Genes that promote Alzheimer's

Alzheimer’s disease is a neurodegenerative disease, associated with improper protein folding, which leads to mental impairment and finally death. The disease arises as a consequence of the misfolding and subsequent clumping together or aggregation of abnormal Beta proteins, and the formation of a toxic misfolded protein in the body. The basic physical properties of a protein molecule may differ and how a protein is able to fold into a stable three-dimensional shape, which can adversely affect the correct formation of properly functioning proteins. The correct three-dimensional structure is essential to function, although some parts of functional proteins may remain unfolded. Failure to fold into the intended shape usually produces inactive proteins with different properties including toxic prions. Several neurodegenerative and other diseases are believed to result from the accumulation of misfolded (incorrectly folded) proteins, such as Alzheimer’s. Rather than becoming present due to an invading infection of the body by a virus or a bacterium, these diseases are of the body's own making. Alzheimer's disease is often referred to as “protein misfolding disorder”. This disease it thought to be genetically induced. This may be due to an APOE ε4 allele, which is most highly associated with Alzheimer’s for individuals with a family history of dementia, and this association is highest for individuals that carry 2 APOE ε4 alleles (ε4/ε4 genotypes). There is not cure for AD at the moment. This means that treatments will only manage to slow down the progression of Alzheimer’s in some patients. There are though to be three genes responsible for the early onset of the disease, which are APP, PSEN1, and PSEN2. This means that Alzheimer’s is becoming more prevalent in younger generation with multiple gene responsible for the disease. In the past only on gene, the APOE gene, which is normally associated with people who are 60 years of age and on. There are several studies where this APOE gene has been studied and it is still unclear why these proteins function in an improper manner. At present, there is no definitive evidence to support that any particular measure is effective in preventing Alzheimer’s. Global studies of measures to prevent or delay the onset of Alzheimer’s have often produced inconsistent results. However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing Alzheimer’s. Only further research, including clinical trials, will reveal whether these factors can help to prevent Alzheimer’s.

Hanna Martin

Genetic predisposition to Obesity leads to risk of type 2 Diabetes

Genetic Predisposition to Obesity leads to increased risk of type 2 Diabetes
H. Zhao and J. Luan
PubMed
Heather L. Mayer

Obesity is a major risk factor for type 2 diabetes. Recent genetic studies have identified that BMI and risk of obesity are linked to multiple loci. Little information is provided about obesity and its association with type 2 diabetes. Type 2 diabetes results from genetics and environmental factors. It has been determined that being overweight or obese is a major risk factor for type 2 diabetes. The rapid increase in obesity has contributed to the rising prevalence of type 2 diabetes over the last three decades. (Zhao) It is not known whether specific DNA sequences of obesity increase the risk of diabetes because not all obese individuals have type 2 diabetes and vice versa. The goal of this study was to examine the associations of the 12 obesity specific DNA sequences with the risk of developing type 2 diabetes. The methods of this study involved individuals from Norwich between the ages 39-79 who has DNA available for genotyping, the process of examining DNA sequences. Of the individuals, the experimenters excluded any of the participants with missing data about their age, sex and BMI. There were 12 specific DNA sequences that the researchers were looking for with a SNP, single nucleo-tide polymorphism, which is just a sequence of DNA with an error. 20,428 individuals were genotyped at the 12 SNPs. There was a follow up of an average of 12.9 years during which 739 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI with the incidence of type 2 diabetes. Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes meaning that eight DNA sequences specific to obesity have been shown to be prone to diabetes. The conclusion that the experimenters derived from this study was that the genetic predisposition to obesity leads to increased risk of developing type 2 diabetes which is completely regulated by its “obesity-predisposing effect.” (Zhao)
I found this article to be interesting because with all the commotion about the obesity in American and the prevalence of type 2 diabetes, I have always questioned what caused this relation. Prior to taking a genetics course I most likely would not have grown to appreciate what scientist/researchers can prove or show with examining ones DNA. It is remarkable to know that there are specific sequences in our DNA that can determine a predisposition to a medical condition. From reading this research article I learned that there are specifically 12 SNPs, altered DNA sequences, that are directly correlated with the prevalence of obesity and of those 12 SNPs, 8 of them show a direct correlation with a predisposition to type 2 diabetes. I still question though how with diet regulation and exercise, how a once obese person who becomes lean and fit no longer suffers from type 2diabetes. What is it about losing weight and eating better changes the diabetes if the DNA sequences remain the same?

