When restriction enzymes are used along with other enzymes that tie together loose ends of DNA, it becomes possible to remove a bit of DNA from one organism's chromosome and to insert it into another organism's chromosome. This allows scientists to produce new combinations of genes that may not exist in nature. For example, a human gene can be inserted into a bacterium or a bacterial gene into a plant.
So far, however, there are limits to this ability. Scientists are unable to start with only test tubes full of nucleotides to create a whole new organism. They must start with the complete genetic material of an already existing organism. Thus, genetic engineering allows the addition of only one or a small number of new characteristics to an organism that remains essentially the same. In addition, only characteristics that are determined by one or a few genes can be transferred. The technology of genetic engineering does not enable scientists to transfer behavioral traits, such as intelligence, that are a complex mixture of many genes and the effects of cultural conditioning.
In practice, genes to be inserted into bacteria are first recombined into a plasmid, which replicates and travels independently from its bacterial host. The modified plasmid is then inserted into another bacterium.
At the time that these methods became available, it was not known whether DNA could be replicated and expressed in a foreign organism. Experiments done in the mid-1970s with these techniques, however, showed clearly that a human gene could be reproduced by a bacterium along with its own genetic material and that the bacterium could make the protein coded for by the human gene. This opened the way to making large amounts of human hormones and other significant human substances in the laboratory, a much easier route than isolating these substances from blood or cadaver glands. One of the first areas in which genetic engineering exerted an influence was the medical field. Genetic engineering techniques allowed the production of large amounts of many medically useful substances, particularly the class of biological compounds called peptides. Peptides are short proteins. Many of the most important chemical messengers in the body are peptides. These include hormones such as insulin, nervous system messengers such as the endorphins, and regulatory messengers from the hypothalamus that control production of hormones by the pituitary gland, the gonads, and the thyroid gland, among others (see Gland; Hormones).
Several biologically useful peptides were made and tested in clinical trials during the late 1970s and early 1980s. The first genetically engineered product to be approved for human use was human insulin made in bacteria. Insertion of the human insulin gene into bacteria was accomplished by the pioneer genetic engineering company Genentech. Testing, approval for medical use, and large-scale production of genetically engineered human insulin were carried out, and the first diabetic patient in the world was injected with human insulin made in bacteria in December 1980, making this the first genetically engineered product to enter medical practice. (Genetically engineered products are often identified by the prefix r, for "recombinant." Thus, genetically engineered insulin is sometimes written, r-insulin.)
The interferons are another medically important group of peptides that became available in abundance only after the development of genetic engineering techniques. Interferon was useful for treating viral infections, and there were strong indications that it might be effective against some cancers. Before the advent of genetic engineering techniques, it took laborious processing of thousands of units of human blood to obtain enough interferon to treat a few patients. And this interferon was not very pure. With the insertion of the interferon gene into bacteria, large amounts of very pure interferon became available. This supply allowed trials of interferon in the early 1980s against more than ten different cancers, including the particularly virulent form of Kaposi's sarcoma often found in persons with acquired immunodeficiency syndrome (AIDS). The human body makes more than 50 different varieties of interferon. It is thought that some types of interferon may be more effective against cancer than others.
Other medically useful human peptides that have been made widely available because of genetic engineering are human growth hormone, which is used to treat persons with congenital dwarfism and was formerly obtained from cadaver pituitary glands, and tissue-type plasminogen activator (t-PA), which is a promising new treatment for persons who suffer a heart attack.
Vaccines
Genetic engineering techniques have also been investigated as a means to produce safer new vaccines. The first step is to identify the gene in a disease-causing virus that stimulates protective immunity. That gene is isolated and inserted into a harmless virus, such as vaccinia, the virus used to immunize against smallpox. The recombinant vaccinia virus is used as a vaccine, producing immunity without exposing people to the disease-causing virus. In the case of viruses about which little is known, such as the AIDS virus, this extra margin of safety is crucial.
Recombinant techniques may be useful in making vaccines against organisms for which no vaccines could be made by traditional methods. These include possible vaccines against the tropical parasites that cause schistosomiasis and malaria.
Diagnosis, Therapy, and Research
Genetic engineering is also being used in the prenatal diagnosis of inherited diseases. Restriction enzymes are used to cut apart the DNA of parents who may carry a gene for a congenital disorder, and the DNA pattern of cells from the fetus is compared. In many situations the disease status of the fetus can be determined. Currently this technique is applicable to thalassemias, Huntington's disease, cystic fibrosis, and Duchenne's muscular dystrophy (see Genetic Disorders).
A future medical use of genetic engineering is for gene therapy. Persons who are born with a congenital disorder resulting from a defective gene could have a sound gene inserted into their cells, preventing the manifestations of the disease. The era of gene therapy began on Sept. 14, 1990, when the first therapeutic, genetically engineered cells were infused into a 4-year-old girl with adenosine deaminase (ADA) deficiency, an inherited life-threatening immune deficiency. The infused cells were lymphocytes from the girl's own blood, into which researchers had inserted copies of a missing gene that directs production of ADA. On Jan. 29, 1991, gene therapy was used for the first time to treat cancer, when two patients with advanced skin cancer were infused with their own white blood cells after the cells had been genetically altered to produce a tumor-killing protein. Many obstacles must be overcome to achieve the promise of gene therapy, but its value could be immense.
Genetic engineering has allowed discoveries that could not have been made any other way. One of the most important is the discovery of oncogenes, specific genes that play an important part in causing some cancers. The identification and isolation of oncogenes depended on being able to cut cancer-causing DNA into manageable segments and finding the specific segments that were responsible for transforming normal cells into cancer cells. Discovery of ribozymes--RNA molecules that act like enzymes to cut and splice themselves--gave scientists hope for a new way of destroying the expression of unwanted genes. (RNA, along with DNA, is a carrier of genetic information.)
Agricultural advances are also expected from genetic engineering. Some of the earliest recombinant organisms made were a soil bacterium that was induced to make a toxin against a worm that destroys corn roots, a bacterium engineered to make potato and strawberry crops more frost-resistant, and a tobacco plant bearing a bacterial gene that protects against herbicides. Work on agricultural applications of genetic engineering proceeds slowly because recombinant organisms must be released outdoors in test fields to find whether they work. They cannot be tested only in a contained laboratory. Government regulatory agencies and ecological scientists are wary of the possible adverse consequences of releasing recombinant organisms, particularly fast-reproducing bacteria, into a field plot. No one knows how likely it is that such organisms may escape the field, grow in some situation in which they are not wanted, and cause unexpected effects.
Public debate about the safety of recombinant organisms began in the 1970s. Government bodies were set up to screen proposed experiments and institute safety guidelines. Chief among them was the Recombinant Advisory Committee of the National Institutes of Health. For many years the public was concerned about the safety of laboratory research with recombinant organisms. As research has continued and no safety hazards have become evident, public concern has abated somewhat.
William A. Check
Genetic Research After Mendel
Chromosomes, structures in the cell nucleus that carry genes, were discovered after Mendel's work was published. However, accurate accounts of their behavior were not generally available until about 1885. Earlier the German biologist August Weismann had suggested that heredity depends on a special material called germ plasma that is transmitted unaltered from one generation to another. In the 1880s Weismann and other scientists advanced the idea that the germ plasm was located in the chromosomes. In 1902 Walter S. Sutton of the United States and Theodor Boveri of Germany independently recognized the connection between the segregation of alleles as described by Mendel and the segregation of homologous pairs of chromosomes in the division of sex cells.
