The concept that all living material is made of cells or the chemical products of cells is a central, unifying one in modern \Tbiology\t. The concept--of the cell as the fundamental, irreducible unit of life--is the basis for an understanding of living organisms as well as the foundation of modern research in the life sciences. History The word cell was introduced by Robert \THooke\t in 1665. In the course of microscopic studies of cork, Hooke noticed that the material under study was made up of many "little boxes." Ten years later, Anton van \TLeeuwenhoek\t, using a hand-held lens, described several tiny microscopic creatures later found to be bacteria and protozoa. Over the next 150 years, numerous investigators, using the \Tmicroscope\t, turned to the examination of living tissue and developed detailed descriptions of it. The cell theory of life is a concept that was developed by many scientists over a period of about 150 years. The initial statement of the cell theory was given by Lorenz Oken (1779-1851) in 1805. In 1839, Theodore \TSchwann\t stated the theory essentially in its contemporary form. Subsequent research in the origin of cells led Rudolf \TVirchow\t to state (1858) the generalization that every cell is formed from a preexisting cell. The current theory of cellular biology may be presented as a set of six statements: (1) all living material is made up of cells or the products of cells; (2) all cells are derived from previously existing cells; most cells arise by cell division, but in sexual organisms they may be formed by the fusion of a sperm and an egg; (3) a cell is the most elementary unit of life; (4) every cell is bounded by a plasma membrane, an extremely thin skin separating it from the environment and from other cells; (5) all cells have strong biochemical similarities; and (6) most cells are small, about 0.001 cm (0.00004 in) in length; for example, the smallest cells of the microorganism mycoplasma are 0.3 microns in size, whereas some giant algal cells may be several centimeters long. Cell Classes In recent years it has become clear that two classes of cells exist: the \Lprokaryote\ls and the \Leukaryote\ls. The Prokaryotes include the bacteria and the blue-green algae (the Monera kingdom). These are all single-celled organisms that lack both a true nucleus and other membrane-bounded cellular substructures. The genetic material responsible for the transmission of characteristics from one generation to another is contained in a single large molecule of circular deoxyribose \Tnucleic acid\t, or \TDNA\t. The eukaryotes include plants, animals, protozoa, and fungi. These cells contain nuclei and other membrane-bounded cell components, or organelles, such as mitochondria and plastids. The genetic material is organized into chromosomes. Methods of Study The study of cell structure includes the fields of \Tcytology\t (for cells) and \Thistology\t (for tissues), whereas the function of cells is studied in \Tcell physiology\t, \Tbiochemistry\t, and cytogenetics. The first instrument used in studying cell structure was the light microscope, which remains an important tool today. The electron microscope and the scanning electron microscope have extended the range of observed detail as well as the kinds of cell structures that can be observed. In examining biological specimens, using microscopic techniques, it is necessary to stain the material and cut it into samples thin enough for a light beam or an electron beam to penetrate them. First, the tissue is treated, to "fix" the structures so they will not be altered by the staining and slicing. Usually this is done by using chemicals such as \Talcohol\t and \Tformaldehyde\t. Machines for slicing embedded tissue preparations are called microtomes, and the procedure is known as sectioning. Stains have been developed that react differently with cell structures, depending on their chemical composition or enzymatic activity. The science of analyzing structures by their chemical reactions is called cytochemistry, and the study of the staining properties of tissues is part of histochemistry. The use of stains containing radioactive atoms, known as autoradiography, may be combined with the study of cell physiology by feeding cells specific compounds with radioactive atoms and then microscopically observing on a photographic emulsion the distribution of radioactive events. The generalized functions of most cells are maintenance, synthesis of cell products, and cell division. These require that the cell take in nutrients and excrete waste products. The nutrients are used either as building blocks in synthesizing large molecules, or they are oxidized, producing energy for powering the cell's activities. Because synthesis, maintenance, and mechanical and electrical activity all require energy, a major chemical activity