Imbalances in Brain Chemicals

Communication between neurones depends on the balance of naturallyoccurring chemicals neurotransmitters. An imbalance in these neurones can result in disorders with physical and mental symptoms. Neurotransmitters are chemicals that transmit nerve impulses across synapses. Examples: dopamine and serotonin.

Parkinsons Disease

This is a disease that involves a loss of dopamine secreting nerve cells in an area of the midbrain called substantia nigra. These dopamine secreting neurones spread through the frontal cortex, brain stem and the spinal cord. Dopamine from these neurones is involved in the control and coordination of movement and emotional responses. So loss in these neurones means low dopamine levels and therefore decrease in the transmission of nerve impulses involved in movement the motor control is lost! Symptoms of Parkinsons disease: Tremors (shaking): which is normally the first symptom. Slow movement Stiffness (rigidity) of muscles Depression Poor Balance Sleeping, walking, talking, breathing problems.

Treatment for Parkinsons Disease Treating diseases means getting drugs across the blood-brain barrier. This is a problem! The blood-brain barrier is formed by the endothelial cells that line the capillaries of the brain which are very tightly joined together. This barrier is good because it makes it difficult for the bacteria to cross into the brain and cause infections. This barrier is bad because it also makes it difficult to get drugs into the brain.

There is no cure for Parkinsons disease, but there are drugs that ease/delay symptoms. As the symptoms are caused by lack of dopamine, drugs should be given to increase levels of dopamine. Dopamine itself cant pass the barrier.

1.

Levadopa (L-Dopa): - This is the molecule used to make dopamine which means more nerve impulses are then transmitted across synapses in the parts that control movement, controlling the symptoms. - It is converted to dopamine once it is in the brain. Dopamine Antagonists: - These have a similar shape protein to the neurotransmitter dopamine. - These bind to dopamine receptors in the brain synapses and mimic the effect of dopamine and trigger action potentials. - They are useful because they avoid higher than normal levels of dopamine in the brain which can cause schizophrenia! MAOB Inhibitors: - These inhibit the enzyme monoamineoxidases which is responsible for breaking down dopamine in the brain. Therefore no break down of dopamine takes place. Gene Therapy: - Even though Parkinsons is not a genetic disease, inserting a healthy gene into affected cell can work. - This is done by, inserting genes for proteins that increase dopamine production or, - Inserting genes that promote the growth and survival of dopamine producing nerve cells. - The problem with this is getting the gene into the midbrain. Stem Cell Therapy:

2.

3.

4.

5.

- This can provide a cure! - This is done by using embryonic stem cells to replace the failing dopamine producing cells in the brain. - Problems with this are the ethics of stem cells and that it could cause uncontrolled growth which could cause cancer. See AS Stem Cells!

Depression

Serotonin is the synaptic neurotransmitter in neurones in the brain stem that have axons that spread throughout into the cortex, the cerebellum and the spinal cord. Serotonin transmits nerve impulses across synapses in the parts of the brain that control mood linked with reward and pleasure. Lack of serotonin results in fewer impulses travelling to the brain and is linked to clinical depression. Symptoms of depression: Insomnia Feelings of sadness Anxiety Hopelessness Loss of interest

Depression is a multi-factorial condition. It could be due to genetics, environmental factors (E.g. work/death), or a chemical inbalance. If two people inherit the same genes linked to depression, they both may not develop the disease because the environment also contributes. Dopamine and noradrenaline may also have a role in some conditions of depression. Treatment for Depression Talking therapies can help a patient come to terms with adverse life events. Drugs are developed to increase the concentration of serotonin in the synapses.

1.

SRRIs (Selective Serotonin Reuptake Inhibitors):

These block the process which removes serotonin (reuptake) from the synaptic cleft. So serotonin remains and more impulses travel along the post-synaptic neurone, relieving the symptoms. An example is prozac.

2. 3.

