Fever, Genetic Engineering & Gene Theraphy

1. Discuss the pathogenesis of fever and acute-phase response. Show illustration • •

Fever definition o Elevation of body temperature to above normal (98.40F) or 370C orally or 99.80F or 37.60C rectally) Challenge to fever o To establish the causative agent – distinguish viral from bacterial disease o Identify the site of a localized infection o

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Physiologic states causing fever:  digestion  exercise  ovulation  pregnancy  warm environment  emotion Pathologic causes  Infection  Inflammation e.g. connective tissue disease  Neoplasms  Vaccines  Dehydration

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Common causes of fever o Minor illness  URTI  Viral exanthems  Gastroenteritis  o Major illnesses  Bacterial meningitis  UTI  Pneumonia  Malaria

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Pathogenesis of fever Exogenous pyrogens: Microbes, microbial toxins, other microbe products Endotoxins ( bacterial toxin) PML, Monocytes, Macrophages

Endogenous pyrogens: IL-1;IL-6;TNF-a & IFN –B and Y Thermosensitive neurons (Anterior hypothalamus) FEVER Thermoregulatory responses:  Redirection of blood to and from Cutaneous vascular beds  Increased or decreased sweating  ECF volume regulation  Behavioral changes •

Why Fever Occurs Exogenous pyrogens: e.g.infectious agents, drugs White blood cells (macrophages, monocytes, neutrophils) Cytokines e.g. IL-1, TNF Hypothalamus in brain Prostaglandins FEVER

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Mechanisms of a Protective Effect of Fever Enhanced neutrophil migration Increased production of antibacterial substances by neutrophils Increased production of interferon Increased antiviral and antitumor activity of interferon Increased T-cell proliferation Decreased growth of microorganisms in iron-poor environment

Pathogenesis of fever If the body temperature is above 37,2 C and is associated with sweating, hyperventilation, and vasodilatation in the skin, we speak of fever. At the beginning, gradual increase in body temperature is observed together with muscle shivering, vasocontriction in the skin, and piloerection. This situation is called chills. Increased body temperature is achieved by lowered loss of heat. Vasoconstriction in the skin and subcutaneous tissue is the cause of pale color and dryness, the affected person has a feeling of coldness. At the same time the production of heat in the organism increases. The muscle tonus increases, the spasms accur. Spasms may occur mainly in children. When the vasodilatation starts in the skin, the feeling of warmth and sweating occurs. Fever may be provoked by many stimuli. Most often, they are bacteria and their endotoxins, viruses, yeasts, spirochets, protozoa, immune reactions, several hormones, medications, and synthetic polynucleotides. These substances are commonly called exogenic pyrogens. Cells stimulated by exogenic pyrogens form and produce cytokines called endogenic pyrogens. Endogenic pyrogens centrally affect the thermosensitive neurons in the preoptic area of the hypothalamus increase the production of heat and decrease in heat loss. The body temperature increses until it reaches the set point. This information is transferred by temperature of blood that flows around the hypothalamus. The decrease of temperature is controlled by activation of mechanisms regulating increased outcome of heat to the surrounding area. Increased outcome continues in favourable case until the new equilibrium is achieved. The most important endogenic pyrogens are IL-1, IL-6 and cachectin also called the tumour necrosis factor- (TNF- ). These are glycoproteins that also have other important effects. They are produced especially by monocytes and macrophages but also by endothelial cells and astrocytes. Also the interferons , and display the pyrogenic activity. After administration an endotoxin in an experiment, the level of plasmatic TNF- increases and fever occurs. Increased concentrations of IL-1 and TNF- are also found in sepsis. The production of these cytokines is regulated by the positive feedback mechanism. Besides this, macrophages activated by IFN- may increase the production of IL-1 and TNF- primary induced by other stimuli. On the other hand, glucocorticoids and prostaglandins of group E may display inhibitory effect on the production of IL-1 and TNF- . Released IL-1 and TNF- are transported by blood. They affect the target cells in the close proximity or in distant sites. The target cells have specific receptors for IL-1 and TNF- . In the hypothalamus, IL-1 and TNFtrigger the synthesis of prostaglandis of group E from the arachidonic acid of cytoplasmic membranes of target cells. Precise mechanism by which prostaglandin PGE reset the central thermostat, is not known. Aspirin and the non-steroidal antiphlogistics display antipyretic activity by inhibiting the cyclo-oxygenase, an enzyme responsible for the synthesis of PGE (these antipyretics don't inhibit the production of TNF- or IL-1). Glucocorticoids work antipyretically by inhibiting the production of IL-1 and TNF- , and by inhibiting the metabolic processes of arachidonic acid. In the process of fever, IL-1 and TNF- play the central role. Except introduced activity in fever, they interfere with many mechanisms in an organism. Some of their effects are executed with the participation of metabolites of arachidonic acid. IL-1 and TNF- affect myelopoesis, release of neutrophils and enhancement of their functions. They cause vasodilatation and the increase the adhesivity of cells, increase the production of PAF and thrombomodulin by endothelial cells, proteolysis and glycogenolysis in muscles, mobilisation of lipids from adipocytes, proteosynthesis and glycogenolysis in the liver, induce proliferation of fibroblasts, activate osteoclasts and the release of collagenase from chondrocytes, induce slow wave sleeping activity in the brain, the release of ACTH, beta endorfins, growth hormone and