in nearly all types of cells is the energy-linked conversion of metabolites. Adenosine triphosphate (\TATP\t) is the universal energy-transfer molecule; it is constantly utilized and regenerated by energy-yielding chemical reactions. COMPONENTS OF CELLS A cell is bounded by a cell membrane. The material known as the cytoplasm lies within the membrane and contains several organelles and granules in suspension. Plant and bacteria cells have an additional membrane, or wall, that lies outside the cell membrane and is not essential to the functioning and growth of the cell. Plasma Membrane Cells are surrounded by a thin membrane of lipid (fat) and protein, about 100 angstroms (0.0000004 in) thick. It controls the transport of molecules in and out of the cell and thus serves as a line of demarkation between the cell and the surrounding tissue. Outside the plasma membrane may be other envelopes such as the outer membrane, the cell wall (in plants), and the extracellular material. Unit membranes also occur in a eukaryote cell's interior, for example, as part of the endoplasmic reticulum, nuclei, and mitochondria. The exterior portions of the cell surfaces determine cell-to-cell interactions and are thus important in the formation and control of tissue. The extracellular material also acts as a glue that holds cells together in tissues. The molecules outside the cell are usually composed of protein and carbohydrate. Nuclei Most cells have a single nucleus bounded by a nuclear envelope, or membrane, with pores. Pores provide continuity between the nucleus and the cytoplasm. The nucleus contains one or more discrete structures, known as nucleoli, which are sites of ribosomal ribonucleic acid (\TRNA\t) synthesis. Hereditary information is carried in the \TDNA\t contained within the chromosomes in the nucleus. This information is transcribed into the \TRNA\t in the nucleus, which serves as a messenger. The messenger then moves outside of the nucleus to the ribosomes where it guides the synthesis of proteins. Thus, the nucleus directs the activity of the cell. Ribosomes Ribosomes are tiny particles within the cell. Made of \TRNA\t and protein, they are present in large numbers in most cells and are the site of protein synthesis (the manufacture of large protein molecules from \Tamino acid\t subunits). Endoplasmic Reticulum Within most eukaryotic cells is a complex set of membranous structures. When viewed in the electron microscope, the membranes are either rough (covered with granules or ribosomes) or smooth. Generally, the rough \Tendoplasmic reticulum\t is highly developed in cells that synthesize large amounts of protein. Golgi Apparatus A special type of membrane aggregate is often found near the nucleus. This collection of membranes is called the \TGolgi apparatus\t. It is visible when viewed under the microscope because the outer portion stains with the metal osmium. In cells that synthesize and secrete products, the Golgi apparatus is the site of the material that is accumulated. Mitochondria Mitochondria (see \Tmitochondrion\t) are composed of an outer membrane and a highly convoluted inner membrane. A series of chemical reactions that occur on the inner membrane convert the energy of oxidation into the chemical energy of \TATP\t. In this process, called oxidative phosphorylation, the predominant energy transfer molecule is \TATP\t. Almost all of the energy passes through this molecule before being utilized in cell function. Cells with high rates of metabolism usually have a large number of mitochondria. Chloroplasts Plant cells contain organelles of photosynthesis known as chloroplasts (see \Tchloroplast\t). These structures have a membranous outer envelope and a high laminated inner membranous structure. The interior membranes contain the chlorophyll and are responsible for photosynthesis. Chloroplasts are viewed as an example of a more general class of organelles called plastids. Centrioles Most cells have two cylindrical bodies, called centrioles, located near the nucleus. The centrioles appear as sets of triple tubules. Centrioles play a part in cell division. Other Organelles The material containing the organelles is called ground substance, or cytoplasm. It contains proteins, small molecules, and a group of entities organized as microfilaments and microtubules. Microfilaments are long, thin, contractile rods that appear to be responsible for the movement of cells, both external and internal. Microtubules are hollow, cylindrical aggregates of tubelike structure that help give the cell shape and form; they are also involved in other cell processes. Lysosomes (see \Tlysosome\t) are small bodies where large numbers of enzymes are stored. Many cells, particularly those of plants, contain large liquid-filled areas known as vacuoles; the vacuoles are believed to be involved