TCAs: - Increase levels of serotonin in the brain. MAOA: - Inhibits the enzymes that break down serotonin, so more remains in the synaptic cleft. MDMA Ecstasy Treatment for Depression? Usually, serotonin is taken back into the presynaptic neurone after an action potential, to be used again. MDMA increases levels of serotonin by inhibiting the reuptake of serotonin into the presynaptic neurone. Also, MDMA releases all serotonin from presynaptic neurone into the cleft. This means the synapses have a high concentration of serotonin, so nerve impulses are constantly triggered in parts that control mood mood elevation! Side effects of ecstasy: Clouded thinking Increased heart rate Muscle Spasms Problems in thermoregulation Hyperthermia (overheating) Kidney failure: due to no urine production and person drinking too much water causing osmosis to destroy cells. Short term effects of ecstasy: Feeling happy Sociable Full of energy

Long term effects of ecstasy: - Depression: because the drug has been stimulated so much, there is a loss of serotonin from neurones due to lack of reuptake. The Effect of Drugs on Synapses

The five stages in synaptic transmission that can be affected 1. Neurotransmitter synthesis and storage: - For example, L-dopa is converted into dopamine, increasing the concentration of dopamine to reduce the symptoms of Parkinsons disease. - If a drug blocks this process, synaptic transmission would be reduced as the amount of neurotransmitter is reduced. This means that nerve impulses wont pass between cells. 2. Neurotransmitter release from the presynaptic membrane: - If a drug blocks this process, this would also stop synaptic transmission. 3. Neurotransmitter receptor binding on the postsynaptic membrane: Some drugs might be stimulatory and bind to the receptors, opening the sodium channels. For example, dopamine agonists that mimic dopamine, binding to the receptors and triggering action potentials. Some drugs might be inhibitory, blocking the receptors and preventing the neurotransmitters binding, therefore stopping post synaptic potentials. 4. Neurotransmitter reuptake: A drug blocking this would reduce the intensity of the response as less neurotransmitter will be resynthesized. For example MDMA (SSRI) works by preventing the reuptake of serotonin. 5. Neurotransmitter break down: - Some drugs may inhibit the enzymes involved in breaking down the neurotransmitter in the synaptic cleft. - A drug blocking this means that stimulation will continue as the concentration of neurotransmitters would increase in the synaptic cleft.

The Human Genome Project

The Human Genome Project was a 13 year multinational project that determined the base sequence of the human genome. It identified all of the genes found in the human DNA and was stored in databases. Using these databases, new genes have been increasingly identified (therefore proteins); including some that are responsible for inherited conditions (disease). New drugs are being created using the information from the Human Genome Project! Using the information from the identified genes, new specific molecules that drugs interact with to have their effects (drug targets) are being identified. For example, an enzyme that helps cancer cells to spread around the body has been identified. So a drug that inhibits this enzyme is being developed. The Human Genome Project has showed genetic variations between people each individual has unique DNA (except identical twins). So until now drugs have been produced to suit the majority of people, even though some of these variations make some drugs less effective for some people. In the future, it may be possible to tailor new drugs to suit all individuals, even people with variations. So, information about a patients genome may help doctors to prescribe drugs that are: More efficient The correct drug The correct dose (by understanding how rapidly a patients body will respond). They will produce new drugs affect the disease without damaging healthy body cells and reducing the chance of adverse reactions (saving NHS millions!). Pharmacogenomics has been developed to link pharmaceutical expertise with the knowledge of the human genome to develop medicines that work with a particular genome.

The Human Genome Project allows some diseases to be prevented because if you know what genes you carry, you can know what disease you are likely to be at risk from. The Human Genome Project also helps to provide information about evolution and increases our knowledge of physiology and cell biology.

Ethical, moral and social Issues Financial Issues: Creating drugs for specific genetic variations (about 25% people) will increase research costs and time for drug companies. Also, the cost will increase because doctors/chemists will have to be trained. These drugs will be more expensive so only wealthy people will afford it. Could this money be used for something that benefits the majority?

Is it ethical to leave people with genetic variations with no treatment available if there is none? Or is it moral or ethical to give them a drug knowing it will have no effect? Revealing that a drug might not work for a person could be psychologically damaging to them because they have the hope to get better.

Who should the information of the genome be assessed to? The information could be used by others, for example insurance companies or bosses, and lead to discrimination.