In 1910 the American geneticist Thomas H. Morgan and his associates discovered that genes occur on chromosomes and that those genes lying close together on the same chromosome form linkage groups that tend to be inherited together. They also showed that linkage groups often break apart naturally as a result of a phenomenon called crossing over.
In the 1940s George W. Beadle and Edward L. Tatum of the United States began to investigate the role played by genes in the production of enzymes. By 1944 Oswald T. Avery had discovered that deoxyribonucleic acid (DNA) was the basic genetic material of the cell. The precise molecular structure of DNA was determined in 1953 by James D. Watson of the United States and Francis H.C. Crick of England. By 1961 the French geneticists Francois Jacob and Jacques Monod had developed a model for the process by which DNA directs the synthesis of proteins, thereby deciphering, in principle, the genetic code of the DNA molecule. In 1988 an international team of scientists began a project to devise a map of the human genome, all the genes that determine the makeup of a human being.
Since the 1970s the techniques of recombinant DNA have allowed researchers to biologically purify, or clone, a gene from one species by inserting it into the DNA of another species, where it is replicated along with the host DNA. In this manner human hormones, such as insulin and growth hormone, have been manufactured economically by colonies of bacteria.
CHROMOSOMES AND CELL DIVISION
Chromosomes are mainly aggregates of deoxyribonucleic acid (DNA) and protein (see Protein). All but the simplest kinds of plants and animals inherit two sets of chromosomes (the diploid number), one set (the haploid number) from each parent. In humans, each somatic cell has a haploid set of 23 chromosomes from each parent, for a total of 46.
The chromosomes within each set vary in appearance. However, each has a homologous partner in the other set, which resembles it in both appearance and genetic characteristics. A given gene is found on only a particular chromosome in each set. Its allele is on that chromosome's homologue in the other set. The alleles are passed on to new cells during mitosis, the division of somatic cells.
Mitosis takes place as soon as a sperm fertilizes an egg. It continues throughout the life of the organism. Prior to mitosis, the cell chromosomes make exact copies of themselves. At this point, twice the diploid number of chromosomes exist in the cell. As mitosis proceeds, one set of the doubled chromosomes goes into each of the two daughter cells. Each thus acquires a full diploid set of chromosomes. This process is repeated again and again as cells divide and the body grows. Sex cells, however, divide in a different way.
Sex cells in the adult reproductive organs produce gametes by meiosis. This process consists of two divisions. As the first division proceeds, the homologous chromosomes in the nucleus of the sex cell seek each other out and join, or synapse. They are called bivalents at this point.
Then the bivalents duplicate themselves to form a bundle, or tetrad, or four intertwined chromatids. The tetrads then thicken and separate, and a pair of homologous chromatids pass into each of two daughter cells.
Meiosis does not stop at this stage, however. The two daughter cells, still with a diploid number of chromosomes, undergo a second division, the reduction division. In this division, the homologous chromatids do not duplicate themselves but merely separate and pass randomly into two additional cells, where they thicken into chromosomes. In meiosis, each sex cell produces four gametes, each with a haploid number of chromosomes (only one allele is in each gamete). When a male gamete fertilizes an egg, the diploid number of chromosomes is restored.
Chromosomes are fully visible under a microscope during the four stages of cell division--prophase, metaphase, anaphase, and telophase. However, between the telophase and the next prophase a lengthy period called the interphase occurs, during which the chromosomes are too thin and strung out to be seen. Important chemical activities take place during the interphase. Ribonucleic acid (RNA), chemically related to DNA, and proteins are synthesized during the lengthy interphase as well as during the relatively short period of cell division.
Late in the interphase, DNA is synthesized and daughter chromosomes are created. First, DNA is made. Soon afterward, in a burst of activity, chromosomal DNA, RNA, and protein are fitted together, the chromosomes begin to take shape, and cell division begins. During sex cell division, however, an important gene exchange between homologous chromosomes takes place. Linked Nonalleles and Crossing Over
As meiosis takes place, homologous chromosomes exchange some of their genes. This phenomenon is known as crossing over. Although the process is not well understood, it is thought that a reciprocal breakage and rejoining of homologous chromatids occurs while the tetrads are intertwined during early meiosis.
Geneticists began to investigate crossing over when they noted that the traits actually inherited did not always adhere to the principle of independent assortment. Testcrosses between AaBb and aabb parents--A, a, B, and b representing the dominant and recessive genes of nonalleles--did not always produce equal numbers of AaBb, aaBb, Aabb, and aabb progeny but a greater number of the parental types AaBb and aabb and a smaller number of the recombinant types Aabb and aaBb. Geneticists concluded that the dominant nonalleles A and B were linked together on one homologous chromosome and that the recessive nonalleles a and b were linked together on the other. If this linkage were unbreakable, in meiosis the hybrid AaBb would form only AB and ab gametes. In fact, however, Ab and aB gametes were also formed--the frequency varying for different linked nonalleles. It was therefore surmised that an exchange, or crossing over, took place.
Sex Linkage
Linked genes occur on the sex chromosomes as well as on the nonsex chromosomes, or autosomes. In humans, a woman carries two X chromosomes and 44 autosomes in each body cell and one X chromosome and 22 autosomes in each egg. A man carries one X and one Y chromosome and 44 autosomes in each body cell and either an X or a Y chromosome and 22 autosomes in each sperm cell.
Only sons inherit traits carried by genes located on the Y chromosome, because a boy (XY) develops whenever a Y sperm fertilizes an egg. Traits carried on genes located on an X chromosome of the father are transmitted only to daughters (XX).
GENES AND THE GENETIC CODE
Genes, the arbiters of body form and organ function, work with precision. They transmit to each cell a genetic code that determines the cell's purpose. Oncogenes and Antioncogenes
Oncogenes are genes that can instruct cells to behave abnormally. Oncogenes are derived from normal genes that belong to a class of genes known as proto-oncogenes. In their normal state, proto-oncogenes participate in important regulatory functions such as cellular signalling and activation of transcription. At some point during the life of a cell, however, these normal genes may become damaged and assume a dangerous role. A simple point mutation--the substitution of one nucleotide for another in the DNA sequence of a gene--can cause a profound change in the protein product encoded by that gene. For example, the substitution of a guanine for a cytosine nucleotide in the DNA sequence of the ras oncogene on chromosome 11 in humans is frequently found in patients with bladder cancer. The substitution results in a change in the amino acid coded by the gene (see Biochemistry). When the DNA is transcribed, ultimately a different amino acid is produced; in this case, a valine is substituted for a glycine. Because of the different binding properties of valine and glycine, this simple change of a single amino acid radically affects the function of the protein being produced by the gene. This protein normally functions with the cell's growth machinery. The malfunctioning version produced by the above scenario won't "turn off," and the associated cell continues to grow and divide, culminating in cancer.
Tumor suppressor genes, sometimes referred to as antioncogenes, are normal genes that appear to prevent the development of cancer. With advances in molecular biology in the 1980's, scientists noted that cancerous cells contained damaged DNA, and they hypothesized that some mechanism should exist which would attempt to repair the damage. If the repair did not work, they predicted that the cell would die since it would no longer be functional. The process of this self-destruction was confirmed and was named apoptosis. One particular area of research was the role played by a class of proteins known collectively as tumor necrosis factors (TNFs), which are produced by the tumor suppressor genes.
