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Huntington's disease is a disorder from a mutated gene that causes a neurodegenerative disorder that causes fatal symptoms, coordination problems, behavioral difficulties, or the loss of thinking ability. The primary cause of the disease is the mutation in the Huntington (HTT) gene, which causes a certain DNA sequence to repeat more than it is suppose to and therefore altering the Huntington protein's appearance and function. The disorder usually occurs in families with a history with the disease and mostly takes affect after the person had children or is in his/her middle age. In addition, the symptoms of the disease could begin to manifest at any point of their life.4 However, there are many experiments performed in order to find out how to control the consequences of this disease as well as prevent to it. However, in this paper, the experiment to control the disease was discussed.
Huntington's disease is caused by an excessive repetition of a single DNA sequence of three nucleotides in the HTT gene located on chromosome 4. The sequence that is repeated is the CAG sequence and causes the Huntington protein to be produced defective. The main purpose of the Huntington protein is still unknown. If the sequence was repeated more than 41 times in a single strand of DNA on the gene, then the person will develop Huntington disease.7 Since the gene has an excessive amount of the CAG segment, the gene is therefore longer and causes the protein to be elongated. This protein has to be cut into smaller pieces by using a specialized protease called caspase.11 Proteases are proteins that break up other proteins into smaller toxic pieces. Since the Huntington, protein is usually located in nerve cells in the brain, the break up of the protein causes the toxic fragments to be released into the neurons causing most of them to die by a process called apoptosis or to alter the normal functions of these cells. Most of the neurons that are affected by the mutation are near the striatum, which is part of the brain close to the thalamus.
When the neuron dies or is altered, the effects of it causes most of the symptoms of Huntington's disease. The symptoms include chorea (abnormal voluntary movement of the body), emotional disturbances, depression, coordination problems, trouble making decisions, and trouble speaking and walking.3. 6, 8 These symptoms can lead to an increase possibility of the patient becoming suicidal or fall in to a major depression phase. However, the disease is also known to be fatal within 15-20 years after diagnosed due to the degenerative nature of the disease.4 Treatment for this disease is limited to a few drugs that relieve the pain and help with the emotional problems caused by the disease since there is nothing to cure the disease. However, there are a few experiments being done to try to figure out the cure for patients with the disease.
The experiment discussed in this paper was carried out by scientists from South Korea and has been preformed on mice to see the effects of transplanting stem cells into mice who exhibited symptoms of Huntington's disease. The experiment involved the use of human Neural Stem Cells (NSCs). These stem cells are more specialized than the embryonic stem cells in that these cells are primordial, uncommitted cells that can differentiate into cells of all neural lineages.3 This means that these cells are only restricted to the nervous system while the embryonic stem cells can be altered to become any other type of cell. The uses of neural stem cells also increases the potential these cells have in helping to treat patients with Huntington's disease. The scientists acquired the cells from an embryo's brain at 15 weeks gestation. They then marked these cells with a nonreplicating retrovirus that is encoded with beta-galactosidase and puromycin-resistant genes.3 These genes infect the cells with a "molecular tag" that can be identified later on in the experiment.
Once the cells were acquired, the mice with Huntington's disease were needed. The scientists obtained almost identical 48 adult male Sprague-Dawley mice and injected them with quinolinic acid (QA). This injection causes the striatum to degenerate producing similar symptoms of Huntington's disease. Each of the mice was given the exact same amount of this injection via the stereotaxic apparatus. The stereotaxic apparatus consists of a frame fixed onto the brain with electrodes that are drilled into specific regions of the brain. After the electrodes are drilled into the brain, small electrical charges are applied to see the effects of the charges.12 However, in this experiment, instead of electrodes dilled into the brain, a needle was injected to the brain and the quinolinic acid was applied at the striatum. The mice were then all placed in a control environment and monitored.
After 7 days after injecting the QA into the mice, 16 randomly selected mice received 500 µL of the NSCs solution, 16 random mice received saline solution, which is just salt, and 16 received nothing.3 These solutions were injected into a vein from the tail of the mice. The mice were then observed and the Apomorphine-induced rotation test was applied to each of the mice. "The Apomorphine-induced rotation test provides a sensitive and rapid behavioral correlate of striatal damage and the apomorphine-induced rotation test provides a sensitive and rapid behavioral correlate of striatal damage and has been used to evaluate the potential efficacy of tissue/ cell grafts in excitotoxic-lesioned striatum." 1, 2 The test was performed from the first week after the QA injection was given to 9 weeks after the mice were injected. During this test, the mice were injected with apomorphine and then tested.
Three weeks after from injecting the human NSCs, three mice from each group were "sacrificed" so their DNA from each hemisphere in the brain can be obtained. They did this because they wanted to check for a specific gene only present in the human genome and not in the rodent genome.3 The gene was the endogenous retrovirus-3 gene (ERV-3). They tested for this gene because they wanted to know if NSCs were present in the brain of the mice and to see if the NSCs had migrated from the point of injection to injured/damaged area of the brain. They tested for the ERV-3 gene by performing a PCR. A PCR is a polymerase chain reaction that can be used to multiply a specific segment of DNA many times really fast.9 This would allow the scientists to isolate the gene if present and amplify it to a level that is sufficient enough for the scientists to show as evidence of the presence of human NSCs. In addition, after the mice were killed for the sample of DNA, their bodies were preserved for histological analysis by fixating the body in a paraformaldehyde solution and cryoprotecting the brains. After all of these preparations and procedures, the scientists compiled their result and presented it statistically, graphically, and in words.