in digestion or excretion, or both. Storage particles comprise a diverse group of structures and contain lipid droplets and glycogen granules whose function is the long-term storage of energy. Organelles and other cellular material are composed of molecules of protein, carbohydrate, lipid, and nucleic acid. Among these, lipids have a specialized role as the structural elements of membranes. MORPHOGENESIS All organisms, regardless of their complexity, begin as a single cell. By repeated cell growth and mitosis, or division, the organism eventually develops into an adult containing thousands of billions of cells. This process of development is called morphogenesis. Since many different types of cells exist in fully grown plants and animals, morphogenesis involves not only cell growth but differentiation into specialized types of cells. This differentiation is controlled by the genes; the information needed to program and guide the growth is contained within the chromosomes. The size, shape, and chemical activity of the cells are governed to some extent by the function of the tissue in which they are found. Each cell contains the same total genetic information that was present in the fertilized egg. Because of this, the question arises as to why the cells are not identical. It appears that in different types of cells, groups of genes are controlled (in effect, switched on and off) by various biochemical processes, so that each cell manufactures the proteins and structures needed for it to function, such as hemoglobin in red blood cells, flagella in sperm, and so forth. The development of a cell is determined by its position in the developing embryo, the chemical products of neighboring cells, and an internal program that is genetically controlled. Ultimately, these are regulated by the \TDNA\t in the nucleus and by the transfer of selected portions of the \TDNA\t information to the cytoplasm, through the intermediate molecules of messenger \TRNA\t. It is estimated that, on average, only about 10 percent of the genes of any cell are functional-which genes, in particular, vary with the type of cell. Although morphogenesis has been scientifically described in great detail for a number of organisms, all of the processes involved at the cellular level are still not understood. The role of the cells and of cell chemistry in the development of an organism remains an active area of research in biology. Harold Morowitz CELL DIVISION Cell division depends on two complementary events--the replication of the \TDNA\t molecules that make up the basic genetic material of all cells, and the orderly separation of the products of this replication. In simple prokaryotes, where only a single unit of \TDNA\t exists, these two events are intimately coupled with an inward growth of the cell membrane (which appears to provide an attachment site for separating the replicated products). In eukaryotes the process is more complex. A pair of proteins, called cyclin and CDC, work together to initiate and orchestrate all stages of cell division. This protein pair activates the histone protein to unravel the \TDNA\t into two or more discrete chromosomes that are enclosed in a distinct nuclear membrane. Division of the nucleus thus precedes division of the cytoplasm, and both are necessary for cell division. During nuclear division, the behavior of the individual chromosomes must be coordinated, both spatially and temporally. This is achieved by the assembly of two temporary sets of microtubules which together form a primary spindle. The products of chromosome replication are oriented and move within this primary spindle system as a result of the activity of specialized chromosome regions, called kinetochores, or centromeres. In most animal cells, pairs of centrioles are present at each pole of the primary spindle. Where centrioles are present, a radiating system of microtubules (the aster) may form around them. During the initial stages of nuclear division, these astral microtubules proliferate and lengthen. Simultaneously, the two members of a centriolar pair move apart until they occupy diametrically opposed positions outside the nuclear membrane. This is accompanied by the development of a system of primary spindle fibers between--but not connected with--the separating centriolar pairs. THE MITOTIC CYCLE Mitosis is part of a more complex cycle that includes a long phase, called interphase, which may be subdivided into three stages--G(1), S, and G(2)--on the basis of the synthetic activities occurring within them. The synthesis of \TDNA\t occurs only during the S phase, when it coincides with the synthesis of histone protein. As a result of these coupled syntheses, each chromosome now consists of two sister chromosomes, called chromatids, that are identical in their morphological and genetic