vasopressin, the release of insulin, cortisol, and catecholamines. TNF- and partially also IL-1 in longlasting operation may cause cachexia mainly by decreasing the appetite. It is so in chronic infections, inflammatory processes, and in neoplastic processes. Beside that, TNF and IL-1 significantly increase the immune response by activation of T-cells and stimulation of IL-2 production. IL-1 enhances B-cells proliferation. It is interesting that these processes have the temperature optimum at 39,5 . It follows that the fever can be supposed as a positive factor. Fever and specific effects of IL-1 and TNF- form together highly integrated processes that are involved in the response to infection and acute inflammation processes. Interferons, and especially IFN- (formed by T lymphocytes and NK cells) may enhance this reponse. Several parts of this complex response have protective and the others may have malignant consequences. Septicemia, or septic shock is an overshot response of the organism. In this complicated reaction of the organism, it is not easy to decide whether fever should be treated by antipyretics or not. By antipyretics the symptoms of fever may be suppressed but it is uncertain if it is reasonable to suppress also the positive efects of fever and everything that is connected with it. This complex process (fever) mobilizes not only the immune system but also those processes that improve the nutrition of cells and have protective importance on their activity. In the majority of diseases, fever is caused by pyrogens. There are situations, when fever may be caused directly by changes in the center of thermoregulation without the participation of exogenic and may be also endogenic pyrogens. This occurs in brain tumours, intracranial bleeding, and thrombosis. Acute Phase Response Increasing levels of prostaglandin E2 in the brain induce an area called the hypothalamus to turn up the body's thermostat a notch. Suddenly, the same external temperature feels colder, and various means are employed to restore the subjective impression of warmth. These include involuntary processes such as shivering, which generates heat by movement, and voluntary behavior such as putting on more clothes, finding a warm radiator to sit next to, and so on. Like pain and swelling, fever plays a vital part in defending the body against infection. Many bacteria reproduce most effectively at normal body temperature. So by raising body temperature the rate at which the bacteria can divide is slowed down. Fever has the opposite effect on most immune cells, causing them to divide more quickly. So fever both slows down the spread of the infection and accelerates the counterattack by the immune system. All injuries and infections, as stated above, cause a fever. This might only manifest itself in a localised heat, and does not always produce an overall increase of the body temperature. Mechanism of the Acute Phase Response In response to acute damage or entrance of foreign material monocytes enlarge and synthesise increased amounts of enzymes which help to break down the material. In doing so they are transformed to more active phagocytes called macrophages. Monocytes are formed in the bone marrow, enter the blood stream and have a longer life than neutrophils (T and B lymphocytes, "white blood cells"), estimated at 12 to 24 hours. Monocytes respond to chemotactic and immobilising factors (migration inhibitory factor) excreted by lymphocytes. This allows them to "stick" at the debris site. Macrophages have surface receptors for antibodies and are capable of synthesising various proteins as messengers. An important function of the macrophage is the presentation of debris material to B and T cells. Large molecules or particular substances, however, require

