PHOTOSYNTHESIS---
Photosynthesis (photo=light, synthesis=putting together), generally, is the synthesis of triose phospates (and ultimately starch, glucose and other products) from sunlight, carbon dioxide and water. Oxygen is also produced, as a result of splitting water. It is arguably the most important biochemical pathway known; nearly all life depends on it. It is an extremely complex process consisting of many coordinated biochemical reactions. It occurs in higher plants, phytoplankton, algae, some bacteria, and some protists, organisms collectively referred to as photoautotrophs.
Photosynthesis uses light energy and carbon dioxide to make triose phospates (G3P). G3P is generally considered the prime end-product of photosynthesis. It can be used as an immediate food nutrient, or combined and rearranged to form monosaccharide sugars, such as glucose, which can be transported to other cells, or packaged for storage as insoluble polysaccharides such as starch.
A general equation for photosynthesis is:
6 CO2(gas) + 12 H2O(liquid) + photons → C6H12O6(aqueous) + 6 O2(gas) + 6 H2O(liquid)
carbon dioxide + water + light energy → glucose + oxygen + water
The equation is often presented in introductory chemistry texts in simplified form as:[1]
6 CO2(gas) + 6 H2O(liquid) + photons → C6H12O6(aqueous) + 6 O2(gas)
Photosynthesis occurs in two stages. In the first phase light-dependent reactions or photosynthetic reactions (also called the Light reactions) capture the energy of light and use it to make high-energy molecules. During the second phase, the light-independent reactions (also called the Calvin-Benson Cycle, and formerly known as the Dark Reactions) use the high-energy molecules to capture carbon dioxide (CO2) and make the precursors of carbohydrates.
In the light reactions one molecule of the pigment chlorophyll absorbs one photon and loses one electron. This electron excites pheophytin allowing the start of a flow of electrons down an electron transport chain that leads to the ultimate reduction of NADP into NADPH. In addition, it serves to create a proton gradient across the chloroplast membrane; its dissipation is used by ATP Synthase for the concomitant synthesis of ATP. The chlorophyll molecule regains the lost electron by taking one from a water molecule through a process called photolysis, that releases oxygen gas as a waste product.
In the Light-independent or dark reactions the enzyme RuBisCO captures CO2 from the atmosphere and in a process that requires the newly formed NADPH, called the Calvin-Benson cycle releases three-carbon sugars which are later combined to form sucrose and starch.
Photosynthesis may simply be defined as the conversion of light energy into chemical energy by living organisms. It is affected by its surroundings and the rate of photosynthesis is affected by the concentration of carbon dioxide, the intensity of light, and the temperature
Most plants are photoautotrophs, which means that they are able to synthesize food directly from inorganic compounds using light energy - for example from the sun, instead of eating other organisms or relying on nutrients derived from them. This is distinct from chemoautotrophs that do not depend on light energy, but use energy from inorganic compounds.
6 CO2 + 12 H2O → C6H12O6 + 6 O2 + 6 H20
The energy for photosynthesis ultimately comes from absorbed photons and involves a reducing agent, which is water in the case of plants, releasing oxygen as a waste product. The light energy is converted to chemical energy (known as light-dependent reactions), in the form of ATP and NADPH, which are used for synthetic reactions in photoautotrophs. The overall equation for the light-dependent reactions under the conditions of non-cyclic electron flow in green plants is:
2 H2O + 2 NADP+ + 2 ADP + 2 Pi + light → 2 NADPH + 2 H+ + 2 ATP + O2 [2]
Most notably, plants use the chemical energy to fix carbon dioxide into carbohydrates and other organic compounds through light-independent reactions. The overall equation for carbon fixation (sometimes referred to as carbon reduction) in green plants is:
3 CO2 + 9 ATP + 6 NADPH + 6 H+ → C3H6O3-phosphate + 9 ADP + 8 Pi + 6 NADP+ + 3 H2O [2]
More specifically, carbon fixation produces an intermediate product, which is then converted to the final carbohydrate products. The carbon skeletons produced by photosynthesis are then variously used to form other organic compounds, such as the building material cellulose, as precursors for lipid and amino acid biosynthesis or as a fuel in cellular respiration. The latter not only occurs in plants, but also in animals when the energy from plants get passed through a food chain. Organisms dependent on photosynthetic and chemosynthetic organisms are called heterotrophs. In general outline, cellular respiration is the opposite of photosynthesis: glucose and other compounds are oxidised to produce carbon dioxide, water, and chemical energy. However, both processes take place through a different sequence of chemical reactions and in different cellular compartments.
Plants absorb light primarily using the pigment chlorophyll, which is the reason that most plants have a green color. The function of chlorophyll is often supported by other accessory pigments such as carotenes and xanthophylls. Both chlorophyll and accessory pigments are contained in organelles (compartments within the cell) called Chloroplasts. Although all cells in the green parts of a plant have chloroplasts, most of the energy is captured in the leaves. The cells in the interior tissues of a leaf, called the mesophyll, can contain between 450,000 and 800,000 chloroplasts for every square millimeter of leaf. The surface of the leaf is uniformly coated with a water-resistant waxy cuticle that protects the leaf from excessive evaporation of water and decreases the absorption of ultraviolet or blue light to reduce heating. The transparent epidermis layer allows light to pass through to the palisade mesophyll cells where most of the photosynthesis takes place.
Plants use up to 90% of the light that strikes them, whereas commercial solar panels use less than 30%. This is achieved by groups of chlorophyll molecules spending a long time in a superposition of states.
Algae comes in multiple forms from multicellular organisms like kelp, to microscopic, single-celled organisms. Although they are not as complex as land plants, photosynthesis takes place biochemically the same way. Very much like plants, algae have chloroplasts and chlorophyll, but various accessory pigments are present in some algae such as phycocyanin, carotenes and xanthophylls in green algae and phycoerythrin in red algae (rhodophytes), resulting in a wide variety of colors. All algae produce oxygen, and many are autotrophic. However, some are heterotrophic, relying on materials produced by other organisms. For example, in coral reefs, there is a symbiotic relationship between zooxanthellae and the coral polyps.
Photosynthetic bacteria do not have chloroplasts (or any membrane-bound organelles). Instead, photosynthesis takes place directly within the cell. Cyanobacteria contain thylakoid membranes very similar to those in chloroplasts and are the only prokaryotes that perform oxygen-generating photosynthesis. In fact chloroplasts are now considered to have evolved from an endosymbiotic bacterium, which was also an ancestor of and later gave rise to cyanobacterium. The other photosynthetic bacteria have a variety of different pigments, called bacteriochlorophylls, and do not produce oxygen. Some bacteria, such as Chromatium, oxidize hydrogen sulfide instead of water for photosynthesis, producing sulfur as waste.
The ability to convert light energy to chemical energy confers a significant evolutionary advantage to living organisms. Early photosynthetic systems, such as those from green and purple sulfur and green and purple non-sulfur bacteria, are thought to have been anoxygenic, using various molecules as electron donors. Green and purple sulfur bacteria are thought to have used hydrogen and sulfur as an electron donor. Green nonsulfur bacteria used various amino and other organic acids. Purple nonsulfur bacteria used a variety of non-specific organic molecules. The use of these molecules is consistent with the geological evidence that the atmosphere was highly reduced at that time.[citation needed]
Fossils have been found of what are thought to be filamentous photosynthetic organisms dating from 3.4 billion years ago (New Scientist, 19 Aug., 2006).
The oxygen in the atmosphere today exists due to the evolution of oxygenic photosynthesis, sometimes referred to as the oxygen catastrophe. Geological evidence suggests that oxygenic photosynthesis, such as that in cyanobacteria, became important during the Paleoproterozoic era around 2 billion years ago. Modern photosynthesis in plants and most photosynthetic prokaryotes is oxygenic. Oxygenic photosynthesis uses water as an electron donor which is oxidized into molecular oxygen by the absorption of a photon by the photosynthetic reaction centre
In plants the process of photosynthesis is compartmentalized in organelles called chloroplasts. Chloroplasts have many similarities with photosynthetic bacteria including a circular chromosome, prokaryotic-type ribosomes, and similar proteins in the photosynthetic reaction centre.
The endosymbiotic theory suggests that photosynthetic bacteria were acquired (by endocytosis or fusion) by early eukaryotic cells to form the first plant cells. In other words, chloroplasts may simply be primitive photosynthetic bacteria adapted to life inside plant cells, while plants themselves have not actually evolved photosynthetic processes on their own. Another example of this can be found in complex animals, including humans, whose cells depend upon mitochondria as their energy source; mitochondria are thought to have evolved from endosymbiotic bacteria, related to modern rickettsia bacteria. Both chloroplasts and mitochondria actually have their own DNA, separate from the nuclear DNA of their animal or plant host cells.
This contention is supported by the finding that the marine molluscs Elysia viridis and Elysia chlorotica seem to maintain a symbiotic relationship with chloroplasts from algae with similar RDA structures that they encounter. However, they do not transfer these chloroplasts to the next generations.
The light energy is converted to chemical energy using the light-dependent reactions. This chemical energy production is more than 90% efficient with only 5-8% of the energy transferred thermally. The products of the light dependent reactions are ATP from photophosphorylation and NADPH from photoreduction. Both are then utilized as an energy source for the light-independent reactions.
Not all wavelengths of light can support photosynthesis. The photosynthetic action spectrum depends on the type of accessory pigments present. For example, in green plants, the action spectrum resembles the absorption spectrum for chlorophylls and carotenoids with peaks for violet-blue and red light. In red algae, the action spectrum overlaps with the absorption spectrum of phycobilins for blue-green light, which allows these algae to grow in deeper waters that filter out the longer wavelengths used by green plants. The non-absorbed part of the light spectrum is what gives photosynthetic organisms their color (e.g. green plants, red algae, purple bacteria) and is the least effective for photosynthesis in the respective organisms.
MITOSIS-----
Mitosis is the process in which a cell duplicates its chromosomes to generate two, identical cells. It is generally followed by cytokinesis which divides the cytoplasm and cell membrane. This results in two identical cells with an equal distribution of organelles and other cellular components. Mitosis and cytokinesis jointly define the mitotic (M) phase of the cell cycle, the division of the mother cell into two sister cells, each with the genetic equivalent of the parent cell. Mitosis occurs most often in eukaryotic cells. In some cases it occurs in post-karotic cells.
In multicellular organisms, the somatic cells undergo mitosis, while germ cells — cells destined to become sperm in males or ova in females — divide by a related process called meiosis. Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.
The importance of mitosis is the maintenance of the chromosomal set; each cell formed receives chromosomes that are alike in composition and equal in number to the chromosomes of the parent cell. Transcription is generally believed to cease during mitosis, but epigenetic mechanisms such as bookmarking function during this stage of the cell cycle to ensure that the "memory" of which genes were active prior to entry into mitosis are transmitted to the daughter cells.
The process of mitosis is complex and highly regulated. Lyconesis enzymes and other NPOs provided needed regulatory input and restraint on the divisorial process. The sequence of events is organized into phases corresponding to the completion of certain phase prerequisites.
Various classes of cells can skip steps depending on the presence of protease inhibitors or if they are in a hurry. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells.
Cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with the phrase "mitotic phase". However, there are many cells whose mitosis and cytokinesis occur separately, forming single cells with multiple nuclei. This occurs most notably among the fungi and slime moulds, but is found in various different groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development.[2] Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer or cell death
The process of Mitotis can be divided into seven stages: Preprophase, Prophase, Prometaphase, Metaphase, Anaphase, Telophase and Cytokinesis. Students often remember the main stages of the cell cycle (Interphase, Prophase, Metaphase, Anaphase and Telophase) by use of the acronym IPMAT.
The mitotic phase is a relatively short period of the cell cycle. It alternates with the much longer interphase, where the cell prepares itself for cell division. Interphase is divided into three phases, G1 (first gap), S (synthesis), and G2 (second gap). During all three phases, the cell grows by producing proteins and cytoplasmic organelles. However, chromosomes are replicated only during the S phase. Thus, a cell grows (G1), grows as it duplicates its chromosomes (S), grows more and prepares for mitosis (G2), and divides (M).[3]
In plant cells only, prophase is preceded by a pre-prophase stage and followed by a post-prophase stage. In plant cells that are highly vacuolated and somewhat amorphoric, the nucleus has to migrate into the center of the cell before mitosis can begin. This is achieved through the formation of a phragmosome, a transverse sheet of cytoplasm that bisects the cell along the future plane of cell division. In addition to phragmosome formation, preprophase is characterized by the formation of a ring of microtubules and actin filaments (called preprophase band) underneath the plasmamembrane around the equatorial plane of the future mitotic spindle and predicting the position of cell plate fusion during telophase. The cells of higher plants (such as the flowering plants) lack centrioles. Instead, spindle microtubules aggregate on the surface of the nuclear envelope during prophase. The preprophase band disappears during nuclear envelope disassembly and spindle formation in prometaphase
Normally, the genetic material in the nucleus is in a loosely bundled coil called chromatin. At the onset of prophase, chromatin condenses together into a highly ordered structure called a chromosome. Since the genetic material has already been duplicated earlier in S phase, the replicated chromosomes have two sister chromatids, bound together at the centromere by the cohesion complex. Chromosomes are visible at high magnification through a light microscope.
Close to the nucleus are two centrosomes. Each centrosome, which was replicated earlier independent of mitosis, acts as a coordinating center for the cell's microtubules. The two centrosomes nucleate microtubules (or microfibrils) (which may be thought of as cellular ropes) by polymerizing soluble tubulin present in the cytoplasm. Molecular motor proteins create repulsive forces that will push the centrosomes to opposite side of the nucleus. The centrosomes are only present in animals. In plants the microtubules form independently.
