CF Heterozygote Advantage: Zach's Rough Draft

Since the discovery of the disease Cystic Fibrosis (CF) is has been proposed that carriers, heterozygotes, of the disease may have a genetic advantage against Cholera. Heterozygotes carriers of the disease Cystic Fibrosis (CF) may have a genetic advantage against Cholera. This is not the first time in which a heterozygous form of a disease was thought to hold a genetic advantage. proposition has been hypothesized before with other diseases. Heterozygous carriers for sickle cell anemia have been found to be resistant to Malaria.People who are heterozygous for sickle cell anemia have been found to be resistant to Malaria. The hypothesis of a heterozygote CF genetic advantage is a relatively new idea. In order to understand how this advantage is possible, one needs to examine each of the diseases CF and Cholera. Understanding how both affect an individual will help in examining the question and understanding how the two can be related, as well as leading to an answer.In order to understand the advantageous hypothesis, CF and Cholera must be explained. (Something like that? Hope that helps.)

Cystic Fibrosis
Cystic fibrosis is a very common autosomal disease among Caucasians. It is estimated to occur in 1 of every 25 Caucasians (Cuthbert, Halstead, Ratcliff, Colledge, & Evans, et al, 1995). Thus, it is possible that those who are heterozygous for the disease have some sort of genetic advantage. However, if one is to be homozygous recessive for the disease, that is they have CF, the outcome is lethal. There is no known cure for CF and, with medication, estimates put the expected life-span somewhere in the 30’s, yet recent advances in the medical field may be pushing this expectancy into the 40’s to early 50’s. (There is no solid proof for this data, this is just an estimation.) (MAYBE SWITCH PLACES WITH THE SENTENCES TO KEEP IDEAS TOGETHER, YOU JUMP FROM CF, TO HETEROZYGOUS BACK TO BASIC INFO ABOUT CF)