digestion by the macrophage before they can be recognised by the other cells of the immune system. Bits of these materials will be displayed on the surface of the macrophage and via contact stimulate both B and T cells into appropriate action. Lymphocytes (including B and T cells) mainly produce immunoglobulins (antibodies) and are also responsible for cellular immunity. Cellular immunity is involved in delayed hypersensitivity (allergies and various overreactions of the body) and homograft rejection. Lymphocytes can also damage foreign cells (bacteria, parasites, fungi, etc.). Human lymphocytes are formed chiefly in the bone marrow. Normal T cells develop only in the presence of a normal functioning thymus. Long lived lymphocytes are primarily T cells, that recirculate through the spleen and the lymph nodes, thoracic duct and bone marrow, leaving and re-entering the circulation repeatedly. There are subpopulations of T cells which serve to enhance (helper T) or reduce (suppressor T) B-cell responses. It is not yet known precisely how the various surface receptors on T and B cells influence cell function, but they are probably involved in antigen recognition and cell-to-cell interactions with macrophages and other lymphocytes. We see the various cells involved in the process under our powerful microscopes in still pictures. We also can measure various substances at various points throughout the inflammation process and we can identify certain specific sites on the cell surface. From this information we piece together the story of cellular immunity. In fact, we tell a number of "separate" stories about the immunological response. There is the story about how antibodies are first formed and then used to illicit a rapid response when exposed to the same "intruder" again. There is the story of how the immune system responds to a bacterial, or similar, invasion. There is the story of how the immune system creates tolerance for the prevention of immunologically induced self-injury. There is the story of autoimmunity, whereby antibodies are formed against the body's own tissue, which will consequently be attacked. There is the story of anaphylaxis, an extreme overreaction of the body defence mechanism. There is the story of the complement system, which consists of at least 15 plasma proteins which interact sequentially, producing substances that mediate several functions of inflammation. A lot of stories in which different substances and pathways are described, but without any serious linking of the various stories or without any knowledge as to why and how the body chooses to follow that particular pathway on that particular occasion. Returning to the acute phase response, the story we are particularly interested in, we know that there are many different cytokines (messengers) involved. One of the first cytokines to be released by the macrophages on detecting signs of injury or infection is known as interleukin1ß (IL-1ß). It diffuses into the tissue surrounding the damaged cells, where it triggers a second wave of cytokines which cause other types of immune cells such as neutrophils and monocytes to migrate to the injured site. The IL-1ß released by the macrophages also enters the blood stream, where it is carried to the brain, but is prevented from entering the brain directly by a layer of cells known as the blood-brain barrier. It therefore adopts a more cunning route into the central nervous system. First, the IL-1ß molecules attach themselves to specially designed receptors on the surface of the cells in the blood-brain barrier. When these receptors are activated, a chain reaction is initiated that eventually leads to the manufacturing of a molecule known as prostaglandin E2, which, unlike IL-1ß, is capable of passing through the blood-brain barrier. When it enters the brain, prostaglandin E2 activates the receptors on both neurons and microglia (immune cells in the brain), which can then initiate the other components of the acute phase response: fever, lethargy, apathy, loss of appetite, anxiety, and increased sensitivity to pain in other areas of the body. But the story does not end there. Once inside the brain, prostaglandin E2 encourages the microglia to manufacture IL-1ß. The net result is that, although IL-1ß cannot cross the blood-brain barrier directly, a build-up of IL-1ß in the blood stream leads to a build-up of IL-1ß in the brain and the cerebrospinal fluid. To complete the cycle, the IL-1ß leads to further synthesis of prostaglandin E2 in the brain, which in turn augments the various components of sickness behaviour. To compensate for the decreased supply of new calories caused by the loss of appetite, the body starts to unleash old calories that have been stored up for just such times of emergencies. These calories are stored in fat deposits around the body, but before the fat can be

used as a source of energy it must be broken down into glucose. So another crucial component of the acute phase response is the secretion of glucocorticoids, which trigger the process of converting fat to glucose. The key glucocorticoid in humans is cortisol, which is released by the adrenal glands in response to a cascade of chemical signals initiated in the brain by IL-1ß. First, the IL-1ß stimulates the hypothalamus to secrete a chemical called corticotrophin releasing hormone (CRH). The CRH travels to the pituitary gland, just below the brain, where it triggers the release of another chemical called adrenocorticotrophic hormone (ACTH). Finally, the ACTH reaches the adrenal glands, which secrete the cortisol. Because of their close interconnections, the three anatomical structures involved in this chemical cascade are known collectively as the hypothalamo-pituitary-adrenal axis.