The best studied of the TNFs is the protein produced by the p53 gene, but until 1997 scientists were unclear about the exact mechanism by which this gene conferred protection against cancer. Scientists believed that many cells start down the road to malignancy when their DNA is damaged by mutagens such as toxic chemicals and free radicals, but then are saved from malignancy by the production of a tumor necrosis factor. Because approximately 50 percent of all human cancers involve a defective copy of the p53 gene, researchers hypothesized that the normal gene must have an important role in protecting the cell against malignancy. They found that the p53 gene has two vital jobs to perform. When a toxic chemical or free radical causes damage to the cell's DNA, the p53 proteins signal the cell to stop dividing temporarily while the cell attempts to repair the damage. If the damage is too severe to be repaired, then the p53 protein activates a pathway leading to cellular suicide. However, if the p53 gene itself is damaged, by means of either mutation by free radicals or an inherited defect, then the damaged cell goes on to become cancerous. The normal function of both genes is to produce proteins that help repair breaks in chromosomes, which contain DNA. The importance of this is that when two complementary strands of DNA in a chromosome are broken and go unrepaired, the workings of many genes are disturbed. Although the genes are quite different in size--BRCA2 is much larger than BRCA1--the proteins they produce seem to have very similar functions, and appear closely associated in cells with the product of another gene called Rad51. The product of the Rad51 gene repairs breaks in chromosomes. Cloning in nature. Cloning is commonplace in nature. Plants and animals become master cloners. The fertilized egg from which a human develops, for example, contains DNA (the basic genetic material that is the blueprint of living organisms) from both mother and father. The egg divides into two identical cells, then four, then eight, and so on. These cells are clones and so is the DNA within them, because it, too, is copied into every cell that is produced. In time, the cells begin to differentiate, or become specialized, into skin cells, eye cells, liver cells, and so on. They still are a single clone with respect to their DNA, each cell having the same DNA as the original fertilized egg. But much of the DNA that constitutes many of the genes becomes inactive. The active genes are the only ones needed by each type of specialized cell (skin, eye, liver, and so on) to stay alive and perform its specific functions. Then, as these specialized cells multiply and organize to form their special organs and other structures, even more clones of thousands, indeed millions, of cells are formed. In this rough sense, most living things are mainly groups of cloned cells. As organisms grow, heal after injury that destroys cells, and replace cells that die naturally, organisms clone cells and their DNA for the rest of their lives.
So-called "identical" twins or triplets in humans and other complex life-forms are clones as well, in that they are produced from the same fertilized eggs and are therefore genetically identical. Other life-forms reproduce asexually by duplicating themselves. Such organisms include bacteria, algae, and single-celled animals such as paramecia and amoebas. In these organisms, all offspring of any single individual are clones of the ancestor. Many far more complex, multicellular plants, including strawberries and the popular home aquarium plant called the African sword plant, can reproduce by generating small plants from themselves. One such method involves runners, specialized stemlike structures that sprout young plants that are genetically identical to the plant from which they grow. These young plants develop roots, sink them into the soil, and become self-sustaining. The ancestor plant and all the plants that spring from it via runners make up a clone. In another example, a tumor in which large numbers of cells are produced from an initial cancerous cell is also the result of cloning.
A less common form of natural cloning is regeneration. In regeneration, pieces cut from an organism grow into whole new organisms. Such is the case with some starfish, whose bodies can be cut into several pieces with the result that each piece grows into a complete starfish. Each of these starfish is genetically identical to the others, so they all are clones of the original starfish. FRANKLIN, Rosalind (1920-58). A British biophysicist, Rosalind Franklin is best known for her contributions to the discovery of the molecular structure of deoxyribonucleic acid (DNA). DNA is the chief substance composing chromosomes and genes, the hereditary material. When Francis Crick, James Watson, and Maurice Wilkins were awarded the 1962 Nobel prize for physiology or medicine for determining the structure of the DNA molecule, many scientists believed that Franklin should have been honored with them.
Born in London on July 25, 1920, Rosalind Elsie Franklin won a scholarship to Newnham College, Cambridge. After graduation in 1941 she began research on the physical structure of coals and carbonized coals. Working in Paris from 1947 to 1950, she gained skill in using X-ray diffraction as an analytical technique. (X-ray diffraction is a method of analyzing the crystal structure of materials by passing X rays through them and observing the diffraction, or scattering, image of the rays.) Franklin used this technique to describe the structure of carbons with more precision than had previously been possible. She also determined that there are two distinct classes of carbons--those that form graphite when they are heated to high temperatures and those that do not.
In 1951 Franklin joined the King's College Medical Research Council biophysics unit. With Raymond Gosling she conducted X-ray diffraction studies of the molecular structure of DNA. Based on these studies, she at first concluded that the structure was helical (having spiral arms). Later research caused her to change her mind, and it was left to Watson and Crick to develop the double-helix model of the molecule that proved to be consistent with DNA's known properties. Some of the data used by those scientists in their successful effort, however, was first produced by Franklin.
From 1953 until her death on April 16, 1958, Franklin worked at the crystallography laboratory of Birkbeck College, London. There she published her earlier work on coals and helped determine the structure of the tobacco mosaic virus.
Sept. 28, 1997--The Role of P53 Gene In Cell Suicide
For many years scientists associated the development of cancer with rampant cell division, and treatments were designed accordingly to target and destroy rapidly dividing cells. However, a study published in the journal Nature confirmed what many scientists had already begun to suspect: the turning point in the development of cancer might instead be the failure of damaged cells to die after their DNA has been damaged beyond repair.
With advances in molecular biology in the 1980's, researchers began to study the role played by genes in the development of cancer. The scientists noted that cancerous cells contained damaged DNA, and they hypothesized that some mechanism should exist which would attempt to repair the damage. If the repair did not work, they predicted that the cell would die since it would no longer be functional. The process of this self-destruction was confirmed and was named apoptosis. One particular area of research was the role played by a class of proteins known collectively as tumor necrosis factors. The most famous of these is the protein produced by the p53 gene.
The role of the p53 gene in human cancers has been well documented. Approximately 50 percent of all human cancers involve a defective copy of the gene, but until recently scientists were unclear about exactly how the p53 gene does its job. One theory was that many cells start down the road to malignancy when their DNA is damaged by mutagens such as toxic chemicals and free radicals, but that they are saved from malignancy by the production of one of the proteins known as tumor necrosis factors. Previous studies identified the protein produced by the p53 gene as belonging to this group, and medical researchers at the Johns Hopkins School of Medicine, the authors of the report in Nature, discovered precisely how the protein works.
The Johns Hopkins team used a human colorectal cancer cell line that lacked a functional p53 gene and injected half of the cells with a working p53 gene. Within approximately 24 hours, the cells that had received the p53 gene began to undergo apoptosis, while the control cells did not. Several hours prior to the onset of apoptosis, the researchers examined the RNA in the cells in order to determine what other genes the p53 genes had turned on, or activated. They found that 14 genes had been turned on in the p53-expressing cells compared with the controls. Upon further examination, the scientists found that many of these p53-induced genes, or PIGs, produced proteins that affect cellular oxygen levels, generally by production of reactive oxygen species (ROS). The ROS, in turn, cause significant damage to the cell's DNA, thereby signaling the onset of apoptosis. When specific inhibitors of ROS were added to the cultures, apoptosis was significantly blocked.
The study revealed that the p53 gene has two vital jobs to perform. When a toxic chemical or free radical causes damage to the cell's DNA, the p53 proteins signal the cell to stop dividing temporarily while the cell attempts to repair the damage. If the damage is too severe to be repaired, then the p53 protein activates the pathway leading to cellular suicide via production of ROS. If the p53 gene itself is damaged, by means of either mutation by free radicals or an inherited defect, then the damaged cell goes on to become cancerous.