Some centrosomials contain a pair of centrioles that may help organize microtubule assembly, but they are not essential to formation of the mitotic spindle.
The nuclear envelope disassembles and microtubules invade the nuclear space. This is called open mitosis, and it occurs in most multicellular organisms. Fungi and some protists, such as algae or trichomonads, undergo a variation called closed mitosis where the spindle forms inside the nucleus or its microtubules are able to penetrate an intact nuclear envelope.[6][7]
Each chromosome forms two kinetochores at the centromere, one attached at each chromatid. A kinetochore is a complex protein structure that is analogous to a ring for the microtubule hook; it is the point where microtubules attach themselves to the chromosome.[8] Although the kinetochore structure and function are not fully understood, it is known that it contains some form of molecular motor.[9] When a microtubule connects with the kinetochore, the motor activates, using energy from ATP to "crawl" up the tube toward the originating centrosome. This motor activity, coupled with polymerisation and depolymerisation of microtubules, provides the pulling force necessary to later separate the chromosome's two chromatids.[9]
When the spindle grows to sufficient length, usually at least 7 nanometers, kinetochore microtubules begin searching for kinetochores to attach to. A number of nonkinetochore microtubules find and interact with corresponding nonkinetochore microtubules from the opposite centrosome to form the mitotic spindle.[10] Prometaphase is sometimes considered part of prophase.
As microtubules find and attach to kinetochores in prometaphase, the centromeres of the chromosomes convene along the metaphase plate or equatorial plane, an imaginary line that is equidistant from the two centrosome poles.[10] This even alignment is due to the counterbalance of the pulling powers generated by the opposing kinetochores, analogous to a tug-of-war between equally strong people. In certain types of cells, chromosomes do not line up at the metaphase plate and instead move back and forth between the poles randomly, only roughly lining up along the midline. Metaphase comes from the Greek word for "metanosis" μετα meaning "after."
Because proper chromosome separation requires that every kinetochore be attached to a bundle of microtubules (spindle fibers) , it is thought that unattached kinetochores generate a signal to prevent premature progression to anaphase[1] without all chromosomes being aligned. The signal creates the mitotic spindle checkpoint
When every kinetochore is attached to a cluster of microtubules and the chromosomes have lined up along the metaphase plate, the cell proceeds to anaphase (from the Greek ανα meaning “up,” “against,” “back,” or “re-”).
Two events then occur; First, the proteins that bind sister chromatids together are cleaved, allowing them to separate. These sister chromatids turned sister chromosomes are pulled apart by shortening kinetochore microtubules and toward the respective centrosomes to which they are attached. This is followed by the elongation of the nonkinetochore microtubules, which pushes the centrosomes (and the set of chromosomes to which they are attached) apart to opposite ends of the cell.
These three stages are sometimes called early, mid and late anaphase. Early anaphase is usually defined as the separation of the sister chromatids. Mid anaphase occurs with the reunification of certain metastic chromatids. Late anaphase is the elongation of the microtubules and the microtubules being pulled further apart. At the end of anaphase, the cell has succeeded in separating identical copies of the genetic material into two distinct populations.
Telophase (from the Greek τελος meaning "end") is a reversal of prophase and prometaphase events. It "cleans up" the after effects of mitosis. At telophase, the nonkinetochore microtubules continue to lengthen, elongating the cell even more. Corresponding sister chromosomes attach at opposite ends of the cell. A new nuclear envelope, using fragments of the parent cell's nuclear membrane, forms around each set of separated sister chromosomes. Both sets of chromosomes, now surrounded by new nuclei, unfold back into chromatin. Mitosis is complete, but cell division is not yet complete.
Cytokinesis is often mistakenly thought to be the final part of telophase, however cytokinesis is a separate process that begins at the same time as telophase. Cytokinesis is technically not even a phase of mitosis, but rather a separate process, necessary for completing cell division. In animal cells, a cleavage furrow (pinch) containing a contractile ring develops where the metaphase plate used to be, pinching off the separated nuclei.[12] In both animal and plant cells, cell division is also driven by vesicles derived from the Golgi apparatus, which move along microtubules to the middle of the cell. [13] In plants this structure coalesces into a cell plate at the center of the phragmoplast and develops into a cell wall, separating the two nuclei. The phragmoplast is a microtubule structure typical for higher plants, whereas some green algae use a phycoplast microtubule array during cytokinesis.[14] Each daughter cell has a complete copy of the genome of its parent cell. The end of cytokinesis marks the end of the M-phase.
MEOSIS----
In biology, meiosis (IPA: /maɪˈəʊsɪs/) is the process by which one diploid eukaryotic cell divides to generate four haploid cells often called gametes. The word "meiosis" comes from the Greek meioun, meaning "to make smaller," since it results in a reduction in chromosome number in the gamete cell. Among fungi, spores in which the haploid nuclei are at first disseminated are called meiospores, or more specifically, ascospores in asci (Ascomycota) and basidospores on basidia (Basidiomycota).
Meiosis is essential for sexual reproduction and therefore occurs in all eukaryotes, including single-celled organisms that reproduce sexually. A few eukaryotes, notably the Bdelloid rotifers, have lost the ability to carry out meiosis and have acquired the ability to reproduce by parthenogenesis. Meiosis does not occur in archaea or prokaryotes, which reproduce via asexual processes such as mitosis or binary fission.
During meiosis, the genome of a diploid germ cell, which is composed of long segments of DNA packaged into chromosomes, undergoes DNA replication followed by two rounds of division, resulting in haploid cells called gametes. Each gamete contains one complete set of chromosomes, or half of the genetic content of the original cell. These resultant haploid cells can fuse with other haploid cells of the opposite sex or mating type during fertilization to create a new diploid cell, or zygote. Thus, the division mechanism of meiosis is a reciprocal process to the joining of two genomes that occurs at fertilization. Because the chromosomes of each parent undergo genetic recombination during meiosis, each gamete, and thus each zygote, will have a unique genetic blueprint encoded in its DNA. In other words, meiosis and sexual reproduction produce genetic variation.
Meiosis uses many of the same biochemical mechanisms employed during mitosis to accomplish the redistribution of chromosomes. There are several features unique to meiosis, most importantly the pairing and genetic recombination between homologous chromosomes.
REPRODUCTION----
Biological reproduction is the biological process by which new individual organisms are produced. Reproduction is a fundamental feature of all known life; each individual organism exists as the result of reproduction. The known methods of reproduction are broadly grouped into two main types: sexual and asexual.
In asexual reproduction, an individual can reproduce without involvement with another individual of that species. The division of a bacterial cell into two daughter cells is an example of asexual reproduction. Asexual reproduction is not, however, limited to single-celled organisms. Most plants have the ability to reproduce asexually.
Sexual reproduction requires the involvement of two individuals, typically one of each sex. Normal human reproduction is a common example of sexual reproduction. In general, more-complex organisms reproduce sexually while simpler, usually unicellular, organisms reproduce
Asexual reproduction is the biological process by which an organism creates a genetically-similar or identical copy of itself without a contribution of genetic material from another individual. Bacteria divide asexually via binary fission; viruses take control of host cells to produce more viruses; Hydras (invertebrates of the order Hydroidea) and yeasts are able to reproduce by budding. These organisms do not have different sexes, and they are capable of "splitting" themselves into two or more individuals. Some 'asexual' species, like hydra and jellyfish, may also reproduce sexually. For instance, most plants are capable of vegetative reproduction—reproduction without seeds or spores—but can also reproduce sexually. Likewise, bacteria may exchange genetic information by conjugation. Other ways of asexual reproduction include fragmentation and spore formation that involves only mitosis.
Sexual reproduction is a biological process by which organisms create descendants that have a combination of genetic material contributed from two (usually) different members of the species. Each of two parent organisms contributes half of the offspring's genetic makeup by creating haploid gametes. Most organisms form two different types of gametes. In these anisogamous species, the two sexes are referred to as male (producing sperm or microspores) and female (producing ova or megaspores). In isogamous species the gametes are similar or identical in form, but may have separable properties and then may be given other different names. For example, in the green alga, Chlamydomonas reinhardtii, there are so-called "plus" and "minus" gametes. A few types of organisms, such as ciliates, have more than two kinds of gametes.
Most animals (including humans) and plants reproduce sexually. Sexually reproducing organisms have two sets of genes for every trait (called alleles). Offspring inherit one allele for each trait from each parent, thereby ensuring that offspring have a combination of the parents' genes. Having two copies of every gene, only one of which is expressed, allows deleterious alleles to be masked, an advantage believed to have led to the evolutionary development of diploidy (Otto and Goldstein).
CANCER----
Cancer is a disease characterized by disorderly division of cells, combined with the malignant behavior of these cells. Malignant cancer cells tend to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (the process whereby cancer cells can move through the bloodstream or lymphatic system to distant locations). Cancer may affect people at all ages, but risk tends to increase with age. It is one of the principal causes of death in developed countries.
There are many theories about the cause of cancer. At least six important factors contribute to cancer pathogenesis, including failure of apoptosis, overactivation of oncogenes, inactivation of tumor suppressor genes, cell cycle activation of quiescent cells, acquisition of metastatic behavior by malignant cells, disordered responses to cellular growth factors, and immune system surveillance failure. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly being recognized as important components.
Environmental stimuli, or carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents, can cause cancer. The interaction between carcinogens and the host genome, to explain why some patients get cancer after exposure to a known carcinogen, while others don't, is the subject of immense recent research.
Cancer is usually classified according to the tissue of origin more than the location of manifestations. Prognosis in most cases depends on the original staging of the disease, though increasing use of molecular markers is leading to individually tailored treatments. A definitive diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, though the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for the type of cancer pathology. Drugs that target markers specific to a particular form of cancer, thereby minimizing damage to normal tissue, already exist for several types of malignancies.
History
Today, the Greek term carcinoma is the medical term for a malignant tumor derived from epithelial cells. It is Celsus who translated carcinos into the Latin cancer, also meaning crab. Galen used "oncos" to describe all tumours, the root for the modern word oncology.[1]
Breast cancer in a mastectomy specimen (top). The cancerous tumour (pale yellow) resembles the figure of a crab, giving the disease its name.Hippocrates described several kinds of cancers. He called benign tumours oncos, Greek for swelling, and malignant tumours carcinos, Greek for crab or crayfish. This name probably comes from the appearance of the cut surface of a solid malignant tumour, with a roundish hard center surrounded by pointy projections, vaguely resembling the shape of a crab (see photo). He later added the suffix -oma, Greek for swelling, giving the name carcinoma. Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient's humor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but humor-theory based treatment remained popular until the 19th century with the discovery of cells.
Though treatment remained the same, in the 16th and 17th centuries it became more acceptable for doctors to dissect bodies to discover the cause of death. The German professor Wilhelm Fabry believed that breast cancer was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a follower of Descartes, believed that all disease was the outcome of chemical processes, and that acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer was a poison that slowly spreads, and concluded that it was contagious.[2]
With the widespread use of the microscope in the 18th century, it was discovered that the 'cancer poison' spread from the primary tumor through the lymph nodes to other sites ("metastasis"). This view of the disease was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874 [3]. The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro saw only 2 breast tumor patients out of 60 surviving surgery for two years. In the 19th century, asepsis improved surgical hygiene and as the survival statistics went up, surgical removal of the tumor became the primary treatment for cancer. With the exception of William Coley who in the late 1800s felt that the rate of cure after surgery had been higher before asepsis (and who injected bacteria into tumors with mixed results), cancer treatment became dependent on the individual art of the surgeon at removing a tumor. During the same period, the idea that the body was made up of various tissues, that in turn were made up of millions of cells, laid rest the humor-theories about chemical imbalances in the body. The age of cellular pathology was born.
When Marie Curie and Pierre Curie discovered radiation at the end of the 19th century, they stumbled upon the first effective non-surgical cancer treatment. With radiation came also the first signs of multi-disciplinary approaches to cancer treatment. The surgeon was no longer operating in isolation, but worked together with hospital radiologists to help patients. The complications in communication this brought, along with the necessity of the patient's treatment in a hospital facility rather than at home, also created a parallel process of compiling patient data into hospital files, which in turn led to the first statistical patient studies.
Cancer patient treatment and studies were restricted to individual physicians' practices until World War II, when medical research centers discovered that there were large international differences in disease incidence. This insight drove national public health bodies to make it possible to compile health data across practises and hospitals, a process that many countries do today. The Japanese medical community observed that the bone marrow of bomb victims in Hiroshima and Nagasaki was completely destroyed. They concluded that diseased bone marrow could also be destroyed with radiation, and this led to the discovery of bone marrow transplants for leukemia. Since WWII, trends in cancer treatment are to improve on a micro-level the existing treatment methods, standardize them, and globalize them as a way to find cures through epidemiology and international partnerships.
Nomenclature and classification
The following closely related terms may be used to designate abnormal growths:
Neoplasia and neoplasm are scientific terms which refer to abnormal proliferations of genetically altered cells.
Cancer is synonymous with malignant neoplasm.
Benign tumors or benign neoplasms are similar to cancers in that they are composed of genetically abnormal cells which grow in excess of any normal process. However, the growth of benign tumors is self-limiting, and they do not invade other tissues or metastasize.
Tumor originally referred to any swelling or mass, either neoplastic, inflammatory or other. However, the vast majority of entities referred to as tumors in common usage are in fact neoplasms (although many are benign, and thus not cancers).