Conclusion: Fever appears to have evolved in vertebrate hosts as an adaptive mechanism for controlling infection. This phenomenon is produced by certain exogenous (largely microbial) stimuli that activated bone-marrow-derived phagocytes to release a fever-inducing hormone (endogenous pyrogen). Endogenous pyrogen, in turn, circulates to the thermoregulatory center of the brain (preoptic area of the anterior hypothalamus) where it causes an elevation in the "setpoint" for normal body temperature. Warm blooded animals produced fever by increasing heat production (through shivering) or reducing heat loss (by peripheral vasoconstriction), whereas cold blooded animals do so only by behavioral mechanisms (seeking a warmer environment). Fever is a part of the acute phase response to infection and inflammation. We now understand that fever is a complex physiological response that is aimed at facilitating survival of the host. The fever is induced by endogenous inflammatory mediators, such as prostaglandins and pyrogenic cytokines, that are released by immune cells activated by exogenous pyrogens. Although the pathways (humoral and/or neuronal) responsible for transfer of the pyretic signals from the blood to the brain are still under discussion, it is generally accepted that they act on the level of the anterior hypothalamus to raise the thermoregulatory set-point. Results of studies of the adaptive value of fever demonstrate an association between a rise in body temperature and a decrease in mortality and morbidity during infection. These data along with data from evolutionary studies provide a strong support for the concept that fever is a beneficial during infection in endotherms and ectotherms, vertebrates as well as in invertebrates. There are also evidence showing that fever may be used as a therapeutic tool, especially in cancer therapy. Fever has evolved as a host defense mechanism which was preserved within the animal kingdom through hundreds of millions of years of evolution.

The Immune System In relation to infection & inflammation to Fever

There are physical, chemical, and cellular defenses against invasion by viruses, bacteria, and other agents of disease. During the early stages of an infection, there is an inflammatory response • •

Non-specific attack Phagocytes active ("eat" pathogen)

During later stages, leucocytes produce immune responses • •

Antigen - a foreign substance which triggers an immune response Some WBC's produce antibodies in huge amounts o Antibodies - substances which bind to specific antigens and tag them for destruction o Other WBC's (executioner cells) directly destroy body cells

Surface coverage - the first line of defense •

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The body is protected from pathogens by the skin and mucous membranes o Skin - dead cellular layer - dry, low pH o Mucous membranes contain lysozymes (enzymes which break down bacteria) o Other cells contain cilia which filter pathogens and particulates Breaks in the protective barrier o Digestive openings o Reproductive openings o Respiratory openings o Sensory Organs

Non-specific responses - the second line of defense • • •

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Non-specific responses are generalized responses to pathogen infection - they do not target a specific cell type The non-specific response consist of some WBC's and plasma proteins Phagocytes - cells which "eat" foreign material to destroy them o Phagocytes are formed from stem cells in bone marrow (stem cells are undifferentiated WBC's)  Neutrophil - phagocytize bacteria  Eosinophils - secrete enzymes to kill parasitic worms among other pathogins Macrophage - "big eaters" phagocytize just about anything

Macrophage destroying bacterial cells •

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Non-phagocytic leucocytes o Basophil - contain granules of toxic chemicals that can digest foreign microorganisms. These are cells involved in an allergic response o Mast Cells - similar to basophils, mast cells contain a variety of inflammatory chemicals including histamine and seratonin. Cause blood vessels near wound to constrict. Complement proteins - plasma proteins which have a role in nonspecific and specific defenses

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Form a cascade effect - if only a few are activated, they will trigger others to become active in great numbers  Some punch holes in bacterial walls (forms holes where cellular components leak out)  Some promote inflammation  Concentration gradients attract phagocytes to irritated or damaged tissue

Encourage phagocytosis in phagocytes (promotes "eating")  Some bind to the surface of invading organisms Chemokines - create a chemical gradient to attract neutrophils and other leucocytes to the wound site Inflammation 

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Causes localized redness, swelling, heat, and pain Changes in capillary wall structure allow interstitial fluid and WBC's to leak out in tissue Promotes macrophage (phagocytic WBC's) activity Macrophages secrete Interleukins (communication proteins among WBC's)  Interleukin-1: increases body temperature (i.e. causes a fever)  This enhances the WBC's ability to protect the body  Causes drowsiness - reduces the body's energy usage and stress