The discovery of the actual mechanism underlying the association of the p53 gene with malignant cells signaled entry into a new phase of cancer research. Treatments that can reactivate the aborted cellular suicide pathway my means of regulating the action of p53 may have a greater effect on reducing the growth of tumors and possibly eliminating them altogether. Discoveries in Genetics
Biologists continued to advance the genetics principles proposed by Mendel as they explored cell metabolism and reproduction. In 1953 James Watson and Francis Crick discovered that the DNA (deoxyribonucleic acid) molecule is in the shape of a double helix. DNA contains the master code of instructions for protein synthesis in the cell. In the late 1980s scientists discovered a second code that plays a key role in a later step in protein synthesis.
Scientists then discovered how to move a gene from one species and insert it into the DNA of another species, where it is replicated with the host DNA. This discovery, a type of cloning, made it possible to use bacteria to produce some types of human hormones, such as insulin and growth hormone. DNA research allowed scientists to map chromosomes and isolate the causes of some genetic anomalies. Genetic engineering has been applied in medicine, agriculture, and other fields. The first human trials of gene therapy began in 1990. (See also Genetics; Heredity.) Reproduction at the Cell Level
All living systems are ordinarily capable of reproducing themselves. The replication of DNA, however, lies at the heart of all other forms of reproduction. Though cell division might seem the supreme act of replication, enzymes and other proteins are continually replicated at the ribosomes. So, too, are membranes and mitochondria. Hence, replication is going on within a cell whether the cell itself is dividing or not.
When cell division does occur, the parent cell splits into two daughter cells, each of which has the same parts the parent had. In this replication process, the two strands of each DNA molecule separate, and each daughter cell receives a strand. Afterward, the DNA strands that the daughter cells receive act as the templates on which their complementary strands are built. As a consequence, the total genetic package received in part from the parent is reestablished in each daughter cell.
In one-celled organisms cell division is the means of reproduction. In many-celled organisms it is the means whereby the organisms' tissues grow and are maintained. Cell division in higher organisms begins when the cell's nuclear membrane breaks down. Then DNA's paired structures, called chromosomes, line up in the middle of the cell and separate through a series of complex maneuvers. Finally, a cleavage furrow forms, and the cell splits in half, providing each daughter cell with its critical structures. Amid this spectacle, membranes are replicated. Many of the details of replication have yet to be determined. The Nucleus
Near the center of the cell is a roundish or oval-shaped nucleus. The nucleus controls the growth and division of the cell. It also contains the structures that transmit hereditary traits (see Genetics).
Enclosed by a two-layered membrane, the nucleus contains a liquid called nucleoplasm as well as strands of deoxyribonucleic acid (DNA) covered with a coating of protein. A strand of DNA consists of a long series of genes, which are the units of heredity of plants and animals. Genes determine the characteristics of a cell. They do this by regulating the production of RNA, which in turn controls the manufacture of specific proteins.
Human cells, for example, make only proteins unique to human beings. DNA strands are usually too thinly strung out to be seen with an optical microscope. Because the strands are readily stained with dyes, they are called chromatin. When a cell begins to divide, however, the chromatin thickens into the form of chromosomes.
A nucleus not undergoing division has at least one nucleolus. The nucleolus contains a concentration of RNA. Biologists think RNA is made initially in the nucleolus according to a DNA "blueprint" and stored there until needed for protein manufacture.
Near the nucleus of animal cells is a spherical structure called the centrosome, from which asters radiate. The centrosome contains a pair of rodded structures, called centrioles, which usually lie at right angles to each other. Although centrioles and centrosomes have not been seen in plant cells, biologists believe that plant cells contain similar structures. The Genetic Determination of Embryonic Structures
Genetic characteristics are determined by the nucleic acid called deoxyribonucleic acid (DNA), a giant molecule in the cell nucleus composed of two long, twisted chains of nucleotides (see Biochemistry). Each chain is made up of units containing the sugar deoxyribose; phosphoric acid; and a nitrogenous base--adenine (A), thymine (T), cytosine (C), or guanine (G). Only two combinations of these nitrogenous bases can be opposite each other in the nucleotide chains--A with T, C with G. Thus only four kinds of double units can run along the length of a DNA molecule--A-T, T-A, C-G, or G-C. However, the varying sequence of these double units constitutes a "code" that makes possible the transmission of a countless variety of genetic traits.
DNA manufactures the chemically related ribonucleic acid (RNA), a messenger that passes on this genetic information. The messenger RNA moves from the cell nucleus to the ribosomes of the cytoplasm (see Cell). There, it directs the assembly of amino acids, the "building blocks" of proteins (see Protein). The nucleotide code of messenger RNA reflects that of its parental DNA.
Nongenetic Factors
Initially, the nature of a cell is determined by its DNA code. The interaction of cells and of tissues affects their subsequent development. Thus, differentiation seems to depend in part on critical mass, or the existence of a minimum number of cells. Experiments show that embryonic muscle tissue appears only after such a minimum has been reached. It is known also that the interaction of the neighboring parts of an embryo affects their differentiation. The mesoderm along the top portion of an early embryo is closely associated with the overlying ectoderm, from which the brain and spinal cord are normally produced. If the mesoderm is experimentally prevented from assuming its normal position, these structures fail to appear.
Tissue affinity also plays a part in embryonic development. When the cells of various kinds of tissues are separated and a mixture of these cells is prepared, those of a like kind have the remarkable ability to sort themselves out and to reconstitute the original tissues. This demonstrates that tissue construction is aided by the ability of cells to cohere selectively during normal embryogeny.
Finally, embryonic development is influenced by chemical controls. Hormones secreted by such endocrine glands as the pituitary, thyroid, and sex glands affect structural differentiation (see Hormones). A number of vitamins, notably vitamins A and D, also exert developmental control (see Vitamins).
HISTORYDiagnosis, Therapy, and Research
Genetic engineering is also being used in the prenatal diagnosis of inherited diseases. Restriction enzymes are used to cut apart the DNA of parents who may carry a gene for a congenital disorder, and the DNA pattern of cells from the fetus is compared. In many situations the disease status of the fetus can be determined. Currently this technique is applicable to thalassemias, Huntington's disease, cystic fibrosis, and Duchenne's muscular dystrophy (see Genetic Disorders).
A future medical use of genetic engineering is for gene therapy. Persons who are born with a congenital disorder resulting from a defective gene could have a sound gene inserted into their cells, preventing the manifestations of the disease. The era of gene therapy began on Sept. 14, 1990, when the first therapeutic, genetically engineered cells were infused into a 4-year-old girl with adenosine deaminase (ADA) deficiency, an inherited life-threatening immune deficiency. The infused cells were lymphocytes from the girl's own blood, into which researchers had inserted copies of a missing gene that directs production of ADA. On Jan. 29, 1991, gene therapy was used for the first time to treat cancer, when two patients with advanced skin cancer were infused with their own white blood cells after the cells had been genetically altered to produce a tumor-killing protein. Many obstacles must be overcome to achieve the promise of gene therapy, but its value could be immense.
Genetic engineering has allowed discoveries that could not have been made any other way. One of the most important is the discovery of oncogenes, specific genes that play an important part in causing some cancers. The identification and isolation of oncogenes depended on being able to cut cancer-causing DNA into manageable segments and finding the specific segments that were responsible for transforming normal cells into cancer cells. Discovery of ribozymes--RNA molecules that act like enzymes to cut and splice themselves--gave scientists hope for a new way of destroying the expression of unwanted genes. (RNA, along with DNA, is a carrier of genetic information.)
