundred nanometers in diameter and globular in shape, whereas others are elongated as large as 1 micrometer in diameter and 7 micrometers long; still others are branching and filamentous. The basic structure of the mitochondrion, shown

in Figure 2–7, is composed mainly of two lipid bilayer–protein membranes: an outer membrane and an inner membrane. Many infoldings of the inner membrane form shelves onto which oxidative enzymes are attached. In addition, the inner cavity of the mitochondrion is filled with a matrix that contains large quantities of dissolved enzymes that are necessary for extracting energy from nutrients. These enzymes operate in association with the oxidative enzymes on the shelves to cause oxidation of the nutrients, thereby forming carbon dioxide and water and at the same time releasing energy. The liberated energy is used to synthesize a “high-energy” substance called adenosine triphosphate (ATP).ATP is then transported out of the mitochondrion, and it diffuses throughout the cell to release its own energy wherever it is needed for performing cellular functions.The chemical details of ATP formation by the mitochondrion are given in Chapter

67, but some of the basic functions of ATP in the cell are introduced later in this chapter. Mitochondria are self-replicative, which means that one mitochondrion can form a second one, a third one, and so on, whenever there is a need in the cell for increased amounts of ATP. Indeed, the mitochondria contain DNA similar to that found in the cell nucleus. In Chapter 3 we will see that DNA is the basic chemical of the nucleus that controls replication of the cell. The DNA of the mitochondrion plays a similar role, controlling replication of the mitochondrion itself.

The fibrillar proteins of the cell are usually organized into filaments or tubules. These originate as precursor protein molecules synthesized by ribosomes in the cytoplasm. The precursor molecules then polymerize to form filaments. As an example, large numbers of actin filaments frequently occur in the outer zone of the cytoplasm, called the ectoplasm, to form an elastic support for the cell membrane. Also, in muscle cells, actin and myosin filaments are organized into a special contractile machine that is the basis for muscle contraction, as discussed in detail in Chapter 6. A special type of stiff filament composed of polymerized tubulin molecules is used in all cells to construct very strong tubular structures, the microtubules. Figure 2–8 shows typical microtubules that were teased from the flagellum of a sperm. Another example of microtubules is the tubular skeletal structure in the center of each cilium that radiates upward from the cell cytoplasm to the tip of the cilium. This structure is discussed later in the chapter and is illustrated in Figure 2–17. Also, both the centrioles and the mitotic spindle of the mitosing cell are composed of stiff microtubules. Thus, a primary function of microtubules is to act as a cytoskeleton, providing rigid physical structures for certain parts of cells.

The nucleus is the control center of the cell. Briefly, the nucleus contains large quantities of DNA, which are the genes. The genes determine the characteristics of the cell’s proteins, including the structural proteins, as well as the intracellular enzymes that control cytoplasmic and nuclear activities. The genes also control and promote reproduction of the cell itself. The genes first reproduce to give two identical sets of genes; then the cell splits by a special process called mitosis to form two daughter cells, each of which receives one of the two sets of DNA genes. All these activities of the nucleus are considered in detail in the next chapter. Unfortunately, the appearance of the nucleus under the microscope does not provide many clues to the mechanisms by which the nucleus performs its control activities. Figure 2–9 shows the light microscopic appearance of the interphase nucleus (during the period between mitoses), revealing darkly staining chromatin material throughout the nucleoplasm. During mitosis, the chromatin material organizes in the form of highly structured chromosomes, which can then be easily identified using the light microscope, as illustrated in the next chapter.

The nuclear membrane, also called the nuclear envelope, is actually two separate bilayer membranes, one inside the other. The outer membrane is continuous with the endoplasmic reticulum of the cell cytoplasm, and the space between the two nuclear membranes is also continuous with the space inside the endoplasmic reticulum, as shown in Figure 2–9.

The nuclear membrane is penetrated by several thousand nuclear pores. Large complexes of protein molecules are attached at the edges of the pores so that the central area of each pore is only about 9 nanometers in diameter. Even this size is large enough to allow molecules up to 44,000 molecular weight to pass through with reasonable ease.