MED school Trey Isaac

Trey Isaac
Dr. Gazdik
Bio 305 Genetics
24 February 2011
In the article “Why medical school students switch careers” by Ian Scott, the author discusses the many factors that influence medical students to switch from Family medicine to specialties in the medical field.
According to Dr. Ian Scott “Seven factors influenced switching career choices; 6 of these (medical lifestyle, encouragement, positive clinical exposure, economics or politics, competence or skills, and ease of residence entry)”. These are the major factors that control a student’s choice to change the focus of their medical school studies. In order to figure out who changed their major focus of study they had students who were entering medical school fill out a questionnaire asking them to list their top three career choices and focuses. Out of the total of 1321 students who were asked complete the survey 1181 of the students replied. After the students had completed their preclinical training they were again asked to complete a second questionnaire. Out of the 1181 students that had completed the survey the first time only 872 responded to the second survey. However, out of the 872 students that replied to the survey 27 of them left the question answering their top three career options blank. This left the focus group with 845 students who gave data for them to research and analyze. In the questionnaire they also asked students certain background information. From this background information they were able to see that “830 students listing their undergraduate training held Bachelor of Science or similar degrees”. This means that fifteen people who had entered medical school held degrees that were different from a degree in science. A conclusion that came out of this study that surprised me was that relationship status had no effect on the students switching their career. The major information that the researchers were looking for was the number of students who changed their career from a specialty to family medicine or from Family medicine to a specialty. According to the data “About 19.6% (166 students) changed their top career choice to a specialty or family medicine; 88 switched to family medicine, and 78 switched to a specialty”. Also the researchers found that 137 of the people who took both surveys retained their interest in the career of family medicine. Then the researchers cross referenced the first questionnaire and the second one to compile the date to fully understand how the factors affect the changes of career. When they cross referenced this is the date they compiled
“At medical school entry, 215 (25.4%) of the 845 students who answered both entry and follow-up questionnaires listed family medicine as their first career choice. This number rose to 225 (26.6%) at the end of the preclinical years”.
So the overall increase to family medicine was ten people which, does not seem like a big shift but one has to look at 88 students who changed their career from a specialty to family medicine in relation to the 73 students that switched from family medicine to a specialty. Out of all of the students that switched their career only a ratio of 1 to 30 said it was for a reason other than the seven major factors that have been stated.



Work cited
Scott, Ian, Margot Gowans, Bruce Wright, and Fraser Brenneis. "Why Medical Students Switch Careers: Changing Course during the Preclinical Years of Medical School." Canadian Family Physician 53: January (2007). PubMed.com. Web. 24 Feb. 2011. .

Plant Genetics

In this article researchers estimated the genetic increase of grain yields of the carioca type (beige with brown stripes) of the common beans after 8 cycles of recurrent selection. They wanted to know if they kept selecting the genes they wanted if they could increase the grain yield in the bean plant. When conducting this experiment the researchers of The Federal University of Lavras (UFLA) did not have a clear hypothesis. They had an idea of what the outcome might be but they never created a hypothesis. They used past studies of different crops such as, wheat, rice, oats, and soybeans to estimate what might happen when they preformed the study with beans.
The researchers started out this experiment by using 10 different genetic bean lines that were created in 1990.They crossed the different genetic lines creating a F1 generation. They then double-crossed them creating F2 generation. They took 150 seeds from the F2 generation to perform this experiment. They planted the seeds in plots that consisted of two 4m rows with 15 seeds per meter. They took the highest yield producing plants and crossed them to create a F3 generation. They continued to repeat this until they had reached the F9 generation. By doing this they were selecting the plants that had the gene for producing a higher yield. Once those plants were cross breed with each other eventually most of the offspring from the parent plant would contain the same high yield gene. They also preformed this experiment in several locations at three different times of the year when beans grow the best, February, July and November. The F9 generation of the recurrent selection process is the eighth selection cycle that the researchers were looking for. Researchers found that recurrent selection is an effective way to increase grain yields in future generation. This is what the researchers thought would happen. They didn’t have a clear hypothesis but they suggested what they thought might happen with reference to previous studies.
I found this article very interesting. Plant genetics has always caught my eye. The thing I liked the most about this article is that I can take what the article says and apply it to something more practical. For example instead of trying to increase grain yields we could breed the beans to be resistant to a certain disease. You would use the same type of procedure but instead of selecting the plants with the gene for higher crop yield you would select the gene for being resistant to the disease. I find it very interesting that people can control the outcome of how a plant will look or any special features it may have just by picking what genes each plant has that you cross. I learned that there is a lot more to plant genetics then just cross breeding for the best genes. It may take years for the trait you are looking for to appear and many different cross breeding cycles for that plant to produce offspring with the same traits. Recurrent selection is also used to improve several other traits in plants such as plant architecture, and pathogen resistance.