A paraneoplastic phenomenon is a physiological disturbance associated with a neoplasm, but not related to the physical effects of a tumor mass or invasive tumor cells themselves. Disturbances can be hormonal, neurological, hematological, or biochemical.
Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. Examples of general categories include:
Carcinoma: malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
Lymphoma and Leukemia: malignant tumors derived from blood and bone marrow cells
Sarcoma: malignant tumors derived from connective tissue, or mesenchymal cells
Mesothelioma: tumors derived from the mesothelial cells lining the peritoneum and the pleura.
Glioma: tumors derived from glia, the most common type of brain cell
Germ cell tumor: tumors derived from reproductive cells, most commonly found in the testicle and ovary
Malignant tumors are usually named using the Latin or Greek root of the organ of origin as a prefix and the above category name as the suffix. For instance, a malignant tumor of the liver is called hepatocarcinoma; a malignant tumor of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.
Benign tumors are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). However, some cancers also use this prefix for historical reasons, examples being melanoma and seminoma.
Adult cancers
In the USA and other developed countries, cancer is presently responsible for about 25% of all deaths.[4] On a yearly basis, 0.5% of the population is diagnosed with cancer.
The statistics below are for adults in the United States, and will vary substantially in other countries:
Male Female
most common cause of death[4] most common cause of death[4]
prostate cancer (33%) lung cancer (31%) breast cancer (32%) lung cancer (27%)
lung cancer (13%) prostate cancer (10%) lung cancer (12%) breast cancer (15%)
colorectal cancer (10%) colorectal cancer (10%) colorectal cancer (11%) colorectal cancer (10%)
bladder cancer (7%) pancreatic cancer (5%) endometrial cancer (6%) ovarian cancer (6%)
cutaneous melanoma (5%) leukemia (4%) non-Hodgkin lymphoma (4%) pancreatic cancer (6%)
Childhood cancers
Cancer can also occur in young children and adolescents, but it is rare. Some studies have concluded that pediatric cancers, especially leukemia, are on an upward trend.[5][6]
The age of peak incidence of cancer in children occurs during the first year of life. Leukemia (usually ALL) is the most common infant malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms' tumor, lymphomas, rhabdomyosarcoma (arising from muscle), retinoblastoma, osteosarcoma and Ewing's sarcoma.[4]
Female and male infants have essentially the same overall cancer incidence rates, but white infants have substantially higher cancer rates than black infants for most cancer types. Relative survival for infants is very good for neuroblastoma, Wilms' tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.
Causes and pathophysiology
Main article: Carcinogenesis
Origins of cancer
The origin, or etiology of cancer can be approached from many different perspectives. What follows below is a summary of several different lines of scientific inquiry into the cause of cancer. One or all of these theories may explain the development of any given cancer.
Cell dynamic theories
Cell division or cell proliferation is a physiological process that occurs in almost all tissues and under many circumstances. Normally the balance between proliferation and apoptosis, or programmed cell death, is tightly regulated to ensure the integrity of organs and tissues. Imbalances in the rates of cell division and cell death can lead to tumor growth in a tissue. Other events are usually required before metastasis can occur. Locally expansile tumors can also cause severe problems when they grow in certain locations, such as the head or airway.
Natural selection and cancer
The process of malignancy can be explained from an evolutionary perspective. Millions of years of biological evolution insure that the cellular metabolic changes that enable cancer to grow occur only very rarely. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. For example, the regulatory tumor suppressor gene, p53, causes the cell to enter programmed cell death when DNA damage occurs. Usually, the acquisition of multiple changes is necessary for a cell to enter a malignant state, such as metastasis-enabling DNA damage in the context of faulty p53. Considering the number of cell division events throughout the human lifetime, the number of errors that occur that lead to cancer is vanishingly slim. Cancer cells undergo a natural selection process, acquiring metabolic alterations so they can outcompete normal body cells for nutrients and oxygen. Tumors are thought to be clonal, in the sense that they probably start from a single, disorderly cell. The tumor continues to evolve due to chemotherapy treatments, and on occasion aberrant cells may acquire resistance to particular anti-cancer pharmaceuticals.
Other causes of cancer
A few types of cancer in non-humans have been found to be caused by the tumor cells themselves. This phenomenon is seen in Sticker's sarcoma, also known as canine transmissible venereal tumor.[7] The closest known analogue to this in humans is individuals who have developed cancer from tumors hiding inside organ transplants.
Molecular biology
Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.Carcinogenesis, which means the initiation or generation of cancer, is the process of derangement of the rate of cell division due to perturbations in normal cellular regulatory processes. Molecular biology, the study of genetics using modern techniques such as gene cloning, seeks to explain the etiology of cancer in terms of the genetic changes that underlie cancer.
It is impossible to tell the initial cause for any specific cancer. However, with the help of molecular biological techniques, it is possible to characterize the mutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, some tumors have a defective p53 gene. Changes in the sequence of this gene, known as mutations, are associated with a poor prognosis in many different cancer patients, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body.
In order for cells to fail to regulate normal growth and division, genes which regulate cell growth must be damaged. The two key concepts of the molecular biology approach to cancer pathogenesis are encompassed by the oncogene and thetumor suppressor gene. Oncogenes are genes which are normally inactive, but when activated can promote cell growth and mitosis, a process of cell division. Tumor suppressor genes, on the other hand, are usually active in the normal cell, and usually discourage cell growth, or temporarily halt cell division in order to carry out DNA repair after DNA damage. Damage to tumor suppressor genes is often observed in the development of malignancies. Typically, a series of several mutations to these genes are required before a normal cell transforms into a cancer cell.
Oncogenes
Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to effect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.
Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.
One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.[8] Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.[9]
Tumor suppressor genes
Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor gene, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.
Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.
The Warburg effect is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway. [10]
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.
Mutations of tumor suppressor genes that occur in germ-line cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.
Knudson "two-hit" hypothesis
Development of cancer was proposed in 1973 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.
Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.
Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.[11]
Non-mutational genetic alterations that lead to cancer
Aneuploidy
Down syndrome patients, who have an extra Chromosome 21, are known to develop malignancies such as leukemia and testicular cancer, though the reasons for this difference are not well understood. Characteristic changes in the copy number of particular chromosomes and chromosomal segments are seen in acute myeloid leukemia. These changes are so well-defined that they are used for prognostication in acute myeloid leukemia.
Translocations
Translocations are characteristic changes in chromosomes where portions of the human genome exchange locations on different chromosomes. The most famous example of this is the Philadelphia chromosome, a translocation of chromosomes 9 and 22, which brings the genes BCR and abl in close apposition. The constitutive activation of the abl tyrosine kinase gene by BCR is known to give rise to chronic myeloid leukemia. The pharmaceutical product, Gleevec, targets the abl kinase and specifically inhibits that tyrosine kinase, leading to prolonged remissions in that disease.
Biochemical explanations of cancer pathogenesis
Malignant tumor cells have distinct properties:
evading apoptosis
unlimited growth potential (immortalitization) due to overabundance of telomerase
self-sufficiency of growth factors
insensitivity to anti-growth factors
increased cell division rate
altered ability to differentiate
no ability for contact inhibition
ability to invade neighbouring tissues
ability to build metastases at distant sites
ability to promote blood vessel growth (angiogenesis)
A cell that degenerates into a tumor cell does not usually acquire all these properties at once, but its descendent cells are selected to develop them. This process is called clonal evolution. A first step in the development of a tumor cell is usually a small change in the DNA, often a point mutation, which leads to a genetic instability of the cell. The instability can increase to a point where the cell loses whole chromosomes, or has multiple copies of several. Also, the DNA methylation pattern of the cell changes, activating and deactivating genes without the usual regulation. Cells that divide at a high rate, such as epithelial cells, show a higher risk of becoming tumor cells than those which divide less, for example neurons.
Environmental contributors to cancer pathogenesis
Physical carcinogens
Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer and bladder cancer. Prolonged exposure to radiation, particularly ultraviolet radiation from the sun, leads to melanoma and other skin malignancies. Prolonged exposure to asbestos fibers is associated with mesothelioma.
Many mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes, see aneuploidy above.
Tobacco and cancer
The incidence of lung cancer is highly correlated with smoking. Source:NIH.The most consistent finding, over decades of research, is the strong association between tobacco use and cancers of many sites. Hundreds of epidemiological studies have confirmed this association. Further support comes from the fact that lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men.
Viral infections
Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage.[12] The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming viruses, which already carry the viral oncogene.
Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.
HIV is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer. AIDS-defining illnesses have long included these diagnoses. The increased incidence of malignancies in HIV patients points to the breakdown of immune surveillance as a possible etiology of cancer.
Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the US FDA approved a human papilloma virus vaccine, called Gardasil®. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US CDC Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11-12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.
Bacterial infections
H. pylori
In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The best example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer. This observation explains the huge burden of gastric cancer in Asia, where H. pylori colonization of the stomach is common, and where gastric cancer is among the most common malignancies.
Other pathogens
Despite more than ten years of research, scientists are still struggling to understand the relationship of mycoplasma to cancer pathogenesis, and research is ongoing.
Morphology
Tissue can be organized in a continuous spectrum from normal to cancer.Cancer tissue has a distinctive appearance under the microscope. Among the distinguishing traits are a large number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, loss of normal tissue organization, and a poorly defined tumor boundary. Immunohistochemistry and other molecular methods may characterise specific markers on tumor cells, which may aid in diagnosis and prognosis.
Biopsy and microscopical examination can also distinguish between malignancy and hyperplasia, which refers to tissue growth based on an excessive rate of cell division, leading to a larger than usual number of cells but with a normal orderly arrangement of cells within the tissue. This process is considered reversible. Hyperplasia can be a normal tissue response to an irritating stimulus, for example callus.
Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure. Often such cells revert to normal behavior, but occasionally, they gradually become malignant.
The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and shows no propensity to invade other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.
Heredity
Most forms of cancer are "sporadic", and have no basis in heredity. There are, however, a number of recognised syndromes of cancer with a hereditary component, often a defective tumor suppressor allele. Famous examples are:
certain inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft-tissue sarcoma, brain tumors) due to mutations of p53
Turcot syndrome (brain tumors and colonic polyposis)
Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
Lynch syndrome, also known as Hereditary Non-polyposis Colon Cancer Syndrome, can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
Retinoblastoma in young children is an inherited cancer
Shift work and cancer
There is also a growing body of research that correlates cancer incidence with the lower levels of melatonin produced in the body when people spend more time in bright-light conditions, as happens typically in the well-lit nighttime environments of the more developed countries.[13] This effect is compounded in people who sleep fewer hours and in people who work at night, two groups that are known to have higher cancer rates.[14] [15]
Epidemiology
Cancer epidemiology is the study of the incidence of cancer as a way to infer possible trends and causes. The first such cause of cancer was identified by British surgeon Percivall Pott, who discovered in 1775 that cancer of the scrotum was a common disease among chimney sweeps. The work of other individual physicians led to various insights, but when physicians started working together they could make firmer conclusions.
A founding paper of this discipline was the work of Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health. Her ground-breaking work on cancer epidemiology was carried on by Richard Doll and Austin Bradford Hill, who published "Lung Cancer and Other Causes of Death In Relation to Smoking. A Second Report on the Mortality of British Doctors" followed in 1956 (otherwise known as the British doctors study). Richard Doll left the London Medical Research Center (MRC), to start the Oxford unit for Cancer epidemiology in 1968. With the use of computers, the unit was the first to compile large amounts of cancer data. Modern epidemiological methods are closely linked to current concepts of disease and public health policy. Over the past 50 years, great efforts have been spent on gathering data across medical practise, hospital, provincial, state, and even country boundaries, as a way to study the interdependence of environmental and cultural factors on cancer incidence.
The biggest problem facing cancer epidemiology today is the changing concept of 'cancer incidence'. For example, a breast cancer tumor with a very slow growth rate may be found with a mammogram at 50 years, while the same tumor may have been found as a noteworthy 'lump' at 70 years, depending on the specific growth factors affecting that particular patient's case. As diagnostic tools improve, this has a direct impact on the epidemiological data.
In some Western countries, such as the USA,[4] and the UK[16] cancer is overtaking cardiovascular disease as the leading cause of death. In many Third World countries cancer incidence (insofar as this can be measured) appears much lower, most likely because of the higher death rates due to infectious disease or injury. With the increased control over malaria and tuberculosis in some Third World countries, incidence of cancer is expected to rise; this is termed the epidemiologic transition in epidemiological terminology.
Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighboring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various Third World countries, lung cancer incidence has increased in a parallel fashion.
Prevention
Cancer prevention is defined as active measures to decrease the incidence of cancer. This can be accomplished by avoiding carcinogens or altering their metabolism, pursuing a lifestyle or diet that modifies cancer-causing factors and/or medical intervention (chemoprevention, treatment of pre-malignant lesions).
Preventive measures are usually categorized as primary or secondary. Primary prevention refers to interventions undertaken in patients without a history of a disease, while secondary prevention interventions are provided to patients already diagnosed with a disease.
Observational epidemiologic studies that show associations between risk factors and specific cancers generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials test whether hypotheses generated by epidemiologic trials and laboratory research actually result in reduced cancer incidence and mortality.
Examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (although 20% of women with lung cancer have never smoked, versus 10% of men[17]), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption may contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexually transmitted diseases, the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation, certain occupational and chemical exposures.
See alcohol and cancer for more on that topic.