CYSTIC FIBROSIS IS A COMMON AUTOSOMAL DISEASE, PREVALANT IN CAUCASINS, OCCURING »> SOMETHING LIKE THAT
Cystic fibrosis is characterized by a high salt content in sweat, causing thick mucus whichto coats the lungs and ducts of the digestive system. and An excessive appetite with poor weight gain USUALLY FOLLOWS. The root of these problems isARE due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein channel. This protein channel is responsible for the cells’ ability to secrete and take in chloride ions (Cl-). Along with the activation of these channels and the movement of Cl comes the movement of water. Therefore, the mucus that coats our lungs and digestive epithelium is dehydrated and creates thick mucus which serves as a great culture for infectious bacteria to grow, especially in the lungs.
PRIOR TO DISCOVERING THE CAUSE OF CF AND HOW IT AFFECTS AND INDIVIDUAL, DEATH WOULD BE INEVITABLE DUE TO MALNURAMENT.Before the discovery of the cause of CF and the means by which it affects an individual, death would occur because the victim could not get adequate nutrition form its diet. This was due to the mucus which essentially blocksed the duct of the pancreas preventing the release of digestive enzymes into the intestines. BY NOT RELEASING THESE ENZYMES, The food that is consumed is not metabolized properly and the individual receives no nutrition from the meal. This explains how those with CF have an excessive diet yet struggle to gain weight. The inability to metabolize food and obtain the required nutrients made it rare for those with CF to live past infancy.
HOWEVER, Today the most common cause of fatality in individuals with CF is due to the mucus which coats the epithelium of the lungs. THE MUCUS IS DEHYDRATED PROVIDING AN OPTIMAL ENVIRONMENT FOR INFECTIOUS BACTERIA. Since this mucus is dehydrated it serves as an excellent culture for infectious bacteria to grow in. One such bacterium is Pseudomonus aeruginosa, which CF individuals are highly susceptible to. (A SEPERATE THOUGHT? TIE THIS IN BETTER) Localization of CFTR is required for signaling in response to P. aeruginosa infection. Such signaling is needed for the coordination of innate immunity to P. aeruginosa lung infection, a process that is defective in CF (Kowalski & Pier, 2004). The mucus then becomes infested with various types and strains of bacteria, many of which can, and do, develop into serious health problems. Another thing the mucus does is reduce the lung capacity volume. As the individual gets older the amount of mucus continues to build up in the lungs and reduces the maximum level of performance the lungs can operate at. This coupled with the invasion of the lungs by infectious bacteria is what ultimately leads to a severe decrease in health, and eventually death.
A less serious result of the disease, but still distinctly specific to CF, is a high concentration of salt in the sweat. As mentioned before the CFTR protein channel does not function properly, therefore, the Cl- in is not reabsorbed by the cell. The Cl- then binds with sodium ions (Na+) to create salt. This salt is highly concentrated in the sweat and individuals are known to leave a salt residue on the surface of the skin after sweating for some. Before the sweat chloride test (WHAT IS THIS? MAYBE EXPLAIN HOW CF IS DETECTED FIRST) was developed to discover CF in an individual the skin of the newborn was licked, if a salty taste was found then the child died, then for unknown reasons, of CF. However even this trait has been known to cause serious health problems in individuals with CF. IS THIS OUT OF PLACE? OR DO YOU MEAN HAVING HIGH SALT CONTENT? In 1948, a devastating heat-wave in New York City resulted in many children with CF becoming dehydrated from losing excessive salt in their sweat (Goodman & Percy, 2005).
The underlying cause to all these problems is related to the malfunction of the CFTR protein channel. Mutations in the CFTR gene have been associated with classic pancreatic-insufficient CF (Miller, Hamosh, Macek Jr., Greenberger, MacLean, Walden, Slavin & Cutting, 1996). The CFTR protein channel is required to transport chloride ions in and out of epithelial cells, therefore, keeping Cl- and salt levels at their appropriate levels within the body. In normal individuals the CFTR works properly and as the chloride ions move in and out of the cell water moves with to keep the concentration at equilibrium. However, in individuals with CF the CFTR does not function properly and the since the chloride ions are not transferred as they normally should be, water is not allowed to move in the same way it should be moving, as well. ( I THINK ALL CFTR CONTENT NEEDS TO BE TOGETHER EXPAINING THE HIGH SALT CONTENT, THEN IT WOULd MAKE MORE SENSE
BUT IT JUMPS FROM ONE IDEA TO ANOTHER THAN BACK TO ORIGINAL IDEA)
Medical advances have made it possible for those with CF to live longer lives with many individuals living into their 30’s. NEW DISCOVERIES, MEDICINE AND MODERN TECHNOLOGY HAVE INCREASED THE LIFE EXPENDANCY OF CF INDIVIDUALS; THESE INCLUDE»»»» It is believed that with modern advances and new discoveries these individuals may be able to extend their lives into their 40’s or possibly even early 50’s. To deal with issue of insufficient pancreatic secretion of digestive enzymes, individuals take artificial enzymes orally before meals to break down the food and extract the required nutrients. Along with these artificial enzymes several other oral medications are taken daily. (I UNDERSTAND YOU ARE TRYING TO TIE THIS IN WITH THE PARAGRAPH BUT IT JUST SEEMS OUT OF PlACE WITHOUT SOME KIND OF LEADING SENTENCE)
(ARE THERE DIFFERENT STAGES OF CF? THESE THOUGHTS NEED TO BE SPLIT UP TO MAKE SENSE) As for the more severe problem of a build up mucus in the lungs several treatments are used. One method used is percussion in order to break-up and loosen the mucus in the lungs. This is often followed by coughing up and spitting out the phlegm. A nebulizer is used to introduce medication, through breathing, to fight any possible infectious bacteria living in the lungs. Sometimes the medication is a hypertonic saline, which has been proven to help improve the health of the lungs and mucus clearance (Donaldson, Bennett, Zeman, Knowles, Tarran, & Boucher, 2006). Along with these two main preventive measures, sinus medication is also prescribed to keep the airways open and healthy. Even with all this medication, which must occur daily, individuals can still develop health complications that require hospitalization where intensive medication is administered. Frequent visits to the doctor are also a must with regular monthly check-ups even when the individual is said to be fully healthy, for someone who has CF.
Cholera
Cholera is an infectious disease caused by the gram negative bacterium Vibrio cholerae. It affects the infected individual’s small intestine by releasing cholera toxin which induces diarrhea. V. cholerae is contracted through contaminated water supply, mainly by ingestion, but simply coming into contact with a contaminated water supply can also lead to an infection. It is most commonly prevalent in third world countries which do not have adequate means of sterilizing their water supply. BETTER IF THIS WAS TOWARDS THE BEGINNING OF PAPER
If and individual infected with cholera does not receive medical attention death can occur within days or even hours. The symptoms are easy to recognize and unpleasant for the individual. They include severe dehydration, due mainly to the induced diarrhea, vomiting, abdominal pain, and fatigue. These symptoms may progress very rapidly and have been known to cause death in less than 18 hours.
The most common strain of V. cholerae is known as O1 El Tor, discovered by Robert Koch who described cholera he observed in the Egyptian city of El Tor (Goodman & Percy, 2005). Many strains are sporadic and for many years O1 El Tor was the only known strain which caused epidemic spread of the disease. However, a new strain recently found to cause epidemic spread of cholera, named O139, was discovered in Bangledesh. Upon further study of four areas of Bangledesh cholera breakouts were found to be seasonal, around the monsoon season (Sack, Siddique, Longini Jr., Nizam, Yunus, Islam, Morris, Ali, Qadri, Faruque, Sack, & Colwell, 2003). The monsoon season would be an ideal time for V. cholerae to thrive as large supplies of water could have been contaminated, especially in the poorer regions of the study area.
Even with its devastating effects, cholera can be prevented, and if still acquired, treated with great success. Prevention of V. cholera is as simple as sterilizing the water supply, which explains why cholera is not very prevalent in developed countries. For individual who become infected simply rehydrating the person is a cheap and simple solution. The cholera toxin induces diarrhea, dehydrating the individual, therefore, replacing the lost fluid and electrolytes is the key to fighting the life-threatening effects. Along with rehydration therapy those who become infected can also take antibiotics, however it should be noted that some strains of V. cholerae have shown a resistance to some antibiotics.
Relationship between CFTR and Cholera
As mentioned before the CFTR protein channel is responsible for the movement of chloride ions in and out of epithelial cells. The cholera toxin released by V. cholerae affects the mechanism of the CFTR to cause the life threatening effects of cholera. The cholera toxin stimulates the production of cAMP, which activates the CFTR and initiates the release of Cl- into the intestine. Following the Cl- into the intestines is water and this results in the symptom of diarrhea. The cholera toxin is so aggressive that dehydration of the cells happens rapidly requiring the immediate treatment of rehydration.
The thought behind the advantage is that heterozygous CF carriers will have an advantage because they only have one working copy of the CFTR gene. Heterozygotes are expected to have only half the normal amount of working CFTR and this smaller amount would translate into decreased fluid secretion response to cholera toxin (Gabriel, Brigman, Koller, Boucher, & Stutts, 1994). When only one CFTR gene works properly then, in theory, only half the amount of chloride should be secreted. With less chloride ions being released there will be less of a need for water and the symptom of diarrhea is reduced to a less serious extent. This proposed advantage is what many believe to be the reason for the high prevalence of CF among Caucasians.
In order to fully understand how this relationship between the CFTR protein and the cholera toxin other causes of secretory diarrhea needed to be studied. Heat-stable enterotoxin and guanylin have also been shown to induce intestinal epithelial chloride secretion. However, the release of Cl- is caused by an increase in the cGMP, as opposed to cAMP. This involvement also suggests a possible heterozygote advantage against forms of secretory diarrhea (Chao, Sauvage, Dong, Wagner, Goeddel, & Gardner, 1994).
Much of the research that has been done still leaves the primary question of whether or not CF heterozygotes have a genetic advantage against cholera. Through the study of how the CFTR protein functions and how it is affected by cholera toxin, along with other inducers of chloride secretion, the idea seems plausible. Yet, when we look at the results a clear conclusion cannot be made. The evidence seems to point towards no genetic advantage for a CF heterzygote, even when intestinal chloride secretion is induced by a variety of sources (Cuthbert, Halstead, Ratcliff, Colledge, & Evans, 1995).
Still I don’t think we can disclaim the fact that CF is so prevalent in Caucasians. In fact, in order to maintain at equilibrium a gene frequency of 0.02, the magnitude of the advantage of the heterozygote to remain in high frequency would only need to be about 2% (Knudson Jr., Wayne, & Hallet, 1965). At the beginning it was noted that CF occurs in 1 of every 25 Caucasians, which is 4%. However, we still do not have any clear cut evidence that can point us in one direction or another.
I believe there is still not enough information on this specific hypothesis of a CF heterozygote genetic advantage against Cholera. Much research has been done to point us in the right direction of answering this question but there is still more to do before it can be answered. I think the idea behind the investigation is plausible but it needs to be studied further before any definitive conclusions can be drawn. Also, by continuing to study this question perhaps we can learn more about the functions of both of these lethal diseases, which will hopefully lead to improved quality of life for individuals who are affected.