Olivia Callahan

Cancer can be a good thing

There are many scientists that are concentrating their research on genetically modified organisms. A GMO is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one molecule to create a new set of genes. This DNA is then transferred into an organism, giving it modified or novel genes. Genetic engineering is being used as a means to speed or supplement conventional breeding of perennial energy crops. In agriculture many plants are genetically modified to be resistant to insects and pesticides, two traits that can be economically valuable to farmers. Small scale experimental plantings of genetically modified (GM) plants began in Canada and the U.S. in the late 1980s. The first approvals for large scale, commercial cultivation came in the mid 1990s. Since that time, adoption of GM plants by farmers has increased annually. In the article I chose, scientists focus on genes that can cause a delay in differentiation. Cellular differentiation is the process in which less specialized cells become more specialized. This means that the cells will develop into a certain kind of cell such as a root or stem cell in plants. In humans this is when cells are developed into liver cells or heart cells. Instead of being a basic cell they now have a specific purpose in that particular organism. If they don’t differentiate then they will be in a continuous state of proliferation. Cellular proliferation is the multiplication or reproduction of cells that result in the expansion of a cell population. This is commonly known as cell growth. When cells are continuously being replicated in humans in can cause tumors. In this article scientists study the characteristics and functions of the gene UPBEAT1. This gene promotes rapid growth in plants by delaying the differentiation process in plants. In other words the gene discovered, called UPBEAT1, causes cancer in plants. In agriculture, especially when it comes to biofuels, cancer can be a really good thing. If plants are continuously growing and growing at a faster rate, farmers are able to get more yields out of their crops. By understanding how UPBEAT1 works, scientists can create GMOs that will drastically increase the yield of certain switch grasses and corn to produce more biofuels. However the article also points out that government regulations are holding back this research and can have a negative impact in the agriculture world. Most regulations and laws have been imposed because officials assume the GE organisms are pests and weeds until proven otherwise by extensive research and experimentation. Since research in not always allowed many of the GMOs in this day and age are pretty much patented by the companies that engineered them. Although a number of exotic species are available and many more are being tested, they pose a serious risk of spread from extensive plantings, which could cause broad ecosystem alterations. However only four species of crops, corn, maize, cotton, and canola, have been genetically engineered for herbicide or insecticide resistance.