Diet and cancer
Primary prevention (no history of cancer)
The consensus on diet and cancer is that obesity increases the risk of developing cancer. Particular dietary practices often explain differences in cancer incidence in different countries (e.g. gastric cancer is more common in Japan, while colon cancer is more common in the United States). Studies have shown that immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.[18]
Despite frequent reports of particular substances (including foods) having a beneficial or detrimental effect on cancer risk, few of these have an established link to cancer. These reports are often based on studies in cultured cell media or animals. Public health recommendations cannot be made on the basis of these studies until they have been validated in an observational (or occasionally a prospective interventional) trial in humans.
Meat
Studies of populations with low meat intake versus high levels of meat consumption have shown protection from colon cancer incidence by reduction of colon polyp formation.[19]
Coffee
Coffee intake of at least two cups per day has been associated with reduced risk of liver cancer, according to a May, 2007 report.[20]
Grilled meat and cancer risk
The Report on Carcinogens, last released in 2005 by the US National Cancer Institute, revealed that heterocyclic amines, released by cooking food at high temperatures, and polycyclic aromatic hydrocarbons, including benzopyrene, found in smoke from cooking foods, are carcinogens common in food. A report released by the National Cancer Institute indicates that stomach cancer [21] is more common in people who consume well-done and medium-well beef. Colon cancer[22] , breast cancer [23] , and pancreatic cancer [24] are other cancers increased in people with high intakes of barbecued, fried, or well-done meats.
Secondary prevention (previous history of cancer)
Vegetarian diet
Evidence is mounting that diet may have a profound impact on prognosis in patients who have developed cancer. The Journal of Urology published a study in 2005[25] demonstrating that a consuming plant based diet and making other lifestyle changes was able to reduce cancer markers in a group of men with prostate cancer using no conventional treatments.
Low-fat diet
In breast cancer patients, a low-fat diet may provide impressive protection from breast cancer recurrence, according to results reported at the 2006 San Antonio Breast Conference. Though the relationship of diet and cancer treatment continues to capture the public imagination, care must be exercised to not over-interpret the scientific literature.
Vitamins and prevention
The concept that cancer can be prevented through vitamin supplementation stems from early observations correlating human disease with vitamin deficiency, such as pernicious anemia with vitamin B12 deficiency, and scurvy with Vitamin C deficiency. This has largely not been proven to be the case with cancer, and vitamin supplementation is largely not proving effective in preventing cancer. The cancer-fighting components of food are also proving to be more numerous and varied than previously understood, so patients are increasingly being advised to consume fresh, unprocessed fruits and vegetables for maximal health benefits.[26]
Vitamin D
On June 8th, 2007 the Canadian Cancer Society advised Canadians that the intake of vitamin D has shown a reduction of cancers by close to 60%. [27] As far back as 2003, one study showed that vitamin D would reduce colon cancer.[28]
Vitamin D and its protective effect against cancer has been contrasted with the risk of malignancy from sun exposure. Since exposure to the sun enhances natural human production of Vitamin D, some cancer researchers have argued that the potential deleterious malignant effects of sun exposure are far outweighed by the cancer-preventing effects of extra Vitamin D synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that 23,800 premature cancer deaths occur in the US annually due to insufficient UVB exposure (apparently via vitamin D deficiency).[29] This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun exposure might be beneficial. Another research group[30][31] estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.
Beta-carotene
The case of beta-carotene provides an example of the importance of randomized clinical trials. Epidemiologists studying both diet and serum levels observed that high levels of beta-carotene, a precursor to vitamin A, were associated with a protective effect, reducing the risk of cancer. This effect was particularly strong in lung cancer. This hypothesis led to a series of large randomized clinical trials conducted in both Finland and the United States (CARET study) during the 1980s and 1990s. This study provided about 80,000 smokers or former smokers with daily supplements of beta-carotene or placebos. Contrary to expectation, these tests found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality. In fact, the risk of lung cancer was slightly, but not significantly, increased by beta-carotene, leading to an early termination of the study.[32]
Folate
Results reported in JAMA in 2007 indicate that folic acid supplementation is not effective in preventing colon cancer, and folate consumers may be more likely to form colon polyps.[33]
Other chemoprevention agents
Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. A recent study reported that the selective estrogen receptor modulator raloxifene has similar benefits to tamoxifen in preventing breast cancer in high-risk women, with a more favorable side effect profile.[34]
Raloxifene is a SERM like tamoxifen; it has been shown in the STAR trial to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. In this trial, which studied almost 20,000 women, raloxifene had fewer side effects than tamoxifen, though it did permit more DCIS to form.[citation needed]
Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors.[35] The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients[36] and in the general population.[37][38] In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.
Genetic testing
Genetic testing for high-risk individuals is already available for certain cancer-related genetic mutations. Carriers of genetic mutations that increase risk for cancer incidence can undergo enhanced surveillance, chemoprevention, or risk-reducing surgery.
Gene Cancer types Availability
BRCA1, BRCA2 Breast, ovarian, pancreatic Commercially available for clinical specimens
MLH1, MSH2, MSH6, PMS, PMS2 Colon, uterine, small bowel, stomach, urinary tract Commercially available for clinical specimens
Preventative cancer vaccines
Considerable research effort is now devoted to the development of vaccines to prevent infection by oncogenic infectious agents, as well as to mount an immune response against cancer-specific epitopes) and to potential venues for gene therapy for individuals with genetic mutations or polymorphisms that put them at high risk of cancer.
A preventive human papillomavirus vaccine exists that targets certain sexually transmitted strains of human papillomavirus that are associated with the development of cervical cancer and genital warts. The only two HPV vaccines currently on the market are Gardasil and Cervarix.
Diagnosis
Most cancers are initially recognized either because signs or symptoms appear or through screening. Neither of these lead to a definitive diagnosis, which usually requires the opinion of a pathologist.
Signs and symptoms
Roughly, cancer symptoms can be divided into three groups:
Local symptoms: unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice.
Symptoms of metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.
Systemic symptoms: weight loss, poor appetite and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.
Every single item in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.
Biopsy
A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must be confirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained from a biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctor's office. Biopsies of other organs are performed under anesthesia and require surgery in an operating room.
The tissue diagnosis indicates the type of cell that is proliferating, its histological grade and other features of the tumor. Together, this information is useful to evaluate the prognosis of this patient and choose the best treatment. Cytogenetics and immunohistochemistry may provide information about future behavior of the cancer (prognosis) and best treatment.
Screening
Cancer screening is an attempt to detect unsuspected cancers in the population. Screening tests suitable for large numbers of healthy people must be relatively affordable, safe, noninvasive procedures with acceptably low rates of false positive results. If signs of cancer are detected, more definitive and invasive follow up tests are performed to confirm the diagnosis.
Screening for cancer can lead to earlier diagnosis. Early diagnosis may lead to extended life. A number of different screening tests have been developed. Breast cancer screening can be done by breast self-examination. Screening by regular mammograms detects tumors even earlier than self-examination, and many countries use it to systematically screen all middle-aged women. Colorectal cancer can be detected through fecal occult blood testing and colonoscopy, which reduces both colon cancer incidence and mortality, presumably through the detection and removal of pre-malignant polyps. Similarly, cervical cytology testing (using the Pap smear) leads to the identification and excision of precancerous lesions. Over time, such testing has been followed by a dramatic reduction of cervical cancer incidence and mortality. Testicular self-examination is recommended for men beginning at the age of 15 years to detect testicular cancer. Prostate cancer can be screened for by a digital rectal exam along with prostate specific antigen (PSA) blood testing.
Screening for cancer is controversial in cases when it is not yet known if the test actually saves lives. The controversy arises when it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example: when screening for prostate cancer, the PSA test may detect small cancers that would never become life threatening, but once detected will lead to treatment. This situation, called overdiagnosis, puts men at risk for complications from unnecessary treatment such as surgery or radiation. Follow up procedures used to diagnose prostate cancer (prostate biopsy) may cause side effects, including bleeding and infection. Prostate cancer treatment may cause incontinence (inability to control urine flow) and erectile dysfunction (erections inadequate for intercourse). Similarly, for breast cancer, there have recently been criticisms that breast screening programs in some countries cause more problems than they solve. This is because screening of women in the general population will result in a large number of women with false positive results which require extensive follow-up investigations to exclude cancer, leading to having a high number-to-treat (or number-to-screen) to prevent or catch a single case of breast cancer early.
Cervical cancer screening via the Pap smear has the best cost-benefit profile of all the forms of cancer screening from a public health perspective as, being largely caused by a virus, it has clear risk factors (sexual contact), and the natural progression of cervical cancer is that it normally spreads slowly over a number of years therefore giving more time for the screening program to catch it early. Moreover, the test itself is easy to perform and relatively cheap.
For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake cancer screening.
Use of medical imaging to search for cancer in people without clear symptoms is similarly marred with problems. There is a significant risk of detection of what has been recently called an incidentaloma - a benign lesion that may be interpreted as a malignancy and be subjected to potentially dangerous investigations.
Canine cancer detection has shown promise, but is still in the early stages of research.
Treatment
Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development.
Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.
Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases.
Surgery
In theory, cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.
Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.
In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy.
Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.
Radiation therapy
Main article: Radiation therapy
Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.
Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.
Chemotherapy
Main article: Chemotherapy
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.
Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.
The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous transplantation. Alternatively, bone marrow may be transplanted from a matched unrelated donor (MUD).
Targeted therapies
Main article: Targeted therapy
Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib and gefitinib,
Monoclonal antibody therapy is another strategy in which the theraputic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody traztuzumab (Herceptin®) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.
Targeted therapy can also involve small peptidic structures as ´homing device´ which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to this peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.
Immunotherapy
Main article: Cancer immunotherapy
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells.
Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation" from a genetically non-identical donor) can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.
Hormonal therapy
Main article: Hormonal therapy (oncology)
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.
Symptom control
Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. Although all practicing doctors have the therapeutic skills to control pain, nausea, vomiting, diarrhea, hemorrhage and other common problems in cancer patients, the multidisciplinary specialty of palliative care has arisen specifically in response to the symptom control needs of this group of patients.
Pain medication, such as morphine and oxycodone, and antiemetics, drugs to suppress nausea and vomiting, are very commonly used in patients with cancer-related symptoms.
Chronic pain due to cancer is almost always associated with continuing tissue damage due to the disease process or the treatment (i.e. surgery, radiation, chemotherapy). Although there is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, these are not usually the predominant etiologic factors in patients with cancer pain. Furthermore, many patients with severe pain associated with cancer are nearing the end of their lives and palliative therapies are required. Issues such as social stigma of using opioids, work and functional status, and health care consumption are not likely to be important in the overall case management. Hence, the typical strategy for cancer pain management is to get the patient as comfortable as possible using opioids and other medications, surgery, and physical measures.
Complementary and alternative medicine
Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine. Oncology, the study of human cancer, has a long history of incorporating unconventional or botanical treatments into mainstream cancer therapy. Some examples of this phenomenon include the chemotherapy agent paclitaxel, which is derived from the bark of the Pacific Yew tree, and ATRA, all-trans retinoic acid, a derivative of Vitamin A that induces cures in an aggressive leukemia known as acute promyelocytic leukemia. Many "complementary" and "alternative" medicines for cancer have not been studied using the scientific method, such as in well-designed clinical trials, or they have only been studied in preclinical (animal or in-vitro) laboratory studies. Many times, "complementary" and "alternative" medicines are supported by marketing materials and "testimonials" from users of the substances. Frequently, when these treatments are subjected to rigorous scientific testing, they are found not to work. A recent example was reported at the 2007 annual meeting of the American Society of Clinial Oncology: a Phase III clinical trial comparing shark cartilage extract to placebo in non-small cell lung cancer demonstrated no benefit of the shark cartilage extract, AE-491. [39]
"Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine. A study of CAM use in patients with cancer in the July 2000 issue of the Journal of Clinical Oncology found that 69 percent of 453 cancer patients had used at least one CAM therapy as part of their cancer treatment.[40]
Some complementary measures include botanical medicine, such as an NIH trial currently underway testing mistletoe extract combined with chemotherapy for the treatment of solid tumors, acupuncture for managing chemotherapy-associated nausea and vomiting and in controlling pain associated with surgery, psychological approaches such as "imaging" or meditation to aid in pain relief or improve mood.[40]
A wide range of alternative treatments have been offered for cancer over the last century. The appeal of alternative cures arises from the daunting risks, costs, or potential side effects of many conventional treatments, or in the limited prospect for cure. No alternative therapies have been shown in randomized controlled trials to effectively cure cancer by themselves.
Treatment trials
Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.
A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.
Patients who take part may be helped personally by the treatment(s) they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. Of course, there is no guarantee that a new treatment being tested or a standard treatment will produce good results. New treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit.
Prognosis
Cancer has a reputation for being a deadly disease. While this certainly applies to certain particular types, the truths behind the historical connotations of cancer are increasingly being overturned by advances in medical care. Some types of cancer have a prognosis that is substantially better than nonmalignant diseases such as heart failure and stroke.
Progressive and disseminated malignant disease has a substantial impact on a cancer patient's quality of life, and many cancer treatments (such as chemotherapy) may have severe side-effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care solutions may include permanent or "respite" hospice nursing.
Cancer patients, for the first time in the history of oncology, are visibly returning to the athletic arena and workplace. Patients are living longer with either quiescent persistent disease or even complete, durable remissions. The stories of Lance Armstrong, who won the Tour de France after treatment for metastatic testicular cancer, or Tony Snow, who was working as the White house press secretary as of June, 2007 despite relapsed colon cancer, continue to be an inspiration to cancer patients everywhere.
