Varahi Trivedi: Design Project: Neurofibromatosis 1
Background:
Neurofibromatosis is a genetic disorder originated in the nervous system which perturbs cell growth and formation, resulting in tumor development in the brain, spinal cord, and nerves. This is the most common neurological disorder caused by a single gene, within which are three separate branches, NF 1, NF 2, and Schwannomatosis, each of which is affected by a different gene. Additionally, an affected individual will not acquire all three subsets, only one. However, out of the three types NF 1 yields to be the most commonly occurring and, therefore, most necessary to treat.
Existing Treatment and Research:
This dire disease unfortunately has no existing treatment; however, this is not to say that there have not been attempts to reduce effects of the disease, if not eliminate it all together. The Children's Tumor Foundation has been engaging in Neurofibromatosis research for the past eighteen years, inventing laser technologies to remove tumors, providing support to victims and family members, promoting public awareness of the disorder, and raising money to encourage even more research to work towards a cure. Research conducted by various organizations collectively helps about 100 million NF patients every year.
Yet, the fact remains that NF is a disease that just keeps expanding, until there is further something done. And that something must involve the core of the disease, down to the genetic exchanges and mishaps that lead to NF.
Genetic Origin of Disease:
Neurofibromatosis 1 occurs when there is a mutation on the NF 1 gene of Chromosome 17. Mutations along this gene are relatively common because the NF 1 gene itself is so long - 8,454 bases - providing much room for error. Within this gene are two proteins: Neurofibromin and Ras. Neurofibromin is essentially a tumor repressing protein produced in nerve cells and specialized cells call oligodendrocytes and Schwann cells. These two work in a cause-and -effect pattern where Neurofibromin regulates Ras. which controls cell division. In a normally functioning cell, Neurofibromin will bind to Ras, and cell division will occur at a controlled pace.
In a mutated cell, the shape of the Neurofibromin protein will become altered and therefore unable to bind with Ras protein. Without Neurofibromin regulating it, Ras cannot control cell division, causing it to occur at a dangerously rapid pace, thus forming tumors in various locations of the body.
Proposed Design:
The main repercussions of NF 1 are physical structure abnormalities and tumors in the bones, arms, groin, and eyes, as well as cognitive defects in sight, hearing, and learning. The main indicator of having NF 1 is a bout of medium to large brown markings called cafe au lait spots. When there are more than six spots present, this demonstrates the initial, yet harmless, signs of NF 1. Another large hint of having NF 1 is from a family history of the disease because the mutation is often inherited. Since the cause of NF 1 is a gene mutation, tackling the disease where is starts is the best way to eliminate it in an individual altogether.
There is no secure way of predicting when a random mutation will occur, nor is it possible to remove an inherited mutation. While prenatal testing is used to screen for diseases, especially in a family with NF 1 history, mutations are not easy to identify, so this method is not very reliable to prepare for or prevent disease. One thing you can do is try to reduce the effects of the mutation by enabling the two proteins Neurofibromin and Ras to bind. Injecting a special bacteria into an individual showing the cafe au lait spots can help target the disease in its early stage and possibly halt tumor growth altogether. This engineered bacteria would essentially alter the shape of the mutated Neurofibromin protein and allow it to bind with Ras and properly carry out cell division.
This injected bacteria is responding the change in shape of Neurofibromin protein, thus enervating the effect of the mutation. The NF 1 gene would be expressed as usual when the proper protein functions are carried out. In a research study, analysis of bovine (cow) heart tissue showed that the mitochondria contained small amounts of neurofibromin, meaning the two are associated. The specialized bacteria would contain mitochondria that would change the neurofibromin shape to fit it with the ras protein.
Step by Step Treatment:
1.) Injection of mitochondria-containing bacteria into the bloodstream and travel to the NF 1 gene.
2.) The bacteria will bind to the neurofibromin and combine the mitochondria with the protein
3.) Once the mitochondria and neurofibromin meet, the bacteria will alter the protein's shape and the mitochondria will retain that shape.
Expected Results:
Using this bacteria, the mutation of the NF 1 gene would prove to be ineffective because it shortens or alters the Neurofibromin shape; however, the specially
engineered bacteria would restore the protein to its original shape. Neurofibromin is a rather vulnerable protein due to its location, and not much is known about
its biological function aside from the fact that it can accelerate the rate by which ras proteins perform GTP-hydrolysis.
The insertion of this special bacteria into the body will prove to be successful in an individual because the root cause's endeavor will be stopped completely. Even if a mutation occurs, its motives cannot be carried out when the protein that is supposed to become malformed restores its shape. This would enable cell division to occur properly and inhibit tumor growth along nerves and skin.
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As opposed to prenatal testing and tumor removal, this method will prove to be advantageous because it is more reliable than searching for a mutation and longer lasting than temporarily getting rid of tumors because the mutation has already occurred and can just sprout more.
This bacteria insertion solution is definitely worth funding because if it goes right, it is fool proof! The mutation has happened, but its designated effect is not followed through upon. When the two proteins neurofibromin and ras bind together properly, no tumors are produced. No method is as specific and promising as this one.
Potential Problems, Safety Measures, and Testing:
The only potential problem that may occur is if the bacteria does not bind, the mutation will succeed and alter neurofibromin's shape and lead to ras going out of control with cell division. Another possibility is if the bacteria for some reason does not reach the proper gene and bind somewhere else along the way.
While dealing with the special bacteria, employees are not to leave the injection unattended or facing anything other than the target region of insertion. Handle the delicate bacterial substance with safety to avoid all risks. In a lab environment, the bacteria injections would be encased in a special container and locked away until it is time for use.
If, throughout time, the protein becomes resistant to the bacteria, the effectiveness could potentially wear off.
The potential rewards are worth the risks because there is so much that could be solved if this solution proves to be effective in majority of the NF 1 cases. The possibility of tumor growth and cognitive defects could be completely out of question.
A simple way to test the effectiveness is to first isolate a mutated NF 1 gene in the lab and attach the bacteria with the neurofibromin protein to see if its shape alters from mitochondria and enables it to bind with ras properly.
Sources;
__http://wsnfsupport.org/about-neurofibromatosis-2/facts-statistics/__
__http://learn.genetics.utah.edu/content/disorders/whataregd/nf1/__
http://learn.genetics.utah.edu/content/begin/dna/neurofibromin/
__http://emedicine.medscape.com/article/1177266-treatment__
__http://www.jneurosci.org/content/23/26/8949.full.pdf__
__http://www.ctf.org/category/r4r-blog.html__
__http://ghr.nlm.nih.gov/gene/NF1__
__http://emedicine.medscape.com/article/950151-overview__
__http://www.ncbi.nlm.nih.gov/pubmed/14999847__
__http://www.sciencedirect.com/science/article/pii/S009030199700356X__
__http://www.millipore.com/references/tech1/7yv3f6__
__http://learn.genetics.utah.edu/content/disorders/whataregd/nf1/__