organization and which are joined at the kinetochore. Chromatids become visible when mitosis sets in; the remainder of the mitotic cycle involves their separation into two offspring nuclei. Mitosis depends on four major events--coiling, orientation, movement, and uncoiling--which, in turn, define five essential stages of the mitotic cycle. Prophase Initially, each chromosome is a long double thread consisting of two chromatids. Changes in the internal configuration of the nucleoprotein component of each chromatid cause a cycle of coiling to be initiated in which the chromosomes become progressively shorter and thicker. Toward the end of the prophase, the microtubules forming the primarily spindle proliferate in the cytoplasm just outside the nuclear membrane. Prometaphase The end of prophase is signaled by the disruption of the nuclear membrane. When the relatively condensed chromosomes come in contact with the primary spindle, their kinetochores accumulate short fibers that establish a connection to the free microtubules. Metaphase The manner in which the chromosomes are distributed at the equator following a reorientation mechanism depends on the relative sizes of the members of the chromosome set, as well as on the size of the cell itself. If the cell is large, the spindle is usually hollow, with all the kinetochores arranged on the periphery of a circle or an oval. Anaphase The association between sister chromatids lapses when the kinetochore divides and the component chromatids (now the chromosomes) have separated completely. All sister kinetochores begin their movement toward the poles simultaneously, apparently triggered by changes in the disposition of the kinetochore fibers. Telophase A new nuclear membrane begins to form at the surface of each of the two separated sets of chromosomes. At the same time, the chromosomes themselves uncoil and return to an extended (and diffuse) interphase state. Cytokinesis The completion of cell division requires that the cell cytoplasm be divided following division of the nucleus. The mechanism of cytoplasm division (cytokinesis) differs between animals and plants. In animals, where no rigid cell wall exists, the cytoplasm becomes shaped like a dumbbell as the result of constriction initiated at the cell's surface, which extends inward. In plants, on the other hand, a new cell wall is built across the middle of the cell and gradually extends outward. THE MEIOTIC CYCLE Whereas mitosis rarely lasts more than 2 hours, the meiotic cycle may take days or weeks to produce the gametes, or sex cells, since it involves not one but two successive sequences of spindle activity and chromosome movement, or two meiotic divisions. The first sequence is preceded by a lengthy prophase during which the key events of pairing and exchange take place. This prophase is divided into five substages whose names appropriately describe the appearance of the chromosomes. The majority of \TDNA\t synthesis is completed before meiosis starts, although this synthesis occasionally extends into the early prophase (leptotene). Prophase-I In the first stage of prophase, called leptotene (literally: "thin thread"), the chromosomes become visible but remain uncoiled. They develop chromomeres, which appear to represent localized areas of increased coiling. Their size and position are constant for homologous (similar) chromosomes. In the second stage, zygotene ("yolked thread"), in a process called synapsis, the chromosomes shorten and homologous chromosomes associate, or meet. Individual pairs in close apposition are called bivalent chromosomes. This pairing can occur anywhere along their lengths. The third stage, pachytene ("thick thread"), is a long period in which the bivalent chromosomes shorten and thicken and appear to be rodlike. The diplotene or double-thread, stage is characterized by partial separation of the chromosomes into four separate chromatids; they are still held together, however, at one or more points, called chiasmata, along their lengths. The chromosome pairs resemble a cross if joined at one point, or, if they adhere at two points, a loop. Meanwhile, the chromosomes continue to coil and shorten internally. In diakinesis, the last prophase stage, the chromosomes contract further, thereby increasing the tightness of the coiling. They also tend to move to the periphery of the nucleus. The chiasmata sometimes move toward the ends of the chromosomes, in a process known as terminalization. Prometaphase-I Disruption of the nuclear membrane enables the bivalents to interact with the primary spindle system formed at this time. Metaphase-I When the above arrangement is complete, the bivalents lie in a temporarily stable state in which their kinetochores are equidistant above and below the spindle equator. The shape adopted by a particular bivalent at this