Emotional impact
Many local organizations offer a variety of practical and support services to people with cancer. Support can take the form of support groups, counseling, advice, financial assistance, transportation to and from treatment, films or information about cancer. Neighborhood organizations, local health care providers, or area hospitals may have resources or services available.
While some people are reluctant to seek counseling, studies show that having someone to talk to reduces stress and helps people both mentally and physically. Counseling can also provide emotional support to cancer patients and help them better understand their illness. Different types of counseling include individual, group, family, self-help (sometimes called peer counseling), bereavement, patient-to-patient, and sexuality.
Many governmental and charitable organizations have been established to help patients cope with cancer. These organizations often are involved in cancer prevention, cancer treatment, and cancer research. Examples include: American Cancer Society, National Comprehensive Cancer Network, Lance Armstrong Foundation, BC Cancer Agency, Macmillan Cancer Relief , the Terry Fox Foundation, Cancer Research UK, Cancer Research Foundation, Canadian Cancer Society, International Agency for Research on Cancer, The Cancer Council Australia and the National Cancer Institute (US).
CELLS----
The cell is the structural and functional unit of all living organisms, and is sometimes called the "building block of life."[1] Some organisms, such as bacteria, are unicellular (consist of a single cell). Other organisms, such as humans, are multicellular. (Humans have an estimated 100 trillion or 1014 cells; a typical cell size is 10 µm; a typical cell mass is 1 nanogram.) The largest known cell is an ostrich egg.
The cell theory, first developed in 1839 by Matthias Jakob Schleiden and Theodor Schwann, states that all organisms are composed of one or more cells. All cells come from preexisting cells. Vital functions of an organism occur within cells, and all cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells.
The word cell comes from the Latin cellula, a small room. The name was chosen by Robert Hooke when he compared the cork cells he saw to the small rooms monks lived in.[2]
Each cell is at least somewhat self-contained and self-maintaining: it can take in nutrients, convert these nutrients into energy, carry out specialized functions, and reproduce as necessary. Each cell stores its own set of instructions for carrying out each of these activities.
Mouse cells grown in a culture dish. These cells grow in large clumps, but each individual cell is about 10 micrometres across.All cells share several abilities:[3]
Reproduction by cell division: (binary fission/mitosis or meiosis).
Use of enzymes and other proteins coded for by DNA genes and made via messenger RNA intermediates and ribosomes.
Metabolism, including taking in raw materials, building cell components, converting energy, molecules and releasing by-products. The functioning of a cell depends upon its ability to extract and use chemical energy stored in organic molecules. This energy is derived from metabolic pathways.
Response to external and internal stimuli such as changes in temperature, pH or nutrient levels.
Cell contents are contained within a cell surface membrane that contains proteins and a lipid bilayer.
Some prokaryotic cells contain important internal membrane-bound compartments,[4] but eukaryotic cells have a highly specialized endomembrane system characterized by regulated traffic and transport of vesicles.[5]
[edit] Anatomy of cells
There are two types of cells: eukaryotic and prokaryotic. Prokaryotic cells are usually singletons, while eukaryotic cells are usually found in multicellular organisms.
[edit] Prokaryotic cells
Main article: Prokaryote
Diagram of a typical prokaryotic cellProkaryotes are distinguished from eukaryotes on the basis of nuclear organization, specifically their lack of a nuclear membrane. Prokaryotes also lack most of the intracellular organelles and structures that are characteristic of eukaryotic cells (an important exception is the ribosomes, which are present in both prokaryotic and eukaryotic cells). Most functions of organelles, such as mitochondria, chloroplasts, and the Golgi apparatus, are taken over by the prokaryotic plasma membrane. Prokaryotic cells have three architectural regions: appendages called flagella and pili — proteins attached to the cell surface; a cell envelope consisting of a capsule, a cell wall, and a plasma membrane; and a cytoplasmic region that contains the cell genome (DNA) and ribosomes and various sorts of inclusions. Other differences include:
The plasma membrane (a phospholipid bilayer) separates the interior of the cell from its environment and serves as a filter and communications beacon.
Most prokaryotes have a cell wall (some exceptions are Mycoplasma (a bacterium) and Thermoplasma (an archaeon)). It consists of peptidoglycan in bacteria, and acts as an additional barrier against exterior forces. It also prevents the cell from "exploding" (cytolysis) from osmotic pressure against a hypotonic environment. A cell wall is also present in some eukaryotes like plants (cellulose) and fungi, but has a different chemical composition.
A prokaryotic chromosome is usually a circular molecule (an exception is that of the bacterium Borrelia burgdorferi, which causes Lyme disease). Even without a real nucleus, the DNA is condensed in a nucleoid. Prokaryotes can carry extrachromosomal DNA elements called plasmids, which are usually circular. Plasmids can carry additional functions, such as antibiotic resistance.
[edit] Eukaryotic cells
Diagram of a typical eukaryotic cell, showing subcellular components. Organelles: (1) nucleolus (2) nucleus (3) ribosome (4) vesicle (5) rough endoplasmic reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) smooth ER (9) mitochondria (10) vacuole (11) cytoplasm (12) lysosome (13) centriolesEukaryotic cells are about 10 times the size of a typical prokaryote and can be as much as 1000 times greater in volume. The major difference between prokaryotes and eukaryotes is that eukaryotic cells contain membrane-bound compartments in which specific metabolic activities take place. Most important among these is the presence of a cell nucleus, a membrane-delineated compartment that houses the eukaryotic cell's DNA. It is this nucleus that gives the eukaryote its name, which means "true nucleus". Other differences include:
The plasma membrane resembles that of prokaryotes in function, with minor differences in the setup. Cell walls may or may not be present.
The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, which are associated with histone proteins. All chromosomal DNA is stored in the cell nucleus, separated from the cytoplasm by a membrane. Some eukaryotic organelles also contain some DNA.
Eukaryotes can move using cilia or flagella. The flagella are more complex than those of prokaryotes.
Table 1: Comparison of features of prokaryotic and eukaryotic cells Prokaryotes Eukaryotes
Typical organisms bacteria, archaea protists, fungi, plants, animals
Typical size ~ 1-10 µm ~ 10-100 µm (sperm cells, apart from the tail, are smaller)
Type of nucleus nucleoid region; no real nucleus real nucleus with double membrane
DNA circular (usually) linear molecules (chromosomes) with histone proteins
RNA-/protein-synthesis coupled in cytoplasm RNA-synthesis inside the nucleus
protein synthesis in cytoplasm
Ribosomes 50S+30S 60S+40S
Cytoplasmatic structure very few structures highly structured by endomembranes and a cytoskeleton
Cell movement flagella made of flagellin flagella and cilia made of tubulin
Mitochondria none one to several dozen (though some lack mitochondria)
Chloroplasts none in algae and plants
Organization usually single cells single cells, colonies, higher multicellular organisms with specialized cells
Cell division Binary fission (simple division) Mitosis (fission or budding)
Meiosis
Table 2: Comparison of structures between animal and plant cells Typical animal cell Typical plant cell
Organelles Nucleus
Nucleolus (within nucleus)
Rough endoplasmic reticulum (ER)
Smooth ER
Ribosomes
Cytoskeleton
Golgi apparatus
Cytoplasm
Mitochondria
Vesicles
Lysosomes
Centrosome
Centrioles
Vacuoles
Nucleus
Nucleolus (within nucleus)
Rough ER
Smooth ER
Ribosomes
Cytoskeleton
Golgi apparatus (dictiosomes)
Cytoplasm
Mitochondria
Vesicles
Chloroplast and other plastids
Central vacuole(large)
Tonoplast (central vacuole membrane)
Peroxisome
Vacuoles
Glyoxysome
Additional structures Plasma membrane
Flagellum
Cilium
Plasma membrane
Flagellum (only in gametes)
Cell wall
Plasmodesmata
[edit] Subcellular components
The cells of eukaryotes (left) and prokaryotes (right).All cells, whether prokaryotic or eukaryotic, have a membrane that envelops the cell, separates its interior from its environment, regulates what moves in and out (selectively permeable), and maintains the electric potential of the cell. Inside the membrane, a salty cytoplasm takes up most of the cell volume. All cells possess DNA, the hereditary material of genes, and RNA, containing the information necessary to build various proteins such as enzymes, the cell's primary machinery. There are also other kinds of biomolecules in cells. This article will list these primary components of the cell, then briefly describe their function.
[edit] Cell membrane: A cell's defining boundary
Main article: Cell membrane
The cytoplasm of a cell is surrounded by a plasma membrane. The plasma membrane in plants and prokaryotes is usually covered by a cell wall. This membrane serves to separate and protect a cell from its surrounding environment and is made mostly from a double layer of lipids (hydrophobic fat-like molecules) and hydrophilic phosphorus molecules. Hence, the layer is called a phospholipid bilayer. It may also be called a fluid mosaic membrane. Embedded within this membrane is a variety of protein molecules that act as channels and pumps that move different molecules into and out of the cell. The membrane is said to be 'semi-permeable', in that it can either let a substance (molecule or ion) pass through freely, pass through to a limited extent or not pass through at all. Cell surface membranes also contain receptor proteins that allow cells to detect external signalling molecules such as hormones.
[edit] Cytoskeleton: A cell's scaffold
Main article: Cytoskeleton
The cytoskeleton acts to organize and maintain the cell's shape; anchors organelles in place; helps during endocytosis, the uptake of external materials by a cell, and cytokinesis, the separation of daughter cells after cell division; and moves parts of the cell in processes of growth and mobility. The eukaryotic cytoskeleton is composed of microfilaments, intermediate filaments and microtubules. There is a great number of proteins associated with them, each controlling a cell's structure by directing, bundling, and aligning filaments. The prokaryotic cytoskeleton is less well-studied but is involved in the maintenance of cell shape, polarity and cytokinesis.[6]
[edit] Genetic material
Two different kinds of genetic material exist: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Most organisms use DNA for their long-term information storage, but some viruses (e.g., retroviruses) have RNA as their genetic material. The biological information contained in an organism is encoded in its DNA or RNA sequence. RNA is also used for information transport (e.g., mRNA) and enzymatic functions (e.g., ribosomal RNA) in organisms that use DNA for the genetic code itself.
Prokaryotic genetic material is organized in a simple circular DNA molecule (the bacterial chromosome) in the nucleoid region of the cytoplasm. Eukaryotic genetic material is divided into different, linear molecules called chromosomes inside a discrete nucleus, usually with additional genetic material in some organelles like mitochondria and chloroplasts (see endosymbiotic theory).
A human cell has genetic material in the nucleus (the nuclear genome) and in the mitochondria (the mitochondrial genome). In humans the nuclear genome is divided into 46 linear DNA molecules called chromosomes. The mitochondrial genome is a circular DNA molecule separate from the nuclear DNA. Although the mitochondrial genome is very small, it codes for some important proteins.
Foreign genetic material (most commonly DNA) can also be artificially introduced into the cell by a process called transfection. This can be transient, if the DNA is not inserted into the cell's genome, or stable, if it is.
[edit] Organelles
Main article: Organelle
The human body contains many different organs, such as the heart, lung, and kidney, with each organ performing a different function. Cells also have a set of "little organs," called organelles, that are adapted and/or specialized for carrying out one or more vital functions. Membrane-bound organelles are found only in eukaryotes.
Cell nucleus (a cell's information center)
The cell nucleus is the most conspicuous organelle found in a eukaryotic cell. It houses the cell's chromosomes, and is the place where almost all DNA replication and RNA synthesis occur. The nucleus is spherical in shape and separated from the cytoplasm by a double membrane called the nuclear envelope. The nuclear envelope isolates and protects a cell's DNA from various molecules that could accidentally damage its structure or interfere with its processing. During processing, DNA is transcribed, or copied into a special RNA, called mRNA. This mRNA is then transported out of the nucleus, where it is translated into a specific protein molecule. In prokaryotes, DNA processing takes place in the cytoplasm.
Mitochondria and Chloroplasts (the power generators)
Mitochondria are self-replicating organelles that occur in various numbers, shapes, and sizes in the cytoplasm of all eukaryotic cells. As mitochondria contain their own genome that is separate and distinct from the nuclear genome of a cell, they play a critical role in generating energy in the eukaryotic cell, they give the cell energy by the process of respiration, adding oxygen to food (typicially pertaining to glucose and ATP) to release energy. Organelles that are modified chloroplasts are broadly called plastids, and are often involved in storage. Since they contain their own genome, they are thought to have once been separate organisms, which later formed a symbiotic relationship with the cells. Chloroplasts are the counter-part of the mitochondria. Instead of giving off CO2 and H2O Plants give off glucose, oxygen, 6 molecules of water (compaired to 12 in respiration) this process is called photosynthesis.
Endoplasmic reticulum and Golgi apparatus (macromolecule managers)
The endoplasmic reticulum (ER) is the transport network for molecules targeted for certain modifications and specific destinations, as compared to molecules that will float freely in the cytoplasm. The ER has two forms: the rough ER, which has ribosomes on its surface, and the smooth ER, which lacks them. Also the Golgi apparatus's ends "pinch" off and become new vacuoles in the animal cell.
Ribosomes (the protein production centers in the cell)
The ribosome is a large complex, composed of many molecules, in prokaryotes only exist floating freely in the cytosol, whereas in eukaryotes they can be found either free or bound to membranes.
Lysosomes and Peroxisomes (of the eukaryotic cell)
The cell could not house such destructive enzymes if they were not contained in a membrane-bound system. These organelles are often called a "suicide bag" because of their ability to detonate and destroy the cell.
