What are cells?
Cells are the basic components of all living things, and the human body is made up of approximately 10 trillion cells. Cells contain complex biochemical systems that use energy sources to power cellular activities such as growth, movement, and reaction to environmental changes or external stimuli. The information required to assemble the enzymatic and structural molecules involved in these activities is stored in a cell's deoxyribonucleic acid (DNA) and is duplicated and passed on in cell division.
A cell can be divided into two major internal regions, the nucleus and cytoplasm, which reflect a fundamental division of labor. In the nucleus are the DNA molecules that store the hereditary information required for cell growth and reproduction. The nucleus also contains enzymes that are capable of copying the hereditary information into ribonucleic acid (RNA), which is used as instructions for making proteins in the cytoplasm. Enzymes within the nucleus also duplicate the DNA in preparation for cell division. The cytoplasm makes proteins according to the directions copied in the nucleus and also synthesizes most other molecules required for cellular activities. The cytoplasm carries out several additional vital functions, including motility and the conversion of fuel substances into usable forms of chemical energy.
Cells are encapsulated by membranes. These layers of lipid and protein molecules, not much more than 7 to 8 nanometers thick, form an outer boundary, called the plasma membrane, that separates the cell contents from the exterior. Several internal membrane systems divide the cell interior into specialized compartments called organelles. The lipid part of membranes consists of a double layer of molecules called a bilayer. The lipid bilayer provides the structural framework of membranes and acts as a barrier to the passage of water-soluble substances. Membrane proteins, which are suspended in the lipid bilayer or attached to its surface, carry out the specialized functions of membranes.
The plasma membrane forming the outer cell boundary has a variety of functions. The most significant is the transport of substances between the cytoplasm and the cell’s exterior, which is carried out by proteins that form channels in the membrane. These channels pass specific water-soluble molecules or ions. The plasma membrane also contains proteins functioning as receptors, which recognize and bind to specific molecules from the surrounding medium. On binding to their target molecules, which include peptide hormones, many receptors trigger internal cellular responses that coordinate the activities of cells in tissues and organs. Other plasma membrane proteins recognize and adhere to molecules on the surfaces of other cells or to extracellular structures such as collagen. These adhesive functions are critical to the development and maintenance of tissues and organs. Other plasma membrane proteins identify cells as part of the individual or as foreign intruders.
The nucleus is separated from the cytoplasm by two concentric membranes, one layered just inside the other, forming a system known as the nuclear envelope. At closely spaced intervals, the envelope is perforated by pores, about 70 to 90 nanometers in diameter, which form channels between the nuclear interior and the surrounding cytoplasm. The pores are filled by a ringlike mass of proteins that control the movement of large molecules, such as proteins and RNA, through the nuclear envelope.
Within the nucleus are chromatin fibers containing the nuclear DNA, held in association with two major types of proteins, the histone and nonhistone chromosomal proteins. The histones are primarily structural molecules that pack DNA into chromatin fibers. The nonhistones include proteins that regulate gene activity. The hereditary information of the human nucleus is subdivided among forty-six linear DNA molecules. Each individual DNA molecule, with its associated histone and nonhistone proteins, is a chromosome of the nucleus.
Each segment of a chromosome containing the information used to make an RNA copy constitutes a gene. One type of gene encodes messenger RNA (mRNA) molecules, which contain information required to make proteins. Another type of gene encodes ribosomal RNA (rRNA) molecules. Ribosomal RNA forms part of ribosomes, complex RNA-protein particles in the cytoplasm that assemble proteins according to the directions carried in mRNA molecules. The regions of the chromosomes active in making rRNA are collected into structures called nucleoli. Within nucleoli, rRNAs are assembled with proteins into subunits of ribosomes.
The cytoplasm surrounding the nucleus is packed with ribosomes and a variety of organelles. The boundary membranes of the organelles set them off as distinct chemical and molecular environments, specialized to carry out different functions. Ribosomes may be either freely suspended in the cytoplasm or attached to the surfaces of a system of flattened, membranous sacs called the endoplasmic reticulum. Freely suspended ribosomes make proteins that enter the cytoplasmic solution as enzymes, structural supports, or motile elements. Ribosomes attached to the endoplasmic reticulum assemble proteins that become part of membranes or eventually enter small, membrane-bound sacs for storage or release to the cell exterior.
Proteins made in the rough endoplasmic reticulum—those sacs with ribosomes—are modified chemically in another system of membranous sacs, the Golgi complex or apparatus. This system usually appears as a cup-shaped stack of flattened, ribosome-free sacs. The modifications carried out in the Golgi complex may include the addition of chemical groups such as sugars, and the clipping of surplus segments from proteins. Following modification, proteins are sorted into small, membrane-bound sacs that pinch off from the Golgi membranes. These sacs may be stored in the cytoplasm or may release their contents to the cell exterior.