Agricultural advances are also expected from genetic engineering. Some of the earliest recombinant organisms made were a soil bacterium that was induced to make a toxin against a worm that destroys corn roots, a bacterium engineered to make potato and strawberry crops more frost-resistant, and a tobacco plant bearing a bacterial gene that protects against herbicides. Work on agricultural applications of genetic engineering proceeds slowly because recombinant organisms must be released outdoors in test fields to find whether they work. They cannot be tested only in a contained laboratory. Government regulatory agencies and ecological scientists are wary of the possible adverse consequences of releasing recombinant organisms, particularly fast-reproducing bacteria, into a field plot. No one knows how likely it is that such organisms may escape the field, grow in some situation in which they are not wanted, and cause unexpected effects.
Public debate about the safety of recombinant organisms began in the 1970s. Government bodies were set up to screen proposed experiments and institute safety guidelines. Chief among them was the Recombinant Advisory Committee of the National Institutes of Health. For many years the public was concerned about the safety of laboratory research with recombinant organisms. As research has continued and no safety hazards have become evident, public concern has abated somewhat.
William A. Check
HEREDITY. The transmission of biological traits from one generation to the next is governed by the process of heredity. Heredity determines certain specific characteristics of plants and animals. Plants inherit traits that affect their physical and metabolic processes. Animals can inherit behavioral, mental, and physical traits. Some traits characteristic of a plant or animal species are generally inherited no matter who the parents are. Other traits, such as human eye color, are specific to individuals, and their inheritance is directly dependent on the genetics of the parents.
The physical key to heredity lies within the nucleus of the cell in structures known as chromosomes. These chromosomes carry smaller units called genes, which contain the hereditary "code." (See also Cell.) Each species of plant and animal has a particular number of chromosomes, which are carried in pairs within each cell of the body. When a somatic, or body, cell divides in a process known as mitosis, it produces exact duplicates of each chromosome. Thus the newly formed cells, as well as all of the cells in the body, have exactly the same genes.
Sex cells are different from somatic cells because they divide by a process known as meiosis, which consists of two divisions rather than one (see Genetics). The process of meiosis occurs in the sex cells of both males and females and results in the gametes, or germ cells, that are used in fertilization. Each gamete receives one of each chromosome pair from the parent. During fertilization a single male and female gamete unite to form a fertilized egg, or zygote (see Embryology). In this way the infant inherits its parents' genes.
Although the genes for each trait are produced in pairs, the expression of the trait in the organism depends on how the two genes are combined. Some genes are dominant, while others are recessive. The presence of one or two dominant genes results in expression of the dominant trait; for example, the gene for brown eyes in humans is dominant over the gene for blue eyes. For the expression of a recessive trait such as blue eyes, however, two recessive genes, inherited independently from the two parents, are required. The translation of genetic information to biological traits is thus a complex process. Many characteristics are influenced by more than one gene. In addition, many genes exist in numerous variations throughout a population. As a result there is a vast potential for variability among hereditary characteristics.
At the microscopic level, the genetic code ultimately determines the purpose of each cell. The process of heredity, however, can be even more finely dissected. Genes transmit the genetic code biochemically; they are composed of deoxyribonucleic acid, or DNA, a complex molecule capable of duplicating itself exactly. It is DNA that is responsible for the replication and transmission of genetic traits at the biochemical level (see Genetics).
Ideally, humans have 23 pairs of chromosomes. These chromosomes carry thousands of genes that pass on traits to following generations. Among the common inherited physical traits are straight or curly hair, color blindness, attached or unattached earlobes, and blood type. Mental traits, including some forms of schizophrenia, can also be inherited.
Most physical and mental traits are the products of many different genes operating in different ways on various metabolic pathways. Skin color, for example, is controlled by several genes--this is why there is so much variation in skin color not only between different races but also between persons of the same race. Likewise, though a person's intelligence may be hereditarily influenced by the intelligence of the parents, individual intelligence is ultimately the product of a wide variety of genetic combinations and environmental influences.
Heredity is also responsible for many human diseases and disorders. Sometimes a single defective gene can be the cause of the problem, as it is in muscular dystrophy, a widespread disorder characterized by degeneration of the muscles. Likewise phenylketonuria, a metabolic disorder, and sickle-cell anemia, a blood disorder, result from disorders of single genes. (See also Genetic Disorders.)
The History of Heredity Theory
An understanding of the basic process of heredity has been achieved only within the last century. Early theories were clouded by superstition. Ancient Greeks believed that blood was responsible for transmitting traits from one generation to the next. The expression bloodline, referring to particular lineage, stems from this ancient theory.
During the 18th century there were two prominent theories of heredity: ovist and preformationist views. Ovists believed that all traits were carried in the ovaries of the female, and that the male's sperm functioned only to stimulate embryonic development. As a result the mother was held responsible when she did not bear a male child. Preformationists believed that the male's sperm carried tiny, fully developed replicas of the infant and that the female's egg simply provided nourishment for the child before birth.
A theory widely held until the late 19th century was that hereditary traits resulted from a mixing of parental characteristics. Thus a short woman and tall man should have children of medium height. Another theory, now known to be false, was proposed in the 1800s by the French biologist Jean-Baptiste Lamarck. He suggested that animals acquired traits and passed them on to their offspring. Thus he presumed that giraffes were born with long necks because their parents were constantly stretching their own necks to feed from tall trees.
Modern genetic and heredity theory had its beginnings in 1866, when Gregor Mendel, an Austrian monk, published the results of his crossbreeding experiments with pea plants. He produced plants that were either tall or short, with flowers that were either red or white. From his experiments, Mendel concluded that certain hereditary factors--now called genes--were present in the sex cells of both male and female plants. He reasoned that the combination of these factors in the two sex cells resulted in the traits expressed in the offspring. From his studies, Mendel derived certain basic laws of heredity: hereditary factors do not mix but remain segregated; some factors are dominant, while others are recessive; each member of the parental generation transmits only half of its hereditary factors to each offspring; and different offspring of the same parents receive different sets of hereditary factors. Mendel's work became the foundation for modern genetics.
The infant science of genetics flowered rapidly. By 1902 Walter Sutton of the United States had proposed that chromosomes were the site of Mendel's hereditary factors. In 1910 the American geneticist Thomas Hunt Morgan began his studies of the fruit fly, Drosophila melanogaster. Morgan provided evidence not only that genes occur on chromosomes, but also that those genes lying close together on the same chromosome form linkage groups that tend to be inherited together. He further showed that linkage groups often break apart naturally as a result of a phenomenon called crossing over.
During the mid-1900s great advances were made in the understanding of the exact structure and working of genes and DNA, including the deduction of the molecular structure of DNA in 1953 by James Watson and Francis Crick. These developments led to the deciphering of the genetic code of the DNA molecule, which in turn made possible the recombinant DNA techniques that hold immense potential for genetic engineering (see Genetic Engineering).
Early in the history of genetic study, there arose a heated debate that is often termed the heredity-environment, or nature-nurture, controversy, a concern among biologists and sociologists regarding the relative roles of heredity versus physical and social surroundings in the total development of an individual. Today it is generally conceded that the genetic background allows certain ranges of expression on which the environment acts to produce individual modification. For example, a trait that is primarily hereditary--skin color in humans--may be modified by environmental influences--suntanning. And conversely, a trait sensitive to environmental modifications--weight in humans--is also genetically conditioned. Thus the development of a trait may be manipulated by environmental changes, and in different environments the carriers of similar genetic traits may develop and behave in different ways.