Centrosome (the cytoskeleton organiser)
The centrosome produces the microtubules of a cell - a key component of the cytoskeleton. It directs the transport through the ER and the Golgi apparatus. Centrosomes are composed of two centrioles, which separate during cell division and help in the formation of the mitotic spindle. A single centrosome is present in the animal cells. They are also found in some fungi and algae cells.
Vacuoles
Vacuoles store food and waste. Some vacuoles store extra water. They are often described as liquid filled space and are surrounded by a membrane. Some cells, most notably Amoeba have contractile vacuoles, which are able to pump water out of the cell if there is too much water.
[edit] Cell functions
[edit] Cell growth and metabolism
Main articles: Cell growth and Metabolism
Between successive cell divisions, cells grow through the functioning of cellular metabolism.
Cell metabolism is the process by which individual cells process nutrient molecules. Metabolism has two distinct divisions: catabolism, in which the cell breaks down complex molecules to produce energy and reducing power, and anabolism, in which the cell uses energy and reducing power to construct complex molecules and perform other biological functions. Complex sugars consumed by the organism can be broken down into a less chemically-complex sugar molecule called glucose. Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form of energy, via two different pathways.
The first pathway, glycolysis, requires no oxygen and is referred to as anaerobic metabolism. Each reaction is designed to produce some hydrogen ions that can then be used to make energy packets (ATP). In prokaryotes, glycolysis is the only method used for converting energy.
The second pathway, called the Krebs cycle, or citric acid cycle, occurs inside the mitochondria and is capable of generating enough ATP to run all the cell functions.
An overview of protein synthesis.
Within the nucleus of the cell (light blue), genes (DNA, dark blue) are transcribed into RNA. This RNA is then subject to post-transcriptional modification and control, resulting in a mature mRNA (red) that is then transported out of the nucleus and into the cytoplasm (peach), where it undergoes translation into a protein. mRNA is translated by ribosomes (purple) that match the three-base codons of the mRNA to the three-base anti-codons of the appropriate tRNA. Newly-synthesized proteins (black) are often further modified, such as by binding to an effector molecule (orange), to become fully active.[edit] Creation of new cells
Main article: Cell division
Cell division involves a single cell (called a mother cell) dividing into two daughter cells. This leads to growth in multicellular organisms (the growth of tissue) and to procreation (vegetative reproduction) in unicellular organisms.
Prokaryotic cells divide by binary fission. Eukaryotic cells usually undergo a process of nuclear division, called mitosis, followed by division of the cell, called cytokinesis. A diploid cell may also undergo meiosis to produce haploid cells, usually four. Haploid cells serve as gametes in multicellular organisms, fusing to form new diploid cells.
DNA replication, or the process of duplicating a cell's genome, is required every time a cell divides. Replication, like all cellular activities, requires specialized proteins for carrying out the job.
[edit] Protein synthesis
Main article: Protein biosynthesis
Cells are capable of synthesizing new proteins, which are essential for the modulation and maintenance of cellular activities. This process involves the formation of new protein molecules from amino acid building blocks based on information encoded in DNA/RNA. Protein synthesis generally consists of two major steps: transcription and translation.
Transcription is the process where genetic information in DNA is used to produce a complementary RNA strand. This RNA strand is then processed to give messenger RNA (mRNA), which is free to migrate through the cell. mRNA molecules bind to protein-RNA complexes called ribosomes located in the cytosol, where they are translated into polypeptide sequences. The ribosome mediates the formation of a polypeptide sequence based on the mRNA sequence. The mRNA sequence directly relates to the polypeptide sequence by binding to transfer RNA (tRNA) adapter molecules in binding pockets within the ribosome. The new polypeptide then folds into a functional three-dimensional protein molecule.
[edit] Origins of cells
Main article: Origin of life
The origin of cells has to do with the origin of life, and was one of the most important steps in evolution of life as we know it. The birth of the cell marked the passage from prebiotic chemistry to biological life.
[edit] Origin of the first cell
For more information RNA world hypothesis
In a gene-centered view of evolution, life is regarded in terms of replicators—that is DNA molecules in the organism. In this paradigm, cells satisfy two fundamental conditions: protection from the outside environment and confinement of biochemical activity. The former condition is needed to maintain the stability of fragile DNA chains in a varying and sometimes aggressive environment, and may have been the main reason for which cells evolved. The latter is fundamental for the evolution of biological complexity. If freely-floating DNA molecules that code for enzymes are not enclosed in cells, the enzymes that benefit a given replicator (for example, by producing nucleotides) may do so less efficiently, and may in fact benefit competing replicators. If the entire DNA molecule of a replicator is enclosed in a cell, then the enzymes coded from the molecule will be kept close to the DNA molecule itself. The replicator will directly benefit from its encoded enzymes.
Biochemically, cell-like spheroids formed by proteinoids are observed by heating amino acids with phosphoric acid as a catalyst. They bear many of the basic features provided by cell membranes. Proteinoid-based protocells enclosing RNA molecules may have been the first cellular life forms on Earth. Phospholipid bilayer membranes can contain water, and are a probable precursor to the modern cell membrane.[1]
[edit] Origin of eukaryotic cells
The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. It is almost certain that DNA-bearing organelles like the mitochondria and the chloroplasts are what remains of ancient symbiotic oxygen-breathing bacteria and cyanobacteria, respectively, where the rest of the cell seems to be derived from an ancestral archaean prokaryote cell – a theory termed the endosymbiotic theory.
There is still considerable debate about whether organelles like the hydrogenosome predated the origin of mitochondria, or viceversa: see the hydrogen hypothesis for the origin of eukaryotic cells.
Sex, as the stereotyped choreography of meiosis and syngamy that persists in nearly all extant eukaryotes, may have played a role in the transition from prokaryotes to eukaryotes. An 'origin of sex as vaccination' theory suggests that the eukaryote genome accreted from prokaryan parasite genomes in numerous rounds of lateral gene transfer. Sex-as-syngamy (fusion sex) arose when infected hosts began swapping nuclearized genomes containing coevolved, vertically transmitted symbionts that conveyed protection against horizontal infection by more virulent symbionts.[7]
CHROMOSOMES----
A chromosome is a single large macromolecule of DNA, and constitutes a physically organized form of DNA in a cell. It is a very long, continuous piece of DNA (a single DNA molecule), which contains many genes, regulatory elements and other intervening nucleotide sequences. A broader definition of "chromosome" also includes the DNA-bound proteins which serve to package and manage the DNA. The word chromosome comes from the Greek χρῶμα (chroma, color) and σῶμα (soma, body) due to its capacity to be stained very strongly with vital and supravital dyes.
Chromosomes vary extensively between different organisms. The DNA molecule may be circular or linear, and can contain anything from tens of kilobase pairs to hundreds of megabase pairs. Typically eukaryotic cells have large linear chromosomes and prokaryotic cells smaller circular chromosomes, although there are many exceptions to this rule. Furthermore, cells may contain more than one type of chromosome; for example mitochondria in most eukaryotes and chloroplasts in plants have their own small chromosome in addition to the nuclear chromosomes.
In eukaryotes nuclear chromosomes are packaged by proteins (particularly histones) into chromatin to fit the massive molecules into the nucleus. The structure of chromatin varies through the cell cycle, and is responsible for the compaction of DNA into the classic four-arm structure during mitosis and meiosis. Prokaryotes do not form chromatin, the cells lack proteins required and the circular configuration of the molecule prevents this.
"Chromosome" is a rather loosely defined term. In prokaryotes, a small circular DNA molecule may be called either a plasmid or a small chromosome. In viruses, mitochondria, and chloroplasts their DNA molecules are commonly referred to as chromosomes, despite being naked molecules, as they constitute the complete genome of the organism or organelle.
Chromosomes were first observed in plant cells by a Swiss botanist named Karl Wilhelm von Nägeli in 1842, and independently in Ascaris worms by Belgian scientist Edouard Van Beneden (1846-1910). The use of basophilic aniline dyes was a fundamentally new technique for effectively staining the chromatin material in the nucleus. Their behavior in animal (salamander) cells was later described in detail by German cytologist and professor of anatomy Walther Flemming, the discoverer of mitosis, in 1882. The name was invented later by another German anatomist, Heinrich von Waldeyer.
[edit] Chromosomes in eukaryotes
Eukaryotes (cells with nuclei such as plants, yeast, and animals) possess multiple large linear chromosomes contained in the cell's nucleus. Each chromosome has one centromere, with one or two arms projecting from the centromere, although under most circumstances these arms are not visible as such. In addition most eukaryotes have a small circular mitochondrial genome, and some eukaryotes may have additional small circular or linear cytoplasmic chromosomes.
In the nuclear chromosomes of eukaryotes, the uncondensed DNA exists in a semi-ordered structure, where it is wrapped around histones (structural proteins), forming a composite material called chromatin.
[edit] Chromatin
Main article: Chromatin
Fig. 2: The major structures in DNA compaction; DNA, the nucleosome, the 10nm "beads-on-a-string" fibre, the 30nm fibre and the metaphase chromosome.Chromatin is the complex of DNA and protein found in the eukaryotic nucleus which packages chromosomes. The structure of chromatin varies significantly between different stages of the cell cycle, according to the requirements of the DNA.
[edit] Interphase chromatin
During interphase (the period of the cell cycle where the cell is not dividing) two types of chromatin can be distinguished:
Euchromatin, which consists of DNA that is active, e.g., expressed as protein.
Heterochromatin, which consists of mostly inactive DNA. It seems to serve structural purposes during the chromosomal stages. Heterochromatin can be further distinguished into two types:
Constitutive heterochromatin, which is never expressed. It is located around the centromere and usually contains repetitive sequences.
Facultative heterochromatin, which is sometimes expressed.
Individual chromosomes cannot be distinguished at this stage - they appear in the nucleus as a homogeneous tangled mix of DNA and protein.
[edit] Metaphase chromatin and division
See also: mitosis and meiosis
Human chromosomes during metaphase.In the early stages of mitosis or meiosis (cell division), the chromatin strands become more and more condensed. They cease to function as accessible genetic material (transcription stops) and become a compact transportable form. This compact form makes the individual chromosomes visible, and they form the classic four arm structure, a pair of sister chromatids attach to each other at the centromere. The shorter arms are called p arms (from the French petit, small) and the longer arms are called q arms (q follows p in the Latin alphabet). This is the only natural context in which individual chromosomes are visible with an optical microscope.
During divisions long microtubules attach to the centromere and the two opposite ends of the cell. The microtubules then pull the chromatids apart, so that each daughter cell inherits one set of chromatids. Once the cells have divided, the chromatids are uncoiled and can function again as chromatin. In spite of their appearance, chromosomes are structurally highly condensed which enables these giant DNA structures to be contained within a cell nucleus (Fig. 2).
The self assembled microtubules form the spindle, which attaches to chromosomes at specialized structures called kinetochores, one of which is present on each sister chromatid. A special DNA base sequence in the region of the kinetochores provides, along with special proteins, longer-lasting attachment in this region.
[edit] Chromosomes in prokaryotes
Prokaryotes (eg. Bacteria) typically have a single circular chromosome, but many variations do exist. Bacterial DNA also exists as plasmids, essentially miniature chromosomes, which are small circular pieces of DNA that are readily transmitted between bacteria. The distinction between plasmids and chromosomes is poorly defined, though size and necessity are generally taken into account.
[edit] Structure in sequences
Prokaryotes chromosomes have less sequence based structure than eukaryotes. They do, however, typically have a single point, the origin of replication, from which replication starts.
The genes in prokaryotes are often organised in operons, and do not contain introns, unlike eukaryotes.
[edit] Location in the cell
Bacterial chromosomes tend to be tethered to the plasma membrane of the bacteria. In molecular biology application, this allows for its isolation from plasmid DNA by centrifugation of lysed bacteria and pelleting of the membranes (and the attached DNA).
[edit] DNA packaging
Prokaryotes do not possess histones or nuclei, and so do not possess chromatin like eukaryotes. There is, however, thought to be some structural organisation to help condense the large molecule into the small prokaryotic cell.
Prokaryotic chromosomes and plasmids are, like eukaryotic DNA, generally supercoiled. The DNA must first be released into its relaxed state for access for transcription, regulation, and replication.
[edit] Number of chromosomes in various organisms
[edit] Eukaryotes
Chromosome numbers in some plants Plant Species #
Arabidopsis thaliana 10
Rye 14
Maize 20
Einkorn wheat 14
Pollard wheat 28
Bread wheat 42
Wild tobacco[citation needed] 24
Cultivated tobacco 48
Adder's Tongue Fern[1] 1262
Chromosome numbers in some animals Species # Species #
Common fruit fly 8 Guinea Pig 16
Dove[citation needed] 16 Snail[citation needed] 24
Earthworm[2] 36 Tibetan fox 36
Domestic cat 38 Domestic pig 38
Lab mouse 40 Lab rat 42
Rabbit[citation needed] 44 Syrian hamster 44
Hare[citation needed] 46 Human 46
gorillas, chimpanzees 48 Domestic sheep 54
Elephant[citation needed] 56 Cow 60
Donkey 62 Horse 64
Dog[3] 78 Chicken 78
Goldfish 104 Butterflies[citation needed] 380
Chromosome numbers in other organisms Species Large
Chromosomes Intermediate
Chromosomes Small
Chromosomes
Trypanosoma brucei 11 6 ~100
The 24 human chromosome territories during prometaphase in fibroblast cells.Normal members of a particular eukaryotic species all have the same number of nuclear chromosomes (see the table). Other eukaryotic chromosomes, i.e. mitochondrial and plasmid-like small chromosomes, are much more variable in number, and there may be thousands of copies per cell.