The Immune System (Specific Responses) - the third line of defense •

Called into action when nonspecific methods are not enough and infection becomes widespread

Types of cells involved in the immune system: • • • •

Macrophages - engulf foreign objects o Inform T lymphocytes at a specific antigen is present Helper T cells - produce and secrete chemicals which promote large numbers of effector and memory cells Cytotoxic T cells - T lymphocytes that eliminate infected body cells and tumor cells B cells - produce antibodies (secrete them in the blood or position them on their cell surfaces)

Each type of virus, bacteria, or other foreign body has molecular markers which make it unique •

Host lymphocytes (i.e. those in your body) can recognize self proteins (i.e. those which are not foreign)

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When a nonself (foreign) body is detected, mitotic activity in B and T lymphocytes is stimulated o While mitosis is occurring, the daughter populations become subdivided  Effector cells - when fully differentiated, they will seek and destroy foreign  Memory cells - become dormant, but can be triggered to rapid mitosis if pathogen encountered again

Thus, immunological specificity and memory involve three events: (1) Recognition of a specific invader (2) Repeated cell divisions that form huge lymphocyte populations (3) Differentiation into subpopulations of effector and memory cells • •

Antigen - a nonself marker that triggers the formation of lymphocyte armies Antibodies - molecules which bind to antigens and are recognized by lymphocytes

Antigen-presenting cell - a macrophage which digests a foreign cell, but leaves the antigens intact. It then binds these antigens to MHC molecules on its cell membrane. The antigen-MHC complexes are noticed by certain lymphocytes (recognition) which promotes cell division (repeated cell divisions)

Molecular cues that stimulate lypmphocytes to create an immune response T cells (Helper T cells and Cytotoxic T cells)

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T cells arise from stem cells in the bone marrow - they then travel to the thymus where the differentiate and mature. At maturity, they acquire receptors for self markers (MHC molecules) and for antigen-specific receptors. They are then released into the blood as "virgin" T cells. T cells ignore other cells with MHC molecules and they ignore free-floating antigens. However, they will bind with a antigen-presenting macrophage (a macrophage possessing a MHC-antigen complex). This binding promotes rapid cell division and differentiation into effector and memory cells (all with receptors for the antigen) Effector helper T cells secrete interlukins (stimulate both T and B cells to divide and differentiate) Effector cytotoxic T cells recognize infected cells with the MHC-antigen complex. They then destroy the cell with perforans (enzymes which perforate the cell membrane, allowing cytoplasm to leak out) and other toxins which attack organelles and DNA

Cell-mediated immune response B cells and Antibodies • • • • •

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B cells also arise from stem cells in the bone marrow. As they develop and mature, they start synthesizing a single type of antibody Antibodies are proteins which recognize antigens The virgin B cell produces antibodies which move to the cell surface and stick out The B cell floats in the blood - when it encounters the specific antigen it becomes primed for replication The B cell must receive an interleukin signal from a helper T cell which has already become activated by a macrophage with a MHC-antigen complex. This promotes rapid cell division. The B cell population then differentiates into effector and memory B cells The effector B cells then produce a staggering amount of free-floating antibodies o When these free-floating antibodies encounter an antigen, they tag it for destruction by phagocytes and complementary proteins o These types of responses are only good for extracellular toxins and pathogens they cannot detect pathogens or toxins located inside of a cell

Antibody-mediated immune response Where do all of these interactions take place? - In the lymph nodes.