The most powerful force for changing the number of particular genes within a given population, called gene frequency, is the force of natural selection, first hypothesized by Charles Darwin in the 1800s (see Darwin, Charles). Darwin observed that organisms with harmful physical or behavioral variations were more likely to die before they could bear young than those with useful variations. In the language of genetics and heredity, the carriers of some genes may survive more often or be more prolific than the carriers of other genes. Thus certain genes are more efficiently transmitted to succeeding generations than other genes, and the "inferior" genes become less frequent with each successive generation.
When such inequality of the transmission rates of genes is imposed by human will, the result is artificial selection, widely practiced in animal husbandry and agriculture. One of its most impressive successes to date is represented by hybrid corn, which is planted by farmers in order to increase their corn yields. Hybrid corn is the result of artificially crossing inbred corn strains. The hybrid assumes the superior traits of the inbred strains and is more vigorous and productive than the original strains alone.
Modern genetic and heredity studies cover a broad spectrum of phenomena. They include population genetics, the study of genetic patterns within populations; classical genetics, how traits are transmitted and expressed; microbial genetics, the heredity of microorganisms; and molecular genetics, the molecular study of genes and related structures. Knowledge gained from these studies has been applied to the diagnosis, prevention, and treatment of hereditary diseases; to the breeding of plants and animals; and to the development of industrial processes that use microorganisms.
J. Whitfield Gibbons
DNA. Deoxyribonucleic acid, a molecule that holds the genetic information needed for heredity. RNA. Ribonucleic acid, the complement to DNA, which transcribes DNA's genetic instructions for the manufacture of proteins. The subcellular and cellular level. Subcellular and cellular biophysics consider how molecules are organized into special cell structures and how these structures perform their specialized functions. For example, the cell chromosomes that pass on genetic information contain DNA. The DNA molecule bears the genetic code that determines the shape and tasks of future cells. Thus, knowledge of the way DNA is synthesized has had important effects on biophysical research. (See also Cell.) Chromosome, microscopic, threadlike part of the cell that carries hereditary information in the form of genes; among simple organisms, such as bacteria and cyanobacteria (formerly called blue-green algae), chromosomes consist entirely of DNA and are not enclosed within a membrane; among all other organisms chromosomes are contained in a membrane-bound cell nucleus and consist of both DNA and RNA; arrangement of components in the DNA molecules determines the genetic information; every species has a characteristic number of chromosomes, called the chromosome number; in species that reproduce asexually the chromosome number is the same in all the cells of the organism; among sexually reproducing organisms, each cell except the sex cell contains a pair of each chromosome For many years, scientists believed that Neanderthals were the direct ancestors of modern humans. However, in 1997, a landmark study of DNA extracted from the 1856 fossil produced strong evidence to suggest that this was not the case. The scientists compared the DNA sequence of a region of the fossil mitochondrial genome with the sequence of a comparable region in the mitochondrial DNA of modern humans. The results indicated a threefold difference between the sequences of modern humans and Neanderthals. Furthermore, the type of differences, as well as their locations in the sequences, suggest it is highly unlikely that Neanderthals contributed to the modern human mitochondrial gene pool. The scientists further calculated that, while Neanderthals and modern humans did indeed share a common ancestor, the two lineages diverged between 550,000 and 690,000 years ago; the first known Neanderthal is placed at approximately 300,000 years ago, while the first modern humans are believed to have evolved around 200,000 years ago.
After the brain-body ratio reached its modern proportions, relative brain size stabilized in all human populations and has remained the same ever since. It is clear that major behavioral changes are indicated by the archaeological record. For the first time, there is evidence for regional differentiation in the style of making stone tools. At first, the areas of shared stylistic similarities are relatively large: all of Western Europe, for example. Subsequently, these regionally restricted areas of shared style elements become smaller and more clearly defined. Although the implications cannot be proven, it may be significant that the regions within which shared styles were maintained are strikingly similar in extent to what are separate language areas for human populations today.
This is probably as close as researchers shall ever get to obtaining evidence for the origin of language as we know it. With language, the innovations of the brightest members of a group can be transmitted to all other members. In the early 1970s genetic researchers discovered recombinant DNA. Scientists found that DNA could be removed from living cells and spliced together in any combination. They were able to alter the genetic code dictating the entire structure and function of cells, tissues, and organs (see Genetic Engineering). Polymerase chain reaction, technique used in molecular biology that allows scientists to isolate, characterize, and produce large quantities of specific pieces of DNA from very small amounts of starting material; specific piece of DNA is repeatedly copied, resulting in enormous amplification of starting material that would otherwise be undetectable; technique first widely publicized in 1985 by team of researchers led by Kary B. Mullis of Cetus Corp. in Emeryville, Calif.; practical applications revolutionized biology; by 1990 applied to prenatal and postnatal diagnosis of genetic diseases, infectious diseases (such as AIDS), and cancer; aids in matching transplant recipients with donors; aids Human Genome Project; tool for studying human genetic history and evolution of species; helps aid forensic scientists with DNA fingerprinting. see also Human Genome Project The Cell and Its Membranes
To understand cell activities one must know about membranes and their functions. A cell is surrounded by a continuous membrane. It walls the cell's interior from the outer environment. The life processes go on inside the cytoplasm, or cell interior. The cell interior contains tiny organelles with membranes. These organelles include the mitochondrion (plural, mitochondria), the chloroplast (in plants only), the endoplasmic reticulum, and the nucleus.
All the membranes of a cell are so thin that their width can be seen only under the extremely high magnification of the electron microscope (see Microscope). A membrane is constructed from two types of molecules--proteins and phospholipids. They nest together to form the membrane. Both types of molecules have two surfaces. One surface, the hydrophilic one, "loves" water. The other surface, the hydrophobic one, "hates" water but likes oil. Membrane proteins and phospholipids are arranged in paired tiers, with protein tiers alternating with phospholipid tiers. Since water is a major component of the cytoplasm and also of the outside environment, the fashion in which protein and phospholipid surfaces react to water forms the unique basis of membranes. Arranged in paired tiers, the membrane molecules expose their water-loving surfaces to the water both inside and outside the cell. By contrast, their water-hating, oil-loving surfaces avoid the water by lining up opposite each other at the middle of the membrane. This tightly organized molecular arrangement is so stable that it tenaciously resists disruption. Even when disrupted by strong forces, it tries to reseal any momentary holes to keep a continuous surface. Only membrane proteins, however, are designed for membrane service. Ordinary proteins having only water-loving surfaces cannot be used in membranes.
Each of the cell's organelles has its own distinctive membrane containing specific types of proteins and phospholipids. The specificity of membranes is possible because they can contain an endless variety of water-loving and oil-loving components as long as their bimodal character is kept.
What does a membrane do? One of its functions is to serve as a container. Another is to act as a barrier for preventing molecules from moving into and out of a cell at random. A membrane does this by providing molecular "turnstiles" that regulate which molecules can enter and which cannot. Still another function is fulfilled by a membrane: it houses some of the cell's enzymes as well as its energy-converting "machines." The membrane enzymes, which are special proteins themselves, carry out respiration needed for energy production, active transport of materials across mem- branes, metabolic cycles essential for life, and many molecule-building activities (see Biophysics; Enzymes).
Enzymes can be easily assembled on membranes. This feature pays enormous dividends to a cell because its vital biochemical reactions are facilitated by these important proteins. The manner in which protein molecules pair together in the double-tier arrangement of membranes is akin to the way in which complementary strands of deoxyribonucleic acid (DNA) pair. Since DNA, the important molecule of heredity, directs the assembly of enzymes and other proteins by complementarily matching certain chemical groups, it is clear why complementarity plays such a major role in cellular activities. Cancer is believed to begin with one wildly multiplying cell in a given tissue. The process so resembles the action of cells in an embryo as they divide and shape the body that scientists think that cancer is tied in with the basic chemistry of the cell. After the embryonic cells have performed their tasks, certain chemical repressors lock up portions of DNA in genes in the cell nucleus.