Population Genetics of Feral Horses: Implications of Behavioral Isolation

Population Genetics of Feral Horses: Implications of Behavioral Isolation Michael C. Ashley United States Department of Agriculture, Agriculture Research Journal of Mammalogy 85(4):611-617. 2004. The Garfield Flat Herd Management area in western Nevada has a large herd of feral horses, which separates into two smaller herds for most of the year. During the winter when food and water are scarce the herds combine into one for a period of time, but remain separate during the other seasons. This study tested these two herds to see if they had any genetic differences from each other, as well as another feral herd from the Granite Range Herd Management Area, in Northwestern Nevada, about 215 km (133 miles) away. They sought to assess the variety of genetics, or degree of inbreeding within and between herds, which is a concern because genetic diversity is vital to keep a population healthy. However, they predicted that behavioral tendencies would affect the spread of genetics. Feral herds can be made up of multiple males and females, but usually consist of one dominant male with a group of females. In addition, some weaker males may be in the herd, but have fewer females to mate than the dominant male does. Females typically have one foal per year, usually in the spring or summer. Foals stay in the herd until sexual maturity, at which time they may be isolated, join a different herd, overpower the dominating male or start their own herds. Females were found by Ashley to be most likely to mate with dominant males in other herds rather than bachelors if they did not mate within their own herds. This is how genetic variety occurs between herds. However, if physical surroundings or behavior patterns prevent the animals from exchanging genetics the species can be endangered. The Garfield Flat Herd Management area, (HMA), is isolated from other outside herds because of the surrounding landscape. The two herds at this location will be referred to as Garfield Flat and Garfield Hills, and at the time of the study included 192 horses while the Granite Range had 473 horses. The horses were captured, blood samples were taken and sex, age, and physical description were all recorded. Herd behavioral patterns were observed and recorded at both sites. Once collected, the blood was taken to a lab where DNA was amplified using PCR techniques, which allowed the DNA to be typed to determine parentage. Parentage allele frequencies were determined, showing high variety between the three groups. Behavior correlated with this finding, since the time of the year the groups combined was during winter, before foaling. Since most mares are rebred within 2-3 weeks after foaling, they were mostly with their own herds at this time. Although a few alleles were shared between the groups, there were 28 unique to the 3 populations. Although the two Garfield groups had a high amount of genetic difference, there was even more between these two groups and the Granite herd. Behavior does have a big influence on genetic variation. Because the two Garfield herds separated during foaling and breeding season there was a much higher diversity between the two groups, however, the overlap found was caused by the ability to travel great distances during the spring then they otherwise separate. Even when the herds combine, they separate at the end of winter into their original groups. These behaviors limit genetic overlap. During herd bottlenecking, when the breeding stock consists of less than 20 animals, the genetics are narrowed even more. Ashley also found that unequal mating of males can also limit the gene variability in a herd. According to Ashley, if endangered, keeping the groups separate would maintain genetic variety between populations, findings which can preserve wildlife of all species, not just horses. Identifying the role of behavior was also key, and how the herds maintain their genetics naturally. I found this article interesting not only because of the strong behaviorial links between genetics between the herds, but also due to the implications this has on other species. If wildlife management wants to preserve a set of genetics, they can base their practices on this study. Sarah Reeves

Pharmacokinetics of sapropterin in patients with phenylketonuria

The article, Pharmacokinetics of sapropterin in patients with phenylketonuria was about a treatment method found to help treat those with phenylketonuria. Phenylketonuria is an inborn error in amino acids metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase (1). A phenylalanine hydroxylase deficiency leads to high blood phenylalanine levels. Pathogenesis is the process of converting phenylalanine to tyrosine. Phenylketonuria collects in all body fluids, because it cannot be converted into tyrosine. A large amount of phenylalanine is converted into tyrosine where as a small portion is integrated into proteins. Phenylketonuria has a pathway that is blocked which causes blood levels of phenylalanine to be extremely higher than levels of a normal healthy human (2). Phenylalanine is an essential amino acid, meaning the body does not make it and it is essential that one must consume it through nutrition.

Phenylalanine is supposed to be broken down by phenylalanine hydroxylase. During hydroxylation, phenylalanine needs certain cofactors and enzymes to allow for the production of tyrosine to occur (3). For the translation to occur the process must involve phenylalanine hydroxylase, cofactor tetrahydrobiopterin (BH₄), and other enzymes like dihydropteridine reductase and 4α-carbinolamine dehydratase to assist in the restoration of tetrahydrobiopterin (4). When phenylketonuria is in question it’s the deficiency of the enzyme phenylalanine hydroxylase that is not present, meaning phenylalanine cannot be further broken down which leads to the increase levels of phenylalanine in blood.

Usually those with phenylketonuria manage their disease with a protein-restricted diet. The difficulty issue with diets is there is often a failure to comply with the routine of the diet. Supplementation of BH₄ has been proven to reduce plasma phenylalanine levels for phenylketonuria patients. Neutral amino acid supplementation works off in a reverse method of L-Phenylalanine to induce the inhibition of the amino acids to cross the blood-brain barrier (5). The blood brain barrier allows a competitive inhibition of the uptake of phenylalanine by the neutral amino acids. One supplement that is on the market that many Phenylketonuria patients have chosen to use is Kuvan, which is saproterin dihydrochoride tablets. Sapropterin dihydrochloride is known and one of the first medical therapies along with diet for phenylketonuria (6). In many trials this product has been tested and it has been proven that it helps control blood phenylalanine levels in Phenylketonuria patients (7). Tetrahydrobiopterin (BH₄₎ is that helps in lowering the levels.