2. Explain the role of genetic engineering and gene therapy in the treatment of neurological disorder. Genetic engineering is the process of inserting new genetic information into natural cells for the purpose to modify a specific organism by altering or enhancing genes. Since the 1970’s, scientists have genetically engineered animals to repair genetic defects and enhance their resistance to disease. Today, scientists genetically engineer animals to enhance their production of useful substances that provide nutrition or treatment medication for humans. For example, a sheep named Tracy was genetically enhanced to produce large quantities of human protein in her milk. Similar to Tracy, cows are also being enhanced to produce extra proteins in their milk to improve the nutritional value. A Hen named Brittany was also one of the first animals to be genetically engineered. She was modified to produce eggs with high levels of protein, which are useful to create anti-cancer drugs. Also, plants are genetically engineered for similar reasons. In particular, they are enhanced to increase crop yields, crop quality (redness of a tomato, prolong freshness), tolerate environmental extremes (cold, dry weather) and have greater resistance to disease and pests. As science around genetic engineering develops, humans may one-day be able to design their children. Today, scientists hold the science to enhance the intelligence of animals, which brings anticipation for future procedures on humans. Joe Tsien, a Princeton University Neurobiologist, genetically engineered a single gene called NR2B into mice to control a brain chemical called NMDA (N-methyl-D-aspartic acid) that plays a role in learning and memory. Tsien’s results showed that after the gene was inserted into the mice, they produced more NMDA. To prove that these mice attained enhanced intelligence, Tsien and his colleagues tested the abilities of these mice compared to unmodified mice. These mice were put to tasks such as recognizing objects in their environment and solving problems such as how to get out of water and or off a high shelf. As a result, the genetically modified mice outperformed the unmodified mice Tsien concludes that these findings suggest that enhancing the intelligence of humans may be possible. He explains that the gene in humans that corresponds with memory and learning has been found and how it performs in the brain is currently being studied. Gene therapy is a medical procedure that may hold the cure for many of the diseases and disorders of humankind. Gene therapy, a rapidly growing field of medicine, is the insertion of genes into a person’s cells and tissues to treat an inherited disease. It is much like a transplant. However, although transplanting a human heart or liver is complex, transferring genes involves thousands of small molecules that cannot be seen with even the most powerful of microscopes. Gene therapy aims to supplant a defective mutant gene with a gene that works. The technology is still in its infancy but has been used with some success although many questions still surround the procedure. To understand gene therapy, it is first necessary to understand heredity.

Neurological conditions were once thought to be off-limits to gene therapy approaches because of the blood–brain barrier. However, genetic research activity in this area is progressing. Scientists are investigating the possibility of gene therapy to treat Alzheimer’s disease, epilepsy, Parkinson’s disease, and other neurological diseases.  ALZHEIMER’S DISEASE (AD) Gene Therapy and AD In 2006 researchers at the Salk Institute and the University of California, San Diego, have used gene therapy to reduce memory loss in mouse models of AD by reducing the amount of an important enzyme ß-secretase, or BACE1. According to Oded Singer, one of the authors of the study, mice with AD overcame deficits after progressing to a severe level of the disease. This finding is important because humans are usually not diagnosed until the disease has progressed into recognizable stages. However, amyloid plaques can precede the onset of dementia by many years. Enzymes cut the APP and release toxic fragments that stick together to form clumps. One of the enzymes that damage APP is ß-secretase or BACE1. Gene theraphy for alzheimer They located the forebrain, where memory cells are held, and injected it with 40 billion viruses through holes drilled on either side of the upper skull. • The vector viruses went into the memory cells and released DNA into the nucleus. • The DNA produced NGF. • NGF (nerve growth factor) was then released to the rest of the brain to maintain cells important to memory.  EPILEPSY On 8 November 2006, researchers at the Children’s Hospital of Philadelphia announced that they had inhibited the onset of epilepsy after a brain insult in animals. A brain insult is an initial episode of epilepsy or an injury such as a severe head trauma; the patient often develops epilepsy after such insults. Using gene therapy to modify signaling pathways in the brain, neurology researchers, Amy R. Brooks-Kayal and her colleagues significantly reduced the development of seizures in rats. Seizures are caused by the rapid firing of brain cells and are thought to be caused by an imbalance between the neurotransmitters and the glutamate system, which stimulates neurons to fire, and the neurotransmitter gamma-aminobutyric acid (GABA), which inhibits that brain activity. Working in a portion of the brain called the dentate gyrus, the scientists focused on type A receptors for GABA. GABA(A) receptors are made up of five subunits of proteins that play an important part in brain development and controlling brain activity. Rats with epilepsy had lower