These repressed pieces of DNA no longer trigger the biochemical reactions associated with rapid embryonic cell division. Thus, the seeds of cancer might be in everyone's body. Then, at some time in the future, an event such as virus infection, radiation intake, inhalation of a carcinogen, or cancer-causing chemical, or an imbalance of hormones might free the genes and permit a mature body cell to revert back to an embryoniclike cell. One theory even holds that the gene-bearing chromosomes of normal cells have certain sections capable of making viruslike particles. These particles could then infect neighboring cells and make them produce more particles, until many cells were proliferating wildly.
Cancer cells produce antigens against which the body reacts with antibodies. Small pockets of cancer cells, called silent cancers, might constantly be springing up in a person's body, only to be destroyed by the body's immunity system before they could do any harm. If the antibodies are ineffective, however, the cell mass grows to the size of a pinhead. Unless it gets enough blood, the pinhead mass will not get bigger. However, such tumors can give off a substance called tumor angiogenesis factor, which "fertilizes" rapid growth of tiny blood vessels into the tumor. Then, it starts growing again because it has an ample supply of food from the blood. When it grows large enough to interfere with a vital body activity, the sufferer dies. Currently, much attention is being focused on the macromolecules that control genetic inheritance, such as deoxyribonucleic acid, or DNA, and its "messenger," ribonucleic acid, or RNA (see Genetics). DNA and RNA are polymers, chains of four basic molecules, known as nucleotides, which are linked together by covalent bonds. Genetic engineers can selectively break and re-form these bonds, altering the genetic code at will (see Genetic Engineering). Clone, process of biologically purifying a gene from one species by inserting it into the DNA of another species where it is replicated along with the host DNA;in 1993 researchers in the U.S. experimentally cloned a human embryo in order to develop new ways of treating human infertility; the experiment, however, raised vehement outcries from the public claiming that technology had gone too far by trying to alter basic human genetic makeup; technique is also used to manufacture insulin Nucleic acid, any of substances comprising genetic material of living cells; divided into two classes: RNA (ribonucleic acid) and DNA (deoxyribonucleic acid); directs protein synthesis and is vehicle for transmission of genetic information from parent to offspring. see also DNA; RNA April 23--Advance Announced in Breast Cancer Research
A further step in helping women with a hereditary risk of breast cancer took place with the apparent determination of the normal functioning of two genes--BRCA1 and BRCA2--that are known to increase the risk of breast cancer when the genes are malfunctioning.
Breast cancer is likely to occur if both copies (one from each parent) of either gene have been damaged or lost, or if they have mutated, so that they either function in a faulty manner or not at all. There is also an increased risk of ovarian cancer associated with the genes when they are malfunctioning. If one copy of the gene is normal, the risks of breast and ovarian cancer are lower.
Two different research teams found that the normal function of both genes is to produce proteins that help repair breaks in chromosomes, which contain DNA. The importance of this is that when two complementary strands of DNA in a chromosome are broken and go unrepaired, the workings of many genes are disturbed.
The discovery of the genes--BRCA1 in 1994 and BRCA2 in 1995--was the first significant achievement in determining why breast cancer is likely to occur in some families. Such occurrence within families accounts for between 5 percent and 10 percent of all breast cancers. Since the discovery of the genes, a number of women who have first-degree relatives--that is, mothers, aunts, or sisters--who have developed breast cancer have undergone testing to see if they, too, carry faulty versions of one of the genes. If they do, their lifetime risk of developing breast cancer is quite high: 85 percent or more for breast cancer. Such women must have frequent mammograms and physical examinations to detect the earliest signs of breast cancer. Some even elect to have their breasts removed before any sign of cancer has appeared.
But lack of knowledge of why faulty versions of these genes impart a tendency toward breast cancer had hampered further progress in helping such women. When the genes were first discovered, their normal function was not known. This is common upon the discovery of a gene whose altered version confers a high risk for developing a specific disease. The lack of knowledge about normal functioning impedes progress toward finding a treatment for the disease because it is not clear what physiological function should be restored to the patient, or what abnormal protein in the body might need to be eliminated. If the enemy is unknown, developing protection is difficult.
After the normal functioning of the genes was determined, the road toward progress in hereditary breast cancer became more open. Although the genes are quite different--BRCA2 is very large, for example--the proteins they produce seem to have very similar functions. The first finding came in January 1997, when scientists at the Dana-Farber Cancer Institute in Boston, Mass., reported that the protein product of BRCA1 is closely associated in cells with the product of another gene called Rad51. The product of the Rad51 gene was known to be able to repair breaks in chromosomes.
Then, in the April 23, 1997, issue of the journal Nature, a second team, from Baylor College of Medicine in Houston, Tex., reported that the product of the BRCA2 gene also is closely associated with the product of the Rad51gene. This team did its research using mice, which carry many genes that are homologous to human genes, such as BRCA2. The group worked with special mice in which the BRCA2-like gene had simply been knocked out of commission, so the researchers could see what happened to the mice as a consequence.
Richard Klausner, director of the National Cancer Institute in Bethesda, Md., said that the new findings were highly significant and suggested new approaches to therapy for inherited breast cancer. The remaining 11 so-called non-essential amino acids are synthesized in the human body by a reaction called transamination. In this process, the organic chemical deoxyribonucleic acid (DNA) normally involved in hereditary processes directs the placement of amino acids in a specific sequence to form a molecule of protein. Amino acids are joined by special bonds to yield such proteins as keratin (the principal component of hair), egg albumin (present in egg whites), casein (a major milk protein), enzymes, venoms, hormones, and other molecules of special biological activity. Most of the common proteins contain more than 100 amino acids. For example, hemoglobin, the oxygen-carrying component of blood, is made of 287 amino acids arranged into four chains.
. DNA is designed for the storage of genetic information, phospholipids for use in membranes, and ATP for the storage of usable energy. Enzymes catalyze the synthesis of DNA, RNA, phospholipids, sugars, polysaccharides (long-chained sugars such as plant starch and animal glycogen), fatty acids, and proteins, among others. They also catalyze all the metabolic cycles of organisms. The Krebs cycle is an example of a metabolic cycle. ATP--The Power Molecule
All living systems need energy in a usable form to drive the vital activities of cells. Nature has selected ATP as the cellular storehouse of chemical energy. ATP is a nucleotide made up of adenine (one of the amino acids in DNA and RNA), ribose (the sugar in RNA), and three interlinked phosphate groups (see Phosphorus). The two so-called high-energy bonds that link the phosphate groups together are the key power sources of ATP. When those bonds are broken, a considerable amount of energy is freed. By the same token, when the bonds are reestablished, a considerable amount of energy is stored in ATP. An inorganic phosphate group is usually symbolized Pi. CANCER. Of all the words in the English language, probably no other inspires as much dread as the word cancer. Although commonly thought of and conveniently referred to as a single disease, cancer is not just one disease. It is a group of more than 100 diseases caused by abnormal cells that cannot be repaired, and thus grow and spread uncontrollably. Cancer can occur in any part of an animal or plant where cells grow and divide.