time depends on the location of its kinetochore and on the number and position of the chiasmata within the bivalent. Bivalents with a single chiasma appear as open crosses. The stability of the first metaphase is the result of the tension exerted on the two kinetochore pairs of each bivalent by the kinetochore fibers, as well as on the continued association of sister chromatid pairs. Anaphase-I When this association ceases, the chiasmata are torn apart, thus freeing the sister kinetochore pairs to move poleward as the kinetochore fibers draw the half-bivalents poleward. The terminal association of homologous chromatids also lapses at this time. Interphase The stages of telophase-I, interphase, and cytokinesis may or may not occur during the first meiotic sequence. In animals, nuclear membranes regularly re-form at telophase-I, and the nucleus returns to an interphase state. Some plants also behave in this way, although in many, anaphase-I is succeeded directly by metaphase-II. Second Meiotic Division In prophase-II, homologous chromatids remain widely spread out, reflecting the lapse of association that triggered the anaphase-I separation, and a spindle is formed. Half-bivalents are now auto-oriented at the equator of the division-II spindle before they separate into their component chromatids in anaphase-II. The combined effects of the two meiotic divisions is to partition the four chromatids of each bivalent into one of each of the four nuclei produced from each cell that entered meiosis. This automatically leads to a halving of the number of chromosomes in each meiotic product as well as compensating for the fertilization that follows meiosis. The two meiotic divisions also lead to a recombination, both of individual chromosomes (reassortment) and of particular parts of the chromosomes (crossing over). Reassortment occurs because the co-orientation of sister kinetochore pairs in the first division and the auto-orientation of sister half-kinetochores in the second divisions are random events. Crossing over is the exchange of like segments between two nonsister chromatids which occurs when chrasmata are formed. Bernard John TYPES OF CELLS Several major types of animal cells may be distinguished, including absorptive, secretory, nerve, sensory, muscle, and reproductive cells. All must arise during morphogenesis from cells that are less differentiated. Absorptive Cells Absorptive cells often occur as continuous sheets on surfaces where material is transported to the cells. For example, the single layer of epithelial cells lining the surface of the small intestine selectively absorbs food molecules from the gut into the blood stream. These cells have a free surface that faces the digestive tract and a base surface that is in contact with the capillaries. The free surface is covered with many projections called microvilli, which vastly increase the area available for molecular flow. In digestion, the products of the ingested food are transported through the microvilli into the cell. They are then pumped into the capillaries from the other side. Similar cells are found in the kidney, where a large surface area is needed for the absorption of protein, water, salts, and other materials. The microvilli are an example of a cell structure fitted to the function of the cell. Because an absorptive cell needs maximum area for transport, the shape of the cell surface is altered to achieve the optimum transfer of molecules. Secretory Cells Secretory cells produce products that are subsequently deposited in either the bloodstream or a special duct to an organ, where they are used. The pancreas and pituitary are glands that have large numbers of secretory cells. Proteins and other cell products are synthesized throughout the cytoplasm and transported to the Golgi apparatus, where they are packaged in membrane-bounded vesicles that come to a cell's surface and discharge the secretion outside the cell. Secretory cells in the spleen, lymph nodes, and other sites synthesize antibodies for the recognition and destruction of foreign molecules; this is a major defense against microorganisms. The study of the synthesis and reactions of antibodies is called \Timmunology\t. Nerve Cells A nerve cell consists of a main cell body and a long thin structure known as an axon. The function of nerve cells is to transmit electrical messages from one part of the cell body to another. These cells function similarly to telephone transmission lines. The connections between nerve cells are called synapses. When these structures are combined, they form an electrical network known as the \Tnervous system\t. The processes that occur at the synapses are both electrical and chemical. The axon is covered with a layer of insulation called myelin; it carries electrical signals called nerve impulses. Sensory Cells