Genetically Modified Organisms

Genetic modification is copying genes and inserting them into other organisms. Genetically modified organisms are organisms that have had their DNA

altered. Our growing knowledge of the human genome is being used in the development of genetically modified organisms to produce proteins which are used as drugs and vaccines to treat human conditions. Microorganisms, plants and animals are used to genetically modify.

Genetically Modified Microorganisms Microorganisms such as bacteria are the most common target for genetic modification because: - They are easy targets for gene transfer as they reproduce rapidly. - They can be grown in large quantities in fermenters. - They are cheap to culture. - It removes problems of uncertain supply and provides constants source of human hormones.

The gene for the protein (drug) is isolated by cutting out the gene with restriction endonuclease enzyme. 2. The gene is copied using PCR. 3. The gene is inserted into a DNA plasmid (type of vector that carry genes into an organism). The plasmid is cut with the same restriction endonuclease enzyme. So the plasmid and gene join with DNA ligase to produce recombinant DNA. 4. A host bacterial cell has its existing plasmids removed and the vector is used to introduce the gene into the host cell. 5. The modified bacterium will grow in large containers so that they divide and produce lots of the useful protein, from the inserted gene 6. The drugs produced can be extracted and purified using downstream processing.
1.

Insulin, to treat type II diabetes, is an example of a drug produced from genetically modified bacteria.

Genetically Modified Plants

To make more complex proteins, desirable human genes are introduced into eukaryotic cells (plant cells) to produce transgenic plants. Drugs produced from genetic modification of plants can be stored and

transported easily in plant products such as bananas or potatoes. These can be genetically modified to carry vaccines to human diseases such as hepatitis B.

Vectors to carry the gene into the plant include Agrobacterium tumefaciens bacterium, gene guns or a virus. The Ti plasmid from the Agrobacterium tumefaciens is extracted. The useful gene can be inserted into the plasmid which is then returned to the bacterium. The modified bacterium infects the plant and the bacterium inserts the gene into the plant cell DNA. So part of the Ti plasmid with the gene becomes part of the plant chromosomes. The A. tumefaciens causes a tumour (crown galls) to develop on the plant so they have abnormal growth. These plant cells contain the new gene. If tumour cells are taken and cultured, whole new plants can be grown from them, containing the new genes. These are transgenic plants. The protein produced from the gene can be purified from the plant tissues or the protein could be delivered by eating the plant.

1. 2. 3.

4.

5. 6.

See AS level stem cells totipotency/pluriplotency

Genetically Modified Animals

The production or proteins using transgenic animals involves the introduction of a copy of a human gene which codes for the protein into the genetic material of an egg of a different animal species.

1.

2. 3.

Liposomes, viruses, microprojectiles and microinjections are used to inject the gene into the nucleus of a fertilised animal egg cell. Microprojectiles DNA is shot into the cell at high speed carried on minute pellets. Microinjection DNA is injected into a cell through a very fine micropipette, this micropipette is manipulated using a micromanipulator humans would destroy the cell! The egg cell is then implanted into and adult animal and it grows into a whole animal that contains a copy of the gene in every cell. The protein produced from the gene is normally purified from the milk or semen of the animal.

The first transgenic sheep, Tracey, produced the human protein AAT in her milk. A promoter sequence was inserted which makes sure the gene will be expressed in the mammary gland of the lactating female so that the protein is expelled as milk. AAT was needed for a vaccine taken by people who suffer a genetic condition that affects their livers and lungs, causing emphysema to develop at a very early stage.

Drugs produced using genetically modified animals include the blood clotting factors used to treat haemophilia.

Benefits with Genetically Modified Organisms 1.

Risks/Ethics with Genetically Modified Organisms

1. 2.

3.

4.

5.

Genetic pollution genes may be transferred into wild species through cross pollination. Antibiotic resistance genes are used to identify genetically modified bacteria which could lead to antibiotic resistance developing in other microbes. Genetically modified crops could become super-weeds that out-compete other plants and may be resistant to herbicides. They could damage natural food chains, resulting in damage to the environment because they would encourage farmers to use more selective herbicides to kill everything but the crop. This is the biggest problem. Genetically modified crops may not produce fertile seeds. This prevents farmers collecting seed and replanting, so they need to buy new seeds for each planting. This is expensive. Some people think it is wrong to genetically modify animals purely for human health.