One type of membrane-bound sac containing stored proteins, the lysosome, is particularly important to cell function. Lysosomes contain a group of enzymes collectively capable of breaking down all major molecules of the cell. Many substances taken into cells are delivered to lysosomes, where they are digested by the lysosomal enzymes. Lysosomes may also release their enzymes into the cytoplasm or to the cell exterior. Release within the cell causes cell death, which may occur due to pathological conditions or as part of normal development.
Most of the chemical energy required for cellular activities is produced by reactions taking place in another cytoplasmic organelle, the mitochondrion. Mitochondria are surrounded by two separate membranes, one enclosed within the other. Within mitochondria occur most of the oxidative reactions that release energy for cellular activities. Fuel for these reactions is provided by the breakdown products of all major cellular molecules, including carbohydrates, fats, proteins, and nucleic acids.
The oxidative functions of mitochondria are supplemented by the activities of peroxisomes (also called microbodies). These structures, which consist simply of a boundary membrane surrounding a solution of enzymes, carry out reactions that link major oxidative pathways occurring elsewhere in the cytoplasm. Microbodies are particularly important to the oxidation of fatty acids.
Almost all cell movements are generated by one of two cytoplasmic structures, microtubules or microfilaments. Microtubules form the motile elements of sperm tails; microfilaments are responsible for the movements of skeletal, cardiac, and smooth muscle. Microtubules are fine, hollow cylinders about 25 nanometers in diameter, assembled from subunits of a protein known as tubulin. Microfilaments are thin, solid fibers 5 to 7 nanometers in diameter, assembled from subunits of a different protein, actin. Both structures produce motion through protein cross-bridges that work as transducers converting chemical energy to mechanical energy. One end of a cross-bridge attaches to the surface of a microtubule or microfilament; the opposite, reactive end attaches to another microtubule or microfilament or to other cell structures. The cross-bridge produces motion by making an attachment at its reactive end, forcefully swiveling a short distance, and then releasing. Distinct proteins form the swiveling cross-bridges for the two motile elements.
In addition to their functions in cell motility, both microtubules and microfilaments form supportive networks inside cells collectively called the cytoskeleton. Another group of supportive fibers with diameters averaging about 100 nanometers, the intermediate filaments, also forms parts of the cytoskeleton. Intermediate filaments assemble from a large family of related proteins that is distinct from the tubulins and actins forming microtubules and microfilaments.
Because cell structure and function underlie the totality of bodily functions, all aspects of health and disease reflect normal and abnormal cellular activities. Perhaps the most critical and important of these activities to contemporary medical science is the conversion of normal cellular activity to abnormal activity, which is responsible for cancer. Cancer occurs when cells grow and divide uncontrollably, break free from their normal cell contacts, and migrate to other regions of the body.
The cell transformations occurring in the development of cancer involve changes at several levels. Most of these changes reflect an alteration of one or more genes in the cell nucleus from normal to aberrant forms called oncogenes. Most oncogenes encode proteins involved in a relatively small number of activities. These include nonhistone proteins regulating gene activity, growth hormones, receptors in the plasma membrane for peptide hormones, and proteins taking part in internal cellular response systems triggered by receptors. Directly or indirectly, the altered proteins encoded in oncogenes induce internal changes that lead to uncontrolled cell division and loss of normal adhesions to neighboring cells.
For example, the oncogene src encodes a protein that adds phosphate groups to other proteins as a cellular control measure. In many types of cancer cells, the src gene or its product is hyperactive. One of the targets of the enzyme encoded in the gene is a receptor protein of the plasma membrane. In some cancer cells, uncontrolled addition of phosphate groups to the receptor causes it to lose its attachment to extracellular structures that hold the cells in place. This loss contributes to the tendency of tumor cells to break loose and migrate to other parts of the body.
In some cases, movement of DNA segments from one chromosome to another is involved in the transformation of cells from normal to cancerous types, including several types of leukemia. For example, in some types of leukemia, breaks occur in chromosomes 8 and 14 in cell lines producing leukocytes, and segments are exchanged between the chromosomes. The exchange moves the gene myc from its normal location in chromosome 8 to a region of chromosome 14 that encodes a major segment of antibody proteins. In its normal location, the myc gene encodes a chromosomal regulatory protein that controls genes involved in cell division. When translocated to chromosome 14, myc comes under the influence of DNA sequences that promote the high activity of the antibody gene. As a result, myc becomes hyperactive in triggering cell division and contributes to the uncontrolled division of white blood cells characteristic of leukemias.