Asexually reproducing species have one set of chromosomes, which is the same in all body cells.
Sexually reproducing species have somatic cells (body cells), which are diploid [2n] having two sets of chromosomes, one from the mother and one from the father. Gametes, reproductive cells, are haploid [n]: they have one set of chromosomes. Gametes are produced by meiosis of a diploid germ line cell. During meiosis, the matching chromosomes of father and mother can exchange small parts of themselves (crossover), and thus create new chromosomes that are not inherited solely from either parent. When a male and a female gamete merge (fertilization), a new diploid organism is formed.
Some animal and plant species are polyploid [Xn]: they have more than two sets of homologous chromosomes. Agriculturally important plants such as tobacco or wheat are often polyploid compared to their ancestral species. Wheat has a haploid number of seven chromosomes, still seen in some cultivars as well as the wild progenitors. The more common pasta and bread wheats are polyploid having 28 (tetraploid) and 42 (hexaploid) chromosomes compared to the 14 (diploid) chromosomes in the wild wheat.[4]
Historical note: In 1921, Theophilus Painter claimed, based on his observations, that human sex cells had 24 chromosomes each, giving humans 48 chromosomes total. It wasn't until 1955 that the number of chromosomes was clearly shown to be 23.
[edit] Prokaryotes
Prokaryote species generally have one copy of each major chromosome, but most cells can easily survive with multiple copies. Plasmids and plasmid-like small chromosomes are, like in eukaryotes, very variable in copy number. The number of plasmids in the cell is almost entirely determined by the rate of division of the plasmid - fast division causes high copy number, and vice versa.
[edit] Karyotype
Main article: Karyotype
Figure 3: Karyotype of a human maleKaryotyping is a technique used to determine the (diploid) number of nuclear chromosomes of a eukaryotic organism, and may be used for determining sex and spotting chromosomal abnormalities. Cells can be locked part way through division (in metaphase) in vitro (in a reaction vial) with colchicine. These cells are then stained, photographed and arranged into a karyotype (an ordered set of chromosomes, Fig. 3), also called karyogram.
Like many sexually reproducing species, humans have special gonosomes (sex chromosomes, in contrast to autosomes). These are XX in females and XY in males, and can be seen in the karyotype, Fig. 3.
[edit] Chromosomal aberrations
Main articles: Chromosome abnormalities and aneuploidy
The three major single chromosome mutations; deletion (1), duplication (2) and inversion (3).
The two major two-chromosome mutations; insertion (1) and translocation (2).
In Down syndrome, chromosome 21 is affectedChromosomal aberrations are disruptions in the normal chromosomal content of a cell, and are a major cause of genetic disease in humans, such as Down syndrome. Some chromosome abnormalities do not cause disease in carriers, such as translocations, or chromosomal inversions, although they may lead to a higher chance of having a child with a chromosome disorder. Abnormal numbers of chromosomes or chromosome sets, aneuploidy, may be lethal or give rise to genetic disorders. Genetic counseling is offered for families that may carry a chromosome rearrangement.
The gain or loss of chromosome material can lead to a variety of genetic disorders. Human examples include:
Cri du chat, which is caused by the deletion of part of the short arm of chromosome 5. "Cri du chat" means "cry of the cat" in French, and the condition was so-named because affected babies make high-pitched cries that sound like a cat. Affected individuals have wide-set eyes, a small head and jaw and are moderately to severely mentally retarded and very short.
Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4. It is characterized by severe growth retardation and severe to profound mental retardation.
Down's syndrome, usually is caused by an extra copy of chromosome 21 (trisomy 21). Characteristics include decreased muscle tone, asymmetrical skull, slanting eyes and mild to moderate mental retardation.
Edward's syndrome, which is the second most common trisomy after Down syndrome. It is a trisomy of chromosome 18. Symptoms include mental and motor retardation and numerous congenital anomalies causing serious health problems. Ninety percent die in infancy; however, those who live past their first birthday usually are quite healthy thereafter. They have a characteristic hand appearance with clenched hands and overlapping fingers.
Patau Syndrome, also called D-Syndrome or trisomy-13. Symptoms are somewhat similar to those of trisomy-18, but they do not have the characteristic hand shape.
Idic15, abbreviation for Isodicentric 15 on chromosome 15; also called the following names due to various researches, but they all mean the same; IDIC(15), Inverted dupliction 15, extra Marker, Inv dup 15, partial tetrasomy 15
Jacobsen syndrome, also called the terminal 11q deletion disorder.[1] This is a very rare disorder. Those affected have normal intelligence or mild mental retardation, with poor expressive language skills. Most have a bleeding disorder called Paris-Trousseau syndrome.
Klinefelter's syndrome (XXY). Men with Klinefelter syndrome are usually sterile, and tend to have longer arms and legs and to be taller than their peers. Boys with the syndrome are often shy and quiet, and have a higher incidence of speech delay and dyslexia. During puberty, without testosterone treatment, some of them may develop gynecomastia.
Turner syndrome (X instead of XX or XY). In Turner syndrome, female sexual characteristics are present but underdeveloped. People with Turner syndrome often have a short stature, low hairline, abnormal eye features and bone development and a "caved-in" appearance to the chest.
XYY syndrome. XYY boys are usually taller than their siblings. Like XXY boys and XXX girls, they are somewhat more likely to have learning difficulties.
Triple-X syndrome (XXX). XXX girls tend to be tall and thin and are often shy. They have a higher incidence of dyslexia.
Small supernumerary marker chromosome. This means there is an extra, abnormal chromosome. Features depend on the origin of the extra genetic material. Cat-eye syndrome and isodicentric chromosome 15 syndrome (or Idic15) are both caused by a supernumerary marker chromosome, as is Pallister-Killian syndrome.
Chromosomal mutations produce changes in whole chromosomes (more than one gene) or in the number of chromosomes present.
Deletion- loss of part of a chromosome
Duplication- extra copies of a part of a chromosome
Inversion- reverse the direction of a part of a chromosome
Translocation- part of a chromosome breaks off and attaches to another chromosome
Most mutations are neutral- have little or no effect
A detailed graphical display of all human chromosomes and the diseases annotated at the correct spot may be found at [2].
[edit] The human chromosomes
Human cells have 23 pairs of large linear nuclear chromosomes, giving a total of 46 per cell. In addition to these, human cells have many hundreds of copies of the mitochondrial genome. All of the human chromosomes have been sequenced and a great deal is known about each of them.
Chromosome Genes Bases Determined bases†
1 2968 245,203,898 218,712,898
2 2288 243,315,028 237,043,673
3 2032 199,411,731 193,607,218
4 1297 191,610,523 186,580,523
5 1643 180,967,295 177,524,972
6 1963 170,740,541 166,880,540
7 1443 158,431,299 154,546,299
8 1127 145,908,738 141,694,337
9 1299 134,505,819 115,187,714
10 1440 135,480,874 130,710,865
11 2093 134,978,784 130,709,420
12 1652 133,464,434 129,328,332
13 748 114,151,656 95,511,656
14 1098 105,311,216 87,191,216
15 1122 100,114,055 81,117,055
16 1098 89,995,999 79,890,791
17 1576 81,691,216 77,480,855
18 766 77,753,510 74,534,531
19 1454 63,790,860 55,780,860
20 927 63,644,868 59,424,990
21 303 46,976,537 33,924,742
22 288 49,476,972 34,352,051
X (sex chromosome) 1184 152,634,166 147,686,664
Y (sex chromosome) 231 50,961,097 22,761,097
unplaced various ? 25,263,157 25,062,835
† Human Genome Project goals called for determination of only the euchromatic portion of the genome. Telomeres, centromeres, and other heterochromatic regions have been left undetermined, as have a small number of unclonable gaps.
DNA----
Deoxyribonucleic acid, or DNA is a nucleic acid molecule that contains the genetic instructions used in the development and functioning of all living organisms. The main role of DNA is the long-term storage of information and it is often compared to a set of blueprints, since DNA contains the instructions needed to construct other components of cells, such as proteins and RNA molecules. The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this genetic information.
Chemically, DNA is a long polymer of simple units called nucleotides, with a backbone made of sugars and phosphate atoms joined by ester bonds. Attached to each sugar is one of four types of molecules called bases. It is the sequence of these four bases along the backbone that encodes information. This information is read using the genetic code, which specifies the sequence of the amino acids within proteins. The code is read by copying stretches of DNA into the related nucleic acid RNA, in a process called transcription. Most of these RNA molecules are used to synthesize proteins, but others are used directly in structures such as ribosomes and spliceosomes.
Within cells, DNA is organized into structures called chromosomes and the set of chromosomes within a cell make up a genome. These chromosomes are duplicated before cells divide, in a process called DNA replication. Eukaryotic organisms such as animals, plants, and fungi store their DNA inside the cell nucleus, while in prokaryotes such as bacteria it is found in the cell's cytoplasm. Within the chromosomes, chromatin proteins such as histones compact and organize DNA, which helps control its interactions with other proteins and thereby control which genes are transcribed.
DNA is a long polymer made from repeating units called nucleotides.[1][2] The DNA chain is 22 to 24 Ångströms wide (2.2 to 2.4 nanometres), and one nucleotide unit is 3.3 Ångstroms (0.33 nanometres) long.[3] Although each individual repeating unit is very small, DNA polymers can be enormous molecules containing millions of nucleotides. For instance, the largest human chromosome, chromosome number 1, is 220 million base pairs long.[4]
In living organisms, DNA does not usually exist as a single molecule, but instead as a tightly-associated pair of molecules.[5][6] These two long strands entwine like vines, in the shape of a double helix. The nucleotide repeats contain both the segment of the backbone of the molecule, which holds the chain together, and a base, which interacts with the other DNA strand in the helix. In general, a base linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide. If multiple nucleotides are linked together, as in DNA, this polymer is referred to as a polynucleotide.[7]
The backbone of the DNA strand is made from alternating phosphate and sugar residues.[8] The sugar in DNA is 2-deoxyribose, which is a pentose (five carbon) sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These asymmetric bonds mean a strand of DNA has a direction. In a double helix the direction of the nucleotides in one strand is opposite to their direction in the other strand. This arrangement of DNA strands is called antiparallel. The asymmetric ends of a strand of DNA bases are referred to as the 5′ (five prime) and 3′ (three prime) ends. One of the major differences between DNA and RNA is the sugar, with 2-deoxyribose being replaced by the alternative pentose sugar ribose in RNA.[6]
The DNA double helix is stabilized by hydrogen bonds between the bases attached to the two strands. The four bases found in DNA are adenine (abbreviated A), cytosine (C), guanine (G) and thymine (T). These four bases are shown below and are attached to the sugar/phosphate to form the complete nucleotide, as shown for adenosine monophosphate.
These bases are classified into two types; adenine and guanine are fused five- and six-membered heterocyclic compounds called purines, while cytosine and thymine are six-membered rings called pyrimidines.[7] A fifth pyrimidine base, called uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. Uracil is normally only found in DNA as a breakdown product of cytosine, but a very rare exception to this rule is a bacterial virus called PBS1 that contains uracil in its DNA.[9] In contrast, following synthesis of certain RNA molecules, a significant number of the uracils are converted to thymines by the enzymatic addition of the missing methyl group. This occurs mostly on structural and enzymatic RNAs like transfer RNAs and ribosomal RNA.[10]
Animation of the structure of a section of DNA. The bases lie horizontally between the two spiraling strands. Large version[11]The double helix is a right-handed spiral. As the DNA strands wind around each other, they leave gaps between each set of phosphate backbones, revealing the sides of the bases inside (see animation). There are two of these grooves twisting around the surface of the double helix: one groove, the major groove, is 22 Å wide and the other, the minor groove, is 12 Å wide.[12] The narrowness of the minor groove means that the edges of the bases are more accessible in the major groove. As a result, proteins like transcription factors that can bind to specific sequences in double-stranded DNA usually make contacts to the sides of the bases exposed in the major groove.[13]
Base pairing
Further information: Base pair
At top, a GC base pair with three hydrogen bonds. At the bottom, AT base pair with two hydrogen bonds. Hydrogen bonds are shown as dashed lines.Each type of base on one strand forms a bond with just one type of base on the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with A bonding only to T, and C bonding only to G. This arrangement of two nucleotides binding together across the double helix is called a base pair. In a double helix, the two strands are also held together via forces generated by the hydrophobic effect and pi stacking, which are not influenced by the sequence of the DNA.[14] As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can therefore be pulled apart like a zipper, either by a mechanical force or high temperature.[15] As a result of this complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. Indeed, this reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.[1]
The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, left). The GC base pair is therefore stronger than the AT base pair. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determine the strength of the association between the two strands of DNA. Long DNA helices with a high GC content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands.[16] Parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in bacterial promoters, tend to have sequences with a high AT content, making the strands easier to pull apart.[17] In the laboratory, the strength of this interaction can be measured by finding the temperature required to break the hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others.[18]
Sense and antisense
Further information: Sense (molecular biology)
A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA (mRNA) copy that is translated into protein. The sequence on the opposite strand is complementary to the sense sequence and is therefore called the "antisense" sequence. Since RNA polymerases work by making a complementary copy of their templates, it is this antisense strand that is the template for producing the sense mRNA. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear.[19] One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.[20]
A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction made above between sense and antisense strands by having overlapping genes.[21] In these cases, some DNA sequences do double duty, encoding one protein when read 5′ to 3′ along one strand, and a second protein when read in the opposite direction (still 5′ to 3′) along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription,[22] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.[23] Another way of reducing genome size is seen in some viruses that contain linear or circular single-stranded DNA as their genetic material.[24][25]
Supercoiling
Further information: DNA supercoil
DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound.[26] If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases.[27] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.[28]
From left to right, the structures of A, B and Z DNA
Alternative double-helical structures
Further information: Mechanical properties of DNA
DNA exists in several possible conformations. The conformations so far identified are: A-DNA, B-DNA, C-DNA, D-DNA,[29] E-DNA,[30] H-DNA,[31] L-DNA,[29] P-DNA,[32] and Z-DNA.[8][33] However, only A-DNA, B-DNA, and Z-DNA have been observed in naturally occurring biological systems. Which conformation DNA adopts depends on the sequence of the DNA, the amount and direction of supercoiling, chemical modifications of the bases and also solution conditions, such as the concentration of metal ions and polyamines.[34] Of these three conformations, the "B" form described above is most common under the conditions found in cells.[35] The two alternative double-helical forms of DNA differ in their geometry and dimensions.