The main result of this experiment proved the hypothesis of this experiment right; NSCs did migrate to cerebral hemisphere after the mice where injected with cells through a vein. The PCR test conformed that because the sample taken from the hemispheres of the mice did contain the ERV-3 gene. This proved that if you have specific enough stem cells, they would circulate the body and most likely form new cells, in this case neurons, in the area damaged or missing the cells.
Another result of this experiment was that the NSCs had decreases the rotations in the apomorphine-induced rotation test. According to the data, the scientists gathered, within a week after the NSCs, there was a noticeable decrease in the rotations by the NSCs mice while an increase in the number of rotations for the mice with out the NSCs. In addition, as time went on, the number rotations kept decreasing for the NSCs mice drastically while the mice with out the NSCs had a drastic increase in the rotations.3
Another result was that there was reduced atrophy of the striatum. This meant that the striatum of the NSCs mice did not degenerate to the extent of the mice with only the QA solution. 3, 13 In addition, there was some cerebromalatic changes in the cortex of the mice with only QA solution.3 However, there was striatum atrophy in the mice with NSC but less than half of what the QA only mice had.
On a side note, the mice that were used exhibited similar symptoms of the disease. They did not have actual Huntington's disease; however, due to similarity both the mice and humans show psychologically, mice were used instead of any other animal. In addition, when mice are induced with QA, their effects were similar to humans with the Huntington's disease and because of this similarity, it is reasonable to assume that this experiment would have the same effects on humans.
This experiment was used to find a less painful way of injecting the neural stem cells in to humans. The original way was using the stereotaxic apparatus; however, with this experiment we were able to show a different way to inject the cells. This method has shown the effects of stem cells in the human body. From these two results, we have the potential to cure many diseases. One of those diseases is Huntington's disease. The scientists also showed the value of stem cells in medicine field. They were able to take embryonic cells from a fetus and make them into neurons that helped treat an untreatable disease. The technique that these scientists used can be used to treat many more incurable diseases like Parkinson's disease, schizophrenia, and many more. However, we cannot use this technique in the United States because of the ethical issues over the topic.
In another experiment done in the United States, scientist Steven Goldman, M.D., Ph.D., conducted a similar experiment where he used stem cells to create more neurons. However, his procedure and methods were very different from the experiment done in South Korea. In Goldman's experiment, he believed that the brain already had a layer of stem cells in the ventricular wall region of the brain. However, the problem was how to specifically make those stem cells into neurons that were damaged or killed in people with Huntington's disease. In order to solve that problem he injected a cold virus called adenovirus with two extra genes.5 These genes were called Noggin and Brain-Derived Neurotrophic Factor (BDNF). Noggin is an astrocyte, which is a star shaped cell that provides structural and metabolic support to neurons in the brain.10 The noggin helps stop the stem cells from becoming any other type of cell in the brain. The BDNF helps the stem cells become neurons. When this virus reached the stem cells in the brain, it caused a reaction to occur with the stem cells and create new neurons near the damaged striatum in the brain of people with Huntington's disease.
In this experiment, the results were similar to the one done in South Korea. In both experiments, the mice lived longer and behaved healthier. They had better coordination and motor skills. Both experiments where performed to show that stem cells can form in to new neurons in damaged areas of the brain and the delivery of these stem cells can be taken place with out much pain or risk. Hopefully, the results of these experiments can change people's perspective on the use of stem cells and that we could be able use them in America more efficiently to treat many of the incurable diseases.
Work Cited Page
1. Norman, A.B., Calderon, S.F., Giordano, M., Sanberg, P.R., 1988. Striatal tissue transplants attenuate apomorphine-induced rotational behavior in rats with unilateral kainic acid lesions. Neuropharmacology 27, 333- 336.
2. Emerich, D.F., Lindner, M.D., Winn, S.R., Chen, E.Y., Frydel, B.R., Kordower, J.H., 1996. Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington's disease. J. Neurosci. 16, 5168-5181.
3. Lee S.-T., Chu K., Park J.-E., Lee K., Kang L., Kim S.U., Kim M. (2005) Intravenous administration of human neural stem cells induces functional recovery in Huntington's disease rat model. Neuroscience Research, 52 (3), pp. 243-249., Retrieved December 15, 2008, from http://www.huntington-assoc.com/injection%20stem%20cells%20ene05.pdf
4. Francis O Walker (2007). Huntington's disease. The Lancet, 369(9557), 218-228. Retrieved December 15, 2008, from Research Library database. (Document ID: 1203633051).
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11. What is a CASPASE? Retrieved December 15, 2008, from The Huntington's Disease Association Web site: http://www.hda.org.uk/research/rs006.html
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13. Striatum. (n.d.). Webster's Revised Unabridged Dictionary. Retrieved December 15, 2008, from Dictionary.com website: http://dictionary.reference.com/browse/striatum