Alterations in cytoplasmic organelles are also directly responsible for some human diseases. The enzymes contained in lysosomes are abnormally secreted in many human diseases. The degenerative changes of arthritis, for example, are suspected to be caused in part by the abnormal release of enzymes from the lysosomes of bone or lymph cells into the fluids that lubricate joints. Some of the damage to lung tissues caused by the inhalation of silica fibers in silicosis is also related to lysosomal function. Microscopic silica fibers are taken in by macrophages and other cells in the lungs; these fibers are delivered to lysosomes for breakdown, as are many other substances. The fibers accumulate in the lysosomes, causing lysosomal enlargement and eventually breakage, causing the destructive release of lysosomal enzymes into the cytoplasm. Other human diseases related to lysosomes are caused by inherited mutations that destroy the activity of lysosomal enzymes. For example, an inherited deficiency in one lysosomal enzyme, hexosaminidase, interferes with reactions clipping carbohydrate segments from molecules removed from the cell surface. As a result, the subparts of these molecules accumulate in lysosomes and cannot be recycled. Their concentration on cell surfaces is diminished; loss of these molecules from nerve cells, particularly a group called gangliosides, can lead to seizures, blindness, loss of intellect, and early death.
Human disease has also been linked to inherited changes in mitochondria. The mutations interfere with the oxidative reactions inside the organelle or have detrimental effects on the transport of substances through the mitochondrial membranes. The mutations cause the most severe problems in locations where the energy supplied by mitochondria is highly critical, particularly in the central nervous system and skeletal and cardiac muscle. Mitochondrial deficiencies in these locations are typically responsible for symptoms such as muscular weakness, irregularities in the heartbeat, and epilepsy.
Deficiencies in motile systems based on microtubules and microfilaments are also associated with human disease. For example, a group of inherited defects known as the immotile cilia or Kartagener’s syndrome is characterized by acute bronchitis, sinusitis, chronic headache, male sterility, and reversal of the position of the heart from the left to the right side of the body. In individuals with the disease, the cyclic cross-bridges driving microtubule-based motion are missing. Male sterility results from loss of motility by sperm tails; other deficiencies result from the immotility of cilia on cells lining the respiratory system and the cavities of the brain. (Cilia are microtubule-based cellular appendages that beat like sperm tails to maintain the flow of fluids over cell surfaces.) In the respiratory system, loss of ciliary beating stops the flow of mucus that normally removes irritating and infectious matter from the lungs and respiratory tract. This deficiency explains the sinusitis and bronchitis. Presumably, an insufficient flow of fluids in the ventricles of the brain, normally maintained by ciliated cells lining these cavities, produces the headaches. The reversed position taken by the heart remains unexplained.
Even the cytoskeleton has been associated with human disease. For example, deficiencies in intermediate filaments of the cytoskeleton have been implicated in the hereditary disease epidermolysis bullosa. In this disease, skin cells are fragile, and slight abrasions that would cause little or no problem in normal individuals lead to severe blistering, ulceration, and scarring.
Knowledge of cell structure and function developed gradually from the first morphological descriptions of cells in the seventeenth century. By the 1830s, enough information had accumulated for Theodor Schwann and Matthias Schleiden to propose that all living organisms are composed of one or more cells and that cells are the minimum functional units of living organisms. Their conclusions were supplemented in 1855 by a third postulate by Rudolf Virchow: that all cells arise only from preexisting cells by a process of division. Further work established that the cell nucleus contains hereditary information and that the essential feature of cell division is transmission of this information from parent to daughter cells.
The study of cell chemistry and physiology began in the late eighteenth and early nineteenth centuries. By the end of the nineteenth century, investigators had isolated, identified, and synthesized many organic substances found in cells and worked out the structural components of proteins and nucleic acids. This chemical work was complemented by biochemical studies leading to the discovery of enzymes. The gradual integration of cell structure, physiology, and biochemistry continued; by the 1930s, the field had shifted from morphological observations to biochemical and molecular studies of cell function. Crucial to this shift was the research of George Beadle and Edward Tatum, who concluded from their studies that mutant genes encode a faulty form of an enzyme necessary to produce a substance needed for normal growth. On this basis, they proposed that each gene codes for a single enzyme—the famous “one gene–one enzyme” hypothesis.
Further biochemical work revealed the oxidative reactions providing chemical energy for cell activities. This research was integrated with structural studies of cytoplasmic organelles by Albert Claude, who developed a technique for isolating and purifying cell parts by cell fractionation and centrifugation. Claude and his associates successfully isolated ribosomes, endoplasmic reticulum, Golgi complexes, lysosomes, microbodies, and mitochondria by these methods, which allowed biochemical analysis of the fractions. This work was facilitated by development of the electron microscope, allowing elucidation of the ultrastructure of many of the organelles studied biochemically in cell fractions.
Experiments in the 1940s implicating DNA as the hereditary molecule sparked an intensive effort to work out the three-dimensional structure of this molecule, culminating in the discovery of DNA's double-helix structure in 1953 by James D. Watson and Francis Crick. Their discovery led to an effort to determine the molecular structure of genes and their modes of action, which was greatly facilitated by the development of rapid methods for nucleic acid sequencing. Using these methods, many genes have been completely sequenced; the sequences, in turn, allowed deduction of the amino acid sequences of many proteins. The comparisons of gene and protein sequences and structure in normal and mutant forms made possible by these developments provided fundamental insights into the mechanisms controlling and regulating genes and the molecular functions of proteins, revolutionizing biology and medicine.
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