Most normal human cells constantly reproduce themselves by a process called cell division. This continues at a relatively rapid pace until adulthood, when the process slows down and cells reproduce mainly to heal wounds and replace cells that have died. A cancerous cell, however, grows and divides endlessly, crowding out nearby healthy cells and eventually spreading to other parts of the body (see Cell). Precisely why this happens is not clear, though several hypotheses have resulted in intense research. For many years scientists associated the development of cancer with rampant cell division, and treatments were designed accordingly to target and destroy rapidly dividing cells. However, many scientists suspect that the turning point in the development of cancer might instead be the failure of damaged cells to die after their DNA has been damaged beyond repair. One-Celled and Many-Celled Plants and Animals
Bacteria are microscopic specks of cytoplasm surrounded by a tough cell wall. Spherical or dumbbell-shaped nuclei containing DNA have been found in the cytoplasm of some bacteria. The cytoplasm of bacteria also contains grains of stored food, vacuoles, and ribosomes. Many types of bacteria live as parasites on higher organisms. . Biochemistry and biophysics, for example, have achieved remarkable results in analyzing and synthesizing DNA and RNA, which are responsible for the mechanisms of heredity and protein synthesis--for life itself. Biochemists have also been able to manufacture biological materials such as hormones using microorganisms as small chemical factories through the techniques of genetic engineering. Nongenetic Factors
Initially, the nature of a cell is determined by its DNA code. The interaction of cells and of tissues affects their subsequent development. Thus, differentiation seems to depend in part on critical mass, or the existence of a minimum number of cells. Experiments show that embryonic muscle tissue appears only after such a minimum has been reached. It is known also that the interaction of the neighboring parts of an embryo affects their differentiation. The mesoderm along the top portion of an early embryo is closely associated with the overlying ectoderm, from which the brain and spinal cord are normally produced. If the mesoderm is experimentally prevented from assuming its normal position, these structures fail to appear. The Genetic Determination of Embryonic Structures
Genetic characteristics are determined by the nucleic acid called deoxyribonucleic acid (DNA), a giant molecule in the cell nucleus composed of two long, twisted chains of nucleotides (see Biochemistry). Each chain is made up of units containing the sugar deoxyribose; phosphoric acid; and a nitrogenous base--adenine (A), thymine (T), cytosine (C), or guanine (G). Only two combinations of these nitrogenous bases can be opposite each other in the nucleotide chains--A with T, C with G. Thus only four kinds of double units can run along the length of a DNA molecule--A-T, T-A, C-G, or G-C. However, the varying sequence of these double units constitutes a "code" that makes possible the transmission of a countless variety of genetic traits.
DNA manufactures the chemically related ribonucleic acid (RNA), a messenger that passes on this genetic information. The messenger RNA moves from the cell nucleus to the ribosomes of the cytoplasm (see Cell). There, it directs the assembly of amino acids, the "building blocks" of proteins (see Protein). The nucleotide code of messenger RNA reflects that of its parental DNA. Recombinant DNA methods have led to recent advances in the manufacture of such proteins as insulin and HGH. (See also The plague genes that confer drug resistance are located on a circular, extrachromosomal piece of DNA called a plasmid, which is easily transferred to other bacteria during conjugation, a form of mating in some bacteria. The ease with which the plasmid transfers to other strains of the bacteria in the laboratory is alarming. Of even greater concern to scientists and public health officials is the likelihood that this easy transfer of drug resistance could occur among the bacteria in their natural environment. Medicine or physiology prize. Controversy also surrounded the awarding of the prize in medicine or physiology to Prusiner, whose much-contested work focused on the link between several neurological disorders and infectious proteins. In 1982 Prusiner first introduced the theory that would eventually garner him the Nobel prize when he suggested that certain types of infectious proteins, which the scientist labeled proteinacious infectious particles, or prions, were responsible for causing such neurological ailments as Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and Alzheimer's disease. Scientists had generally assumed that diseases were caused only by infectious agents containing genetic material--either DNA or RNA--and not by such substances as proteins. While several scientists continued to doubt that prions alone caused the mental diseases in question, Prusiner's theory of the infectious capability of prions gained enough support over the years to be accepted by much of the scientific community. Polymers make up many of the materials in living organisms. Proteins are polymers of amino acids, cellulose is a polymer of sugar molecules, and nucleic acids such as deoxyribonucleic acid (DNA) are polymers of nucleotides. Many synthetic materials, including nylon, paper, plastics, and rubbers, are also polymers. Unlike viruses, bacteria, and other conventional types of infection-causing microbes, prions have no RNA or DNA, which formerly were thought to be necessary for any infectious agent to multiply within host cells. Furthermore, although most proteins within cells are easily broken down, prions resist breakdown by means of enzymes--one reason these "rogue" disease agents are able to propagate so relentlessly. Organisms can create likenesses of themselves because they possess genes, the basic units that transmit a species' characteristics to the next generation. Genes, composed of deoxyribonucleic acid (DNA), are arranged on strands of chromosomes. Each chromosome of each species has a definite number and sequence of genes that govern the structure and function of the entire organism. Structure and Composition
Viruses are exceedingly small; they range in size from about 0.02 to 0.25 micron in diameter (1 micron 0.000039 inch). By contrast, the smallest bacteria are about 0.4 micron in size. As observed with an electron microscope, some viruses are rod-shaped, others are roughly spherical, and still others have complex shapes consisting of a multisided "head" and a cylindrical "tail." A virus consists of a core of nucleic acid surrounded by a protein coat called a capsid; some viruses also have an outer envelope composed of fatty materials and proteins. The nucleic-acid core is the essential part of the virus--it carries the virus's genes. The core consists of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), substances that are essential to the transmission of hereditary information (see Genetics, "Genes and the Genetic Code"). The protein capsid protects the nucleic acid and may contain molecules that enable the virus to enter the host cell--that is, the living cell infected by the virus. Adenine, a purine base that codes hereditary information in the genetic code in DNA and RNA Cytosine, pyrimidine base that codes genetic information in DNA or RNA Jumping gene (or transposon), in biology, a segment of bacterial DNA capable of transferring its genetic properties from one bacterium to another, or from one site in a cell to another site.
Paternity testing, legal use of blood tests to help decide if a particular man fathered a particular child; blood samples are taken from child, man, and sometimes child's mother; blood samples are examined and compared for presence of genetically determined substances, such as proteins that determine blood type, blood antigens, short lengths of DNA; if man's blood does not display similarities he can be excluded from paternity; genetic fingerprinting makes it possible to exclude false results almost 100 percent of the time. Wilson, Allan Charles (1934-91), New Zealand-born U.S. biochemist. Wilson used innovative molecular techniques to set forth two important evolutionist theories while serving as professor of biochemistry and molecular biology at the University of California at Berkeley, where he taught from 1964 to 1991.
Allan Charles Wilson was born on Oct. 18, 1934, in Ngaruawahia, N.Z. His first work, conducted during the 1960s with Berkeley colleague Vincent Sarich, relied on a "molecular clock" that could be used to trace human origins. The idea of a molecular clock stemmed from the assumption that a given gene (and its protein product) from a species of organism acquires mutations at a reasonably steady rate over time. Consequently, the number of mutations by which the corresponding genes from two species differ can be used to estimate how long ago the species diverged from a common ancestor. The two scientists proposed that humans and apes evolved from different lineages that split off from one another five million years ago. Wilson used mitochondrial DNA comparisons of different living human populations to estimate the source and time of origin of modern humans. He concluded that modern human populations originated in Africa approximately 100,000 to 200,000 years ago and then spread over the Earth, displacing other hominid species in the process. He also hypothesized in 1987 the existence of an "African Eve," a single female who served as the ancestral mother to all modern humans. Wilson died on July 21, 1991, in Seattle, Wash.