Sapropterin dihydrochloride, also referred to as sapropterin is an artificial invention of 6R-tetrahydrobiopterin (6R-BH4), which had been proven to be effective in decreasing the blood phenylalanine levels in patients with phenylketonuria. The purpose of the study in Pharmacokinetics of saproterin in patients with phenylketonuria was to identify the characteristics that influence variability of sapropterin.

The study lasted for twelve weeks with fixed amount of doses given to the patients. Patients with phenylketonuria were allowed to participate in the study if there were at least eight years of age and if they had taken the recommended doses in another study that was prior to this twelve week study. There were a total of 78 patients that were involved in this study. The patients received oral once a day doses of sapropterin (Kuvan) in the amounts of 5, 10 or 20 mg/kg. The results showed that the amount of saproterin needed to lower the levels of phenylalanine was based on the patient’s bodyweight, but for all patients the supplement worked and lowered the levels (8).

The topic of phenylketonuria has become an interest of my over the past semester, because I have been doing research on it for a paper. I began to feel sympathetic for those who have this condition, because it can take over one’s life if not treated at a young age and treatment continue throughout their life. If makes one think how hard their life really is, when you look at someone who just may have it a little harder than you.

References:

1. Ding, Z, P Georgiev, and B Thony. “Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. (Original Article). “ Gene Therapy 13.7 (2006): 587. Academic OneFile. Web.31 Jan. 2011.

2. Tymoczko, John, Jeremy Berg, and Lubert Stryer. Biochemistry: A Short Course. W H

Freeman &Co, 2010. Print.

3. Harding CO. Progress towards cell-directed therapy for phenylketonuria. Clin Genet

2008: 74: 97-104. Blackwell Munksgaard, 2008.

4. Williams, Robin A, Cyril DS Mamotte, and John R Burnett. “ Phenylketonuria: An

Inborn Error of Phenylalanine Metabolism. Clin Biochem Rev. 2008 Februrary;26(1):31-41.

5. Pey, Angel L., et al. “Identification of pharmacological chaperones as potential

therapeutic agents to treat phenylketonuria.” Journal of Clinical Investigation

118.8 (2008):2858+. General OneFile. Web.31 Jan.2011

6. Thompson, Cheryl A. “First drug approved for treatment of phenylketonuria.” American

Journal of Health-System Pharmacy 65.2 (2008): 100. Academic One File.Web.31 Jan. 2011.

7. Rollins, Judy A. “First specific drug therapy approved for the treatment of PKU.”

Pediatric Nursing 34.2 (2008): 182. General OneFile. Web.31 Jan 2011.

8. Feillet, Francois, et al. “Pharmacokinetics of sapropterin in patients with

phenylketonuria.” Clinical Pharmacokinetics 47.12 (2008): 817+. Academic OneFile. Web 4 Apr. 2011.

Amber Dowdy

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Population Isolates and Ophthalmic Diseases.

This article is discussing the relevance between genetic isolates and ophthalmic diseases. It will mainly focus on population isolates and the role they play in searching for the underlying genes responsible for monogenic and complex heterogeneous eye diseases. For some background information, population isolates are a group of individuals who are known to have descended from the founder of a population. Because of this, they have been able to maintain a relative degree of genetic homogeneity due to geographical and cultural isolation. There have been many gains in better understanding the genetic etiology (the genes responsible for casing disease) of age-related macular degeneration and eye diseases that are similar. However, the etiology of the heritable blinding diseases (e.g. primary open-angle glaucoma and myopia) are still issues at hand that are working with the population isolated theory, to hopefully gain a better understanding. Population isolates are found in both recessive traits and complex traits

Population isolates are effective ways to further investigate recessive traits. A high frequency rate of new mutations occurring within humans makes it conceivable that there is a high prevalence of recessive diseases in some isolated populations. This happens because of random chance; also known as genetic drift. This also explains why some alleles are able to be more common or rare over consecutive generations. An increased risk of recessive diseases is also associated with consanguineous relationships meaning blood relatives (incest). Consanguinity is lower than it was in isolated populations and this has been shown in a Finnish isolate study. In the study there were thirty monogenic (meaning only one gene) recessive disorders that are more frequent there than anywhere else. One account for this may be linked to non-random migration of families clustering in small geographical areas.