Sensory cells respond to impulses by emitting electrical signals. An example is the rod cell of the eye, in which the central cell body has two long, thin appendages. One appendage has an outer segment consisting of specialized stacked membranes for the reception of light. At the other end is a long, thin connection to a nerve cell that leads to the optic nerve fiber. About half of the material in the outer segment consists of rhodopsin, the pigment used in detecting light. Muscle Cells Muscles are of three types--skeletal, cardiac, and smooth. All function similarly: the contraction of fibers generates a mechanical force. The skeletal muscle is a multinucleate structure that has an outer envelope known as the sarcolemma. This system does not fit the definition of a cell given above and may be regarded, instead, as a tissue in which the cells have merged. Most of the interior consists of long, thin myofibrils that are actually the contractile elements. Reproductive Cells Gametes are formed after completion of the process of meiosis, which halves the number of chromosomes. Male gametes are usually motile, whereas female gametes are usually larger and are stationary; the function of the latter is to store supplies of food for the developing embryo. Fertilization occurs when a sperm is fused with an egg, this stage is followed by morphogenesis. CELL CULTURE A major proof that the cell is the fundamental unit of life came early in the 20th century, when it was shown that cells can be removed from adult tissue, placed in a nutrient medium, and cultivated. Years passed before it was shown that a single mammalian cell may, under the appropriate conditions, give rise to a clone, a population consisting of the descendants of one cell (see \Tcloning\t). The technique of cell culture has become one of the principal tools of modern biology. In cell culture, growth commonly takes place on a glass or a plastic surface (usually the inside of a jar) covered with a nutrient solution. Alternatively, the cells may be suspended in a liquid growth-medium. As the cells divide and their number increases, some are transferred to fresh nutrient, and the process of growth and transfer is continued. Many normal tissue cells divide several times (usually 40 to 50), then the cells die. Some researchers believe this indicates a built-in aging mechanism in the cells of higher organisms. Their study of these systems is expected to provide insight into the process of aging in humans and other animals. The existence of cultures of human cells allows scientists to perform a wide range of experiments that could not be carried out in humans. Thus drugs and environmental toxins may be tested and virus growth in human cells studied. Various types of cells can be fused, yielding hybrids that provide information about the \Tgenetic code\t and \Tgenetic diseases\t, as well as of the relationship of genes to cell activity. Plant cells may also be grown in cultures, thus allowing studies of hormonal action and differentiation to be conducted. Using cell cultures from carrot roots, it has been possible to grow an entire plant from a single cell. Differentiated carrot cells still carry all the genetic information needed to specify an entire adult plant. In addition to the normal cell types discussed above, most organisms may occasionally give rise to abnormal cells. The most significant abnormality is seen in \TCancer\t cells, which are cells that have some permanent alteration in their cell-division mechanism. Such cells divide rapidly and form large masses called \Ltumor\ls. In a process called metastasis, malignant tumors release cells that spread to other parts of the body and grow. Cancer cells may be grown indefinitely in cell cultures and still possess all the organelles of normal cells. Cancer cells are less highly differentiated. They also appear to lack some control mechanisms that regulate the life cycle of the cell. In cultures, they appear capable of undergoing cell division indefinitely. The process of forming cancer cells from normal cells is of tremendous importance in understanding the disease. Many causes may be involved, such as viruses, toxic chemicals (carcinogens), or the failure of the body's control mechanisms. Harold Morowitz Bibliography: Borek, Ernest, The Sculpture of Life (1973); Cudmore, L. L., The Center of Life (1978); DeDuve, C. A., A Guided Tour of the Living Cell (1984); DeRobertis, E. D. and E. M., Jr., Cell and Molecular Biology, 7th ed. (1980); Loewy, A. G., and Siekevitz, Philip, Cell Structure and Function, 2d ed. (1969); Novikoff, Alex, and Holtzman, Eric, Cells and Organelles, 2d ed. (1976); Parker, Gary, The Structure and Function of the Cell, 2d ed. (1977); Swanson, Carl P., and Webster, Peter, The Cell, 4th ed. (1977); Wolfe, Stephen L., Introduction to Cell Biology (1983).