levels of the alpha1 subunits of these receptors and higher levels of alpha4 subunits. The researchers used gene therapy to alter the expression of alpha1 subunits and then injected an AD virus carrying the gene that alters the expression of the protein in the brain. Later they injected pilocarpine, a drug that causes status epilepticus (SE), a convulsive seizure. They found that rats that received gene therapy had elevated levels of A1 proteins and either failed to develop seizures or took three times as long to express spontaneous seizure compared to rats that did not receive the gene. According to Brooks-Kayal, this trial shows that there is a window for intervening after a brain insult; it provides proof of the concept that altering signaling pathways in nerve cells after such an insult could provide a scientific basis for prevention of epilepsy.  PARKINSON’S DISEASE (PD) In 1817 James Parkinson first described a neurological disorder in which patients have shaking tremors in the hands, muscular stiffness, difficulty in balancing and walking, and progressive physical and mental deterioration. The face takes on a frozen, mask-like expression that may become fixed. PD is caused by the death of brain cells that produce a vital chemical known as dopamine. A specific area of the midbrain, called the substantia nigra, that controls motor coordination is affected. Treatment at present consists of giving a precursor of dopamine, L-Dopa, which can diffuse into the brain. However, over a span of years the medicine becomes less effective. PD may be a good target for gene therapy for the following reasons: • Neurological damage is restricted to one area of the brain; this contrasts with AD, in which the entire thinking part of the brain is affected and then the damage spreads to other areas. • A specific type of cell, the dopamine-producing neuron, is needed to relieve the symptoms of PD. Researchers experimenting with gene therapy in one PD treatment found longlasting production of L-Dopa. Using adeno-associated viruses (AAV), researchers delivered two human genes to the specific area of the brain: production was stable for 1 year and there were no observable toxic effects after the treatment. Genetic research on PD is difficult and inconclusive. Tracing of families with incidents of PD has to concentrate on geographical regions where a condition might have appeared spontaneously in a single individual. The difficulty in this work is that familial cases do not differ from sporadic cases. Presenting at the Fourteenth Annual Congress of the European Society of Gene Therapy in Athens, Greece, November, 2006, the UK firm Oxford BioMedica released preclinical efficacy data on a gene-based product showing that ProSavin outperformed the standard L-Dopa treatment for PD. Long-term therapeutic benefits showed benefits for at least 15 months without loss of effects. Also, ProSavin does not induce the disabling dyskinesias, or movement disorders,

associated with L-Dopa. ProSavin is administered locally to the striatum area of the brain and delivers genes for three enzymes that are required for the synthesis of dopamine. Oxford BioMedica plans to start European phase I and phase II trials in 2007 in patients with late-stage PD, and proposes a clinical plan to follow in a phase III trial, which could begin in 2009. A different perspective on PD was published in the November 2006 issue of the British journal Lancet Neurology. H. C. Fung and colleagues announced that there does not appear to be a gene that strongly influences the risk of PD in most patients, although genes of small influence may still be discovered. Conclusion: Advances in molecular biology have triggered an unprecedented expansion of knowledge about human genetics. The rise of new genetic technologies, and their implied power, has engendered concerns among religious, scientific, and civic leaders that these new technologies may be growing more rapidly than our ability to prudently control and productively use them. The ability to insert human genes into human patients to treat specific genetic diseases–human gene therapy and genetic engineering “engineering” of humans– has been one of the concerns noted by those observing the evolution of genetic technologies. Human gene therapy will first be considered in a clinical situation where it might be possible to treat with a human gene an individual patient suffering from a genetic disease. Gene therapy would be attempted only when there is no other therapeutic alternative, or when the alternatives are judged to be of greater risk or less potential benefit. Application of gene therapy for a human genetic disease should require evidence that it is safe, might prove beneficial, is technically possible, and is ethically acceptable. Judgments should be made in a procedurally sound and objective regulatory framework. Genetic engineering and gene therapy plays a role in the treatment of neurological disorders. Making some adjustment or articulation in the genes of a human being can make a big difference in health and well being of a person. Gene therapy could even enhance memory of an Alzheimer’s patient, prevent & control seizure (Epilepsy), relieve symptoms of Parkinson disease and even prevent further damage of the brain. Studies also show that genetic engineering could enhance intelligence of a person based on the experiment done to a rat. Our technology has gone so far. We have benefited a lot in our technology but it doesn’t stop here because it is continually being developed to help uplift our lives. Hope we could use the new discoveries in a good way so that there will always be a positive outcome. We should not abuse it instead we must use it for the improvement of our life and better health.