Retinoschisis is an X-linked retinal disease related to population isolates. This is described as the worsening visual cavity, radial and peripheral superficial retinal detachment. Cases with highest prevalence were reported in Finland based upon age and sex (88 males) from 31 families. This particular ophthalmic disease is located on the short arm of the X-chromosome leaving insight into three other founder mutations with high prevalence disease in Finland families. Some other noted examples of retinal diseases within consanguineous relationships is complex strabismus and nanophthalmos. Complex strabismus is a misalignment of the eye and varies with gaze direction. Several Saudi Arabian families were studied and reported to have a basis for autosomal recessive complex strabismus. Nanophthalmos is very rare and is described by small axial lengths with high-hypermetropia on three separate loci of the eleventh chromosome. There are two forms of this that exist, autosomal dominant and recessive, and there is evidence of a founder effect in the Faroe Islands.

Population isolates are also effective means for studying complex traits in ophthalmic diseases. Age Related Macular Degeneration (AMD) is one example of many complex traits. AMD is characterized by two forms, wet and dry. Dry makes up on average 80% of AMD with being described as serous detachment of the retinal pigment epithelium (RPE). AMD varies considerably between ethnic groups. There was a link reported between the US and Japanese populations in correlation with the complement factor H gene contributing to nearly half of all cases of AMD.

Another example of complex traits is primary open angle glaucoma which is asymptomatic with gradual progressive loss of peripheral vision. This is also accompanied by having a cupped head of the optic nerve. This particular complex trait is reportedly found in the French-Canadian populations of Quebec. Four families were studied and later concluded to have been carrying four MYOC mutations that were believed to have been derived from the original Quebec settlers. Also, 14 additional families with glaucoma carried eight of the MYOC mutation from these original settlers.

In conclusion, it has been both successful and helpful in using population isolates. We now have a better knowledge of recessive traits as well as complex traits and the role they play in ophthalmic disease. Isolated populations may only allow for the identification for a few major diseases; however these genes are identified more efficiently than those from non isolated populations. Being able to identify founder effects helps simplify the analysis of genetic diseases as well as helps the screening service in any populations.

Marcee Amos

Giving HIV a Poor Reception: New AIDS Treatment Tinkers with Immune Cell Genes

An article written by Bob Roehr titled, “Giving HIV a Poor Reception: New AIDS Treatment Tinkers with Immune Cell Genes” shows hope for a possible cure for the HIV virus in the future. HIV has long been perceived as an incurable disease that has killed millions of people throughout the course of history. However, scientists have started to learn how HIV enters the body and from that they are now trying to block the entry site to prevent HIV from taking over.

HIV enters cells in the body by attaching to a special region on a cell called a receptor molecule; in this case the receptor is called CD4. Then the virus attaches itself to a co-receptor molecule called CCR5. Scientists then discovered a mutation to the gene that encodes for CCR5. A mutation is a permanent change in the sequence of DNA in a gene. The mutation (called delta-32) prevents CCR5 from being created. With this said, if an individual inherits only one copy of this gene then they have a less likely chance of contracting HIV and if they do, the disease will play out much slower since they will have fewer CCR5 receptors for the virus to attach to. An individual who inherits the mutant gene from both parents will not have any CCR5 receptors which make it close to impossible for HIV to enter the cell.

When all of this was realized, pharmaceutical companies sought out a way to chemically block the CCR5 receptor thus artificially blocking HIV from entering the cell. With this new insight came the production of a small molecule drug called maraviroc.

I chose this article because before I read this article I only thought that HIV entered the body based on what my teachers told me in health class. Their explanation was that it is spread and enters the body through bodily fluids. I never thought about it past that