I WOULD SUGGEST KEEPING INFORMATION TOGETHER MAKING THE PAPER FLOW BETTER, THE PARAGRAPHS ALSO NEEDS TO BE REARRANGED IN ORDER TO FOLLOW AN OUTLINE. THIS WOULD ALSO HELP THE PAPER MAKE SENSE BECAUSE YOU JUMP FROM ONE IDEA AND PARTIALLY EXPLAIN IT, JUMP TO ANOTHER IDEA, AND BACK TO THE ORIGINAL IDEA, MAKING THE READER TO PUT THE INFORMATION TOGETHER THEMSELVES. THIS IS CONFUSING. ALSO, THE CONCLUSION SHOULD TIE IN ALL POINTS DISCUSSED, INCLUDING GENETIC ADAVANTAGE OF HETERZYGOTES. NOT SURE ABOUT USING FIRST PERSON.

INTRODUCTION
CF
CHOLERA
GENETIC ADVANTAGE
CAUSES
MEDICATION
TREATMENT

…….AND SO ON

MAYBE YOU COULD USE CATEGORIES TO KEEP THE IDEAS TOGETHER? YOU HAVE REALLY GOOD INFORMATION THOUGH AND YOU DO A GOOD JOB OF EXPLAINING THINGS. INTERESTING SUBJECT.

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