The nuclei of most cells contain one or more highly staining structures called nucleoli. The nucleolus, unlike most other organelles discussed here, does not have a limiting membrane. Instead, it is simply an accumulation of large amounts of RNA and proteins of the types found in ribosomes.The nucleolus becomes considerably enlarged when the cell is actively synthesizing proteins. Formation of the nucleoli (and of the ribosomes in the cytoplasm outside the nucleus) begins in the nucleus. First, specific DNA genes in the chromosomes cause RNA to be synthesized. Some of this is stored in the nucleoli, but most of it is transported outward through the nuclear pores into cytoplasm. Here, it is used in conjunction with specific proteins to assemble “mature” ribosomes that play an essential role in forming cytoplasmic proteins.

A typical cell, as seen by the light microscope, is shown in Figure 2–1. Its two major parts are the nucleus and the cytoplasm. The nucleus is separated from the cytoplasm by a nuclear membrane, and the cytoplasm is separated from the surrounding fluids by a cell membrane, also called the plasma membrane. The different substances that make up the cell are collectively called protoplasm. Protoplasm is composed mainly of five basic substances: water, electrolytes, proteins, lipids, and carbohydrates. 

Water. The principal fluid medium of the cell is water, which is present in most cells, except for fat cells, in a concentration of 70 to 85 per cent. Many cellular chemicals are dissolved in the water. Others are suspended in the water as solid particulates. Chemical reactions take place among the dissolved chemicals or at the surfaces of the suspended particles or membranes.

Ions. The most important ions in the cell are potassium, magnesium, phosphate, sulfate, bicarbonate, and smaller quantities of sodium, chloride, and calcium. These are all discussed in more detail in Chapter 4, which considers the interrelations between the intracellular and extracellular fluids. The ions provide inorganic chemicals for cellular reactions. Also, they are necessary for operation of some of the cellular control mechanisms. For instance, ions acting at the cell membrane are required for transmission of electrochemical

impulses in nerve and muscle fibers. 

Proteins. After water, the most abundant substances in most cells are proteins, which normally constitute 10 to 20 per cent of the cell mass. These can be divided into two types: structural proteins and functional proteins. Structural proteins are present in the cell mainly in the form of long filaments that themselves are polymers of many individual protein molecules. A prominent use of such intracellular filaments is to form microtubules that provide the “cytoskeletons” of such cellular organelles as cilia, nerve axons, the mitotic spindles of mitosing cells, and a tangled mass of thin filamentous tubules that hold the parts of the cytoplasm and nucleoplasm together in their respective compartments. Extracellularly, fibrillar proteins are found especially in the collagen and elastin fibers of connective tissue and in blood vessel walls, tendons, ligaments, and so forth. The functional proteins are an entirely different type of protein, usually composed of combinations of a few molecules in tubular-globular form. These 

proteins are mainly the enzymes of the cell and, in contrast to the fibrillar proteins, are often mobile in the cell fluid. Also, many of them are adherent to membranous structures inside the cell. The enzymes come into direct contact with other substances in the cell fluid and thereby catalyze specific intracellular chemical reactions. For instance, the chemical reactions that split glucose into its component parts and then combine these with oxygen to form carbon dioxide and water while simultaneously providing energy for cellular function are all catalyzed by a series of protein enzymes.

Lipids. Lipids are several types of substances that are grouped together because of their common property of being soluble in fat solvents. Especially important lipids are phospholipids and cholesterol, which together constitute only about 2 per cent of the total cell mass. The significance of phospholipids and cholesterol is that they are mainly insoluble in water and, therefore, are used to form the cell membrane and intracellular membrane barriers that separate the different cell compartments. In addition to phospholipids and cholesterol, some cells contain large quantities of triglycerides, also called neutral fat. In the fat cells, triglycerides often account for as much as 95 per cent of the cell mass.The fat stored in these cells represents the body’s main storehouse of energy-giving nutrients that can later be dissoluted and used to provide energy wherever in the body it is needed.