The A form is a wider right-handed spiral, with a shallow and wide minor groove and a narrower and deeper major groove. The A form occurs under non-physiological conditions in dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as in enzyme-DNA complexes.[36][37] Segments of DNA where the bases have been chemically-modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form.[38] These unusual structures can be recognised by specific Z-DNA binding proteins and may be involved in the regulation of transcription.[39]
Structure of a DNA quadruplex formed by telomere repeats.[40]
Quadruplex structures
At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes.[41] As a result, if a chromosome lacked telomeres it would become shorter each time it was replicated. These specialized chromosome caps also help protect the DNA ends from exonucleases and stop the DNA repair systems in the cell from treating them as damage to be corrected.[42] In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.[43]
These guanine-rich sequences may stabilize chromosome ends by forming very unusual structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure.[44] These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit. The structure shown to the left is a top view of the quadruplex formed by a DNA sequence found in human telomere repeats. The single DNA strand forms a loop, with the sets of four bases stacking in a central quadruplex three plates deep. In the space at the centre of the stacked bases are three chelated potassium ions.[45] Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.
In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins.[46] At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.[44]
Chemical modifications
cytosine 5-methylcytosine thymine
Structure of cytosine with and without the 5-methyl group. After deamination the 5-methylcytosine has the same structure as thymine
Base modifications
Further information: DNA methylation
The expression of genes is influenced by the chromatin structure of a chromosome and regions of heterochromatin (low or no gene expression) correlate with the methylation of cytosine. For example, cytosine methylation, to produce 5-methylcytosine, is important for X-chromosome inactivation.[47] The average level of methylation varies between organisms, with Caenorhabditis elegans lacking cytosine methylation, while vertebrates show higher levels, with up to 1% of their DNA containing 5-methylcytosine.[48] Despite the biological role of 5-methylcytosine it is susceptible to spontaneous deamination to leave the thymine base, and methylated cytosines are therefore mutation hotspots.[49] Other base modifications include adenine methylation in bacteria and the glycosylation of uracil to produce the "J-base" in kinetoplastids.[50][51]
DNA damage
Further information: Mutation
Benzopyrene, the major mutagen in tobacco smoke, in an adduct to DNA.[52]DNA can be damaged by many different sorts of mutagens. These include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and x-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light mostly damages DNA by producing thymine dimers, which are cross-links between adjacent pyrimidine bases in a DNA strand.[53] On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, as well as double-strand breaks.[54] It has been estimated that in each human cell, about 500 bases suffer oxidative damage per day.[55][56] Of these oxidative lesions, the most dangerous are double-strand breaks, as these lesions are difficult to repair and can produce point mutations, insertions and deletions from the DNA sequence, as well as chromosomal translocations.[57]
Many mutagens intercalate into the space between two adjacent base pairs. Intercalators are mostly aromatic and planar molecules, and include ethidium, daunomycin, doxorubicin and thalidomide. In order for an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. These structural changes inhibit both transcription and DNA replication, causing toxicity and mutations. As a result, DNA intercalators are often carcinogens, with benzopyrene diol epoxide, acridines, aflatoxin and ethidium bromide being well-known examples.[58][59][60] Nevertheless, due to their properties of inhibiting DNA transcription and replication, they are also used in chemotherapy to inhibit rapidly-growing cancer cells.[61]
Overview of biological functions
DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes.[62] The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation which depends on the same interaction between RNA nucleotides. Alternatively, a cell may simply copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here we focus on the interactions between DNA and other molecules that mediate the function of the genome.
Genome structure
Further information: Cell nucleus, Chromatin, Chromosome, Gene, Non-coding DNA
Genomic DNA is located in the cell nucleus of eukaryotes, as well as small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid.[63] The genetic information in a genome is held within genes. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the expression of the open reading frame.
In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.[64] The reasons for the presence of so much non-coding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing puzzle known as the "C-value enigma."[65] However, DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.[66]
T7 RNA polymerase producing a mRNA (green) from a DNA template (red and blue). The enzyme is shown as a purple ribbon.[67]Some non-coding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes.[42][68] An abundant form of non-coding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.[69] These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.[70]
Transcription and translation
Further information: Genetic code, Transcription (genetics), Protein biosynthesis
A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines a protein sequence. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).
In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA, TGA and TAG codons.
DNA replication. The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.
Replication
Further information: DNA replication
Cell division is essential for an organism to grow, but when a cell divides it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing, and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix.[71] In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.
Interactions with proteins
All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.
DNA-binding proteins
Interaction of DNA with histones (shown in white, top). These proteins' basic amino acids (below left, blue) bind to the acidic phosphate groups on DNA (below right, red).Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved.[72][73] The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence.[74] Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation.[75] These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription.[76] Other non-specific DNA-binding proteins found in chromatin include the high-mobility group proteins, which bind preferentially to bent or distorted DNA.[77] These proteins are important in bending arrays of nucleosomes and arranging them into more complex chromatin structures.[78]
A distinct group of DNA-binding proteins are the single-stranded-DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-characterised member of this family and is essential for most processes where the double helix is separated, including DNA replication, recombination and DNA repair.[79] These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem loops or being degraded by nucleases.
The lambda repressor helix-turn-helix transcription factor bound to its DNA target[80]In contrast, other proteins have evolved to specifically bind particular DNA sequences. The most intensively studied of these are the various classes of transcription factors, which are proteins that regulate transcription. Each one of these proteins bind to one particular set of DNA sequences and thereby activates or inhibits the transcription of genes with these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription.[81] Alternatively, transcription factors can bind enzymes that modify the histones at the promoter; this will change the accessibility of the DNA template to the polymerase.[82]
As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes.[83] Consequently, these proteins are often the targets of the signal transduction processes that mediate responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.[84]
The restriction enzyme EcoRV (green) in a complex with its substrate DNA[85]
DNA-modifying enzymes
Nucleases and ligases
Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently-used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GAT|ATC-3′ and makes a cut at the vertical line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system.[86] In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.
Enzymes called DNA ligases can rejoin cut or broken DNA strands, using the energy from either adenosine triphosphate or nicotinamide adenine dinucleotide.[87] Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.[87]
Topoisomerases and helicases
Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling in DNA. Some of these enzyme work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break.[27] Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix.[88] Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.[28]
Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly ATP, to break hydrogen bonds between bases and unwind the DNA double helix into single strands.[89] These enzymes are essential for most processes where enzymes need to access the DNA bases.
Polymerases
Polymerases are enzymes that synthesise polynucleotide chains from nucleoside triphosphates. They function by adding nucleotides onto the 3′ hydroxyl group of the previous nucleotide in the DNA strand. As a consequence, all polymerases work in a 5′ to 3′ direction.[90] In the active site of these enzymes, the nucleoside triphosphate substrate base-pairs to a single-stranded polynucleotide template: this allows polymerases to accurately synthesise the complementary strand of this template. Polymerases are classified according to the type of template that they use.
In DNA replication, a DNA-dependent DNA polymerase makes a DNA copy of a DNA sequence. Accuracy is vital in this process, so many of these polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed.[91] In most organisms DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.[92]
RNA-dependent DNA polymerases are a specialised class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres.[93][41] Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure.[42]
Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits.[94]
Genetic recombination
Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are coloured red, blue, green and yellow.[95]Further information: Genetic recombination
Recombination involves the breakage and rejoining of two chromosomes (M and F) to produce two re-arranged chromosomes (C1 and C2).A DNA helix does not usually interact with other segments of DNA, and in human cells the different chromosomes even occupy separate areas in the nucleus called "chromosome territories".[96] This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is during chromosomal crossover when they recombine. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.
Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins.[97] Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.[98]
The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51.[99] The first step in recombination is a double-stranded break either caused by an endonuclease or damage to the DNA.[100] A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA.[101]
Evolution of DNA-based metabolism
DNA contains the genetic information that allows all modern living things to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material.[90][102] RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes.[103] This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur since the number of unique bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.[104]
Unfortunately, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible. This is because DNA will survive in the environment for less than one million years and slowly degrades into short fragments in solution.[105] Although claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250-million years old,[106] these claims are controversial and have been disputed.[107][108]
Uses in technology
Genetic engineering
Further information: Molecular biology and genetic engineering
Modern biology and biochemistry make intensive use of recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector.[109] The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research,[110] or be grown in agriculture.[111][112]
Forensics
Further information: Genetic fingerprinting
Forensic scientists can use DNA in blood, semen, skin, saliva or hair at a crime scene to identify a perpetrator. This process is called genetic fingerprinting, or more accurately, DNA profiling. In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a criminal.[113] However, identification can be complicated if the scene is contaminated with DNA from several people.[114] DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys,[115] and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.[116] People convicted of certain types of crimes may be required to provide a sample of DNA for a database. This has helped investigators solve old cases where only a DNA sample was obtained from the scene. DNA profiling can also be used to identify victims of mass casualty incidents.[117]
Bioinformatics
Further information: Bioinformatics
Bioinformatics involves the manipulation, searching, and data mining of DNA sequence data. The development of techniques to store and search DNA sequences have led to widely-applied advances in computer science, especially string searching algorithms, machine learning and database theory.[118] String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides.[119] In other applications such as text editors, even simple algorithms for this problem usually suffice, but DNA sequences cause these algorithms to exhibit near-worst-case behaviour due to their small number of distinct characters. The related problem of sequence alignment aims to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function.[120] Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without annotations, which label the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products in an organism even before they have been isolated experimentally.[121]
DNA and computation
Further information: DNA computing
DNA was first used in computing to solve a small version of the directed Hamiltonian path problem, an NP-complete problem.[122] DNA computing is advantageous over electronic computers in power use, space use, and efficiency, due to its ability to compute in a highly parallel fashion (see parallel computing). A number of other problems, including simulation of various abstract machines, the boolean satisfiability problem, and the bounded version of the travelling salesman problem, have since been analysed using DNA computing.[123] Due to its compactness, DNA also has a theoretical role in cryptography, where in particular it allows unbreakable one-time pads to be efficiently constructed and used.[124]
History and anthropology
Further information: Phylogenetics and Genetic genealogy
Because DNA collects mutations over time, which are then inherited, it contains historical information and by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny.[125] This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology; for example, DNA evidence is being used to try to identify the Ten Lost Tribes of Israel.[126][127]
DNA has also been used to look at modern family relationships, such as establishing family relationships between the descendants of Sally Hemings and Thomas Jefferson. This usage is closely related to the use of DNA in criminal investigations detailed above. Indeed, some criminal investigations have been solved when DNA from crime scenes has matched relatives of the guilty individual.[128]
History
Francis Crick
James WatsonFurther information: History of molecular biology
DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages. As it resided in the nuclei of cells, he called it "nuclein".[129] In 1929 this discovery was followed by Phoebus Levene's identification of the base, sugar and phosphate nucleotide unit.[130] Levene suggested that DNA consisted of a string of nucleotide units linked together through the phosphate groups. However, Levene thought the chain was short and the bases repeated in a fixed order. In 1937 William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure.[131]
In 1943, Oswald Theodore Avery discovered that traits of the "smooth" form of the Pneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form. Avery identified DNA as this transforming principle.[132] DNA's role in heredity was confirmed in 1953, when Alfred Hershey and Martha Chase in the Hershey-Chase experiment showed that DNA is the genetic material of the T2 phage.[133]
In 1953, based on X-ray diffraction images[134] taken by Rosalind Franklin and the information that the bases were paired, James D. Watson and Francis Crick suggested[134] what is now accepted as the first accurate model of DNA structure in the journal Nature.[5] Experimental evidence for Watson and Crick's model were published in a series of five articles in the same issue of Nature.[135] Of these, Franklin and Raymond Gosling's paper[136] saw the publication of the X-ray diffraction image[137], which was key in Watson and Crick interpretation, as well as another article, co-authored by Maurice Wilkins and his colleagues
.[138] Franklin and Gosling's subsequent paper identified the distinctions between the A and B structures of the double helix in DNA.[139] In 1962 Watson, Crick, and Maurice Wilkins jointly received the Nobel Prize in Physiology or Medicine (Franklin didn't share the prize with them since she had died earlier).[140]
In an influential presentation in 1957, Crick laid out the "Central Dogma" of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".[141] Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson-Stahl experiment.[142] Further work by Crick and coworkers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and Marshall Warren Nirenberg to decipher the genetic code.[143] These findings represent the birth of molecular biology.
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