Carbohydrates. Carbohydrates have little structural function in the cell except as parts of glycoprotein molecules, but they play a major role in nutrition of the cell. Most human cells do not maintain large stores of carbohydrates; the amount usually averages about 1 per cent of their total mass but increases to as much as 3 per cent in muscle cells and, occasionally, 6 per cent in liver cells. However, carbohydrate in the form of dissolved glucose is always present in the surrounding extracellular fluid so that it is readily available to the cell. Also, a small amount of carbohydrate is virtually always stored in the cells in the form of glycogen, which is an insoluble polymer of glucose that can be depolymerized and used rapidly to supply the cells’ energy needs.

Each of the 100 trillion cells in a human being is a living structure that can survive for months or many years, provided its surrounding fluids contain appropriate nutrients. To understand the function of organs and other structures of the body, it is essential that we first understand the basic organization of the cell and the functions of its component parts.

The human body has thousands of control systems in it. The most intricate of these are the genetic control systems that operate in all cells to help control intracellular function as well as extracellular function.

Many other control systems operate within the organs to control functions of the individual parts of the organs; others operate throughout the entire body to control the interrelations between the organs. For instance, the respiratory system, operating in association with the nervous system, regulates the concentration of carbon dioxide in the extracellular fluid. The liver and pancreas regulate the concentration of glucose in the extracellular fluid, and the kidneys regulate concentrations of hydrogen, sodium, potassium, phosphate, and other ions in the extracellular fluid.

Regulation of Oxygen and Carbon Dioxide Concentrations in the Extracellular Fluid. Because oxygen is one of the major substances required for chemical reactions in the cells, it is fortunate that the body has a special control mechanism to maintain an almost exact and constant oxygen concentration in the extracellular fluid. This mechanism depends principally on the chemical characteristics of hemoglobin, which is present in all red blood cells. Hemoglobin combines with oxygen as the blood passes through the lungs. Then, as the blood passes through the tissue capillaries, hemoglobin, because of its own strong chemical affinity for oxygen, does not release oxygen into the tissue fluid if too much oxygen is already there. But if the oxygen concentration in the tissue fluid is too low, sufficient oxygen is released to re-establish an adequate concentration. Thus, regulation of oxygen concentration in the tissues is vested principally in the chemical characteristics of hemoglobin itself. This regulation is called the oxygen-buffering function of hemoglobin. Carbon dioxide concentration in the extracellular fluid is regulated in a much different way. Carbon dioxide is a major end product of the oxidative reactions in cells. If all the carbon dioxide formed in the cells continued to accumulate in the tissue fluids, the mass action of the carbon dioxide itself would soon halt all energy-giving reactions of the cells. Fortunately, a higher than normal carbon dioxide concentration in the blood excites the respiratory center, causing a person to breathe rapidly and deeply. This increases expiration of carbon dioxide and, therefore, removes excess carbon dioxide from the blood and tissue fluids. This process continues until the concentration returns to normal.

Regulation of Arterial Blood Pressure. Several systems contribute to the regulation of arterial blood pressure. One of these, the baroreceptor system, is a simple and excellent example of a rapidly acting control mechanism. In the walls of the bifurcation region of the carotid arteries in the neck, and also in the arch of the

aorta in the thorax, are many nerve receptors called baroreceptors, which are stimulated by stretch of the arterial wall.When the arterial pressure rises too high, the baroreceptors send barrages of nerve impulses to the medulla of the brain. Here these impulses inhibit the vasomotor center, which in turn decreases the number of impulses transmitted from the vasomotor center through the sympathetic nervous system to the heart and blood vessels. Lack of these impulses causes diminished pumping activity by the heart and also dilation of the peripheral blood vessels, allowing increased blood flow through the vessels. Both of these effects decrease the arterial pressure back toward normal.

Table 1–1 lists the more important constituents and physical characteristics of extracellular fluid, along with their normal values, normal ranges, and maximum limits without causing death. Note the narrowness of the normal range for each one. Values outside these ranges are usually caused by illness. Most important are the limits beyond which abnormalities can cause death. For example, an increase in the body temperature of only 11°F (7°C) above normal can lead to a vicious cycle of increasing cellular metabolism that destroys the cells. Note also the narrow range for acid-base balance in the body, with a normal pH value of 7.4 and lethal values only about 0.5 on either side of normal. Another important factor is the potassium ion concentration, because

whenever it decreases to less than one third normal, a person is likely to be paralyzed as a result of the nerves’ inability to carry signals. Alternatively, if the potassium ion concentration increases to two or more times normal, the heart muscle is likely to be severely depressed. Also, when the calcium ion concentration falls below about one half of normal, a person is likely to experience tetanic contraction of muscles throughout the body because of the spontaneous generation of excess nerve impulses in the peripheral nerves. When the glucose concentration falls below one half of normal, a person frequently develops extreme mental irritability and sometimes even convulsions. These examples should give one an appreciation for the extreme value and even the necessity of the 

vast numbers of control systems that keep the body operating in health; in the absence of any one of these controls, serious body malfunction or death can result.

The aforementioned examples of homeostatic control mechanisms are only a few of the many thousands in the body, all of which have certain characteristics in common. These characteristics are explained in this section.

Most control systems of the body act by negative feedback, which can best be explained by reviewing some of the homeostatic control systems mentioned previously. In the regulation of carbon dioxide concentration, a high concentration of carbon dioxide in the extracellular fluid increases pulmonary ventilation. This, in turn, decreases the extracellular fluid carbon dioxide concentration because the lungs expire greater amounts of carbon dioxide from the body. In other words, the high concentration of carbon dioxide initiates events that decrease the concentration toward normal, which is negative to the initiating stimulus. Conversely, if the carbon dioxide concentration falls too low, this causes feedback to increase the concentration. This response also is negative to the initiating stimulus. In the arterial pressure–regulating mechanisms, a high pressure causes a series of reactions that promote a lowered pressure, or a low pressure causes a series of reactions that promote an elevated pressure. In both instances, these effects are negative with respect to the initiating stimulus. Therefore, in general, if some factor becomes excessive or deficient, a control system initiates negative feedback, which consists of a series of changes that return the factor toward a certain mean value, thus maintaining homeostasis. 

“Gain” of a Control System. The degree of effectiveness with which a control system maintains constant conditions is determined by the gain of the negative feedback. For instance, let us assume that a large volume of blood is transfused into a person whose baroreceptor pressure control system is not functioning, and the arterial pressure rises from the normal level of 100 mm Hg up to 175 mm Hg. Then, let us assume that the same volume of blood is injected into the same person when the baroreceptor system is functioning, and this time the pressure increases only 25 mm Hg. Thus, the feedback control system has caused a “correction” of --50 mm Hg that is, from 175 mm Hg to 125 mm Hg. There remains an increase in pressure of +25 mm Hg, called the “error,” which means that the control system is not 100 per cent effective in preventing change. The gain of the system is then calculated by the following formula:

Thus, in the baroreceptor system example, the correction is -50 mm Hg and the error persisting is +25 mm Hg. Therefore, the gain of the person’s baroreceptor system for control of arterial pressure is –50 divided by +25, or –2. That is, a disturbance that increases or decreases the arterial pressure does so only one third as much as would occur if this control system were not present. The gains of some other physiologic control systems are much greater than that of the baroreceptor system. For instance, the gain of the system controlling

internal body temperature when a person is exposed to moderately cold weather is about –33. Therefore, one can see that the temperature control system is much more effective than the baroreceptor pressure control system.

One might ask the question, Why do essentially all control systems of the body operate by negative feedback rather than positive feedback? If one considers the nature of positive feedback, one immediately sees that positive feedback does not lead to stability but to instability and often death. Figure 1–3 shows an example in which death can ensue from positive feedback. This figure depicts the pumping effectiveness of the heart, showing that the heart of a healthy human being pumps about 5 liters of blood per minute. If the person is suddenly bled 2 liters, the amount of blood in the body is decreased to such a low level that not enough blood is available for the heart to pump effectively. As a result, the arterial pressure falls, and the flow of blood to the heart muscle through the coronary vessels diminishes.This results in weakening of the heart, further diminished pumping, a further decrease in coronary blood flow, and still more weakness of the heart; the cycle repeats itself again and again until death occurs. Note that each cycle in the feedback results in further weakening of the heart. In other words, the initiating stimulus causes more of the same, which is positive feedback.

Positive feedback is better known as a “vicious cycle,” but a mild degree of positive feedback can be overcome by the negative feedback control mechanisms of the body, and the vicious cycle fails to develop. For instance, if the person in the aforementioned example were bled only 1 liter instead of 2 liters, the normal negative feedback mechanisms for controlling cardiac output and arterial pressure would overbalance the positive feedback and the person would recover, as shown by the dashed curve of Figure 1–3.

Positive Feedback Can Sometimes Be Useful. In some instances, the body uses positive feedback to its advantage. Blood clotting is an example of a valuable use of positive feedback. When a blood vessel is ruptured and a clot begins to form, multiple enzymes called clotting factors are activated within the clot itself. Some of these enzymes act on other unactivated enzymes of the immediately adjacent blood, thus causing more blood clotting. This process continues until the hole in the vessel is plugged and bleeding no longer occurs. On occasion, this mechanism can get out of hand and cause the formation of unwanted clots. In fact, this is what initiates most acute heart attacks, which are caused by a clot beginning on the inside surface of an atherosclerotic plaque in a coronary artery and then growing until the artery is blocked. 

Childbirth is another instance in which positive feedback plays a valuable role.When uterine contractions become strong enough for the baby’s head to begin pushing through the cervix, stretch of the cervix sends signals through the uterine muscle back to the body of the uterus, causing even more powerful contractions. Thus, the uterine contractions stretch the cervix, and the cervical stretch causes stronger contractions. When this process becomes powerful enough, the baby is born. If it is not powerful enough, the contractions usually die out, and a few days pass before they begin again. 

Another important use of positive feedback is for the generation of nerve signals. That is, when the membrane of a nerve fiber is stimulated, this causes slight leakage of sodium ions through sodium channels in the nerve membrane to the fiber’s interior. The sodium ions entering the fiber then change the membrane potential, which in turn causes more opening of channels, more change of potential, still more opening of channels, and so forth. Thus, a slight leak becomes an explosion of sodium entering the interior of the nerve fiber, which creates the nerve action potential. This action potential in turn causes electrical current to flow along both the outside and the inside of the fiber and initiates additional action potentials. This process continues again and again until the nerve signal goes all the way to the end of the fiber. 

In each case in which positive feedback is useful, the positive feedback itself is part of an overall negative feedback process. For example, in the case of blood clotting, the positive feedback clotting process is a negative feedback process for maintenance of normal blood volume.Also, the positive feedback that causes nerve signals allows the nerves to participate in thousands of negative feedback nervous control systems.

Later in this text, when we study the nervous system, we shall see that this system contains great numbers of interconnected control mechanisms. Some are simple feedback systems similar to those already discussed. Many are not. For instance, some movements of the body occur so rapidly that there is not enough time for nerve signals to travel from the peripheral parts of the body all the way to the brain and then back to the periphery again to control the movement.Therefore, the brain uses a principle called feed-forward control to cause required muscle contractions. That is, sensory nerve signals from the moving parts apprise the brain whether the movement is performed correctly. If not, the brain corrects the feed-forward signals that it sends to the muscles the next time the movement is required. Then, if still further correction is needed, this will be done again for subsequent movements.This is called adaptive control. Adaptive control, in a sense, is delayed negative feedback. Thus, one can see how complex the feedback control systems of the body can be. A person’s life depends on all of them. Therefore, a major share of this text is devoted to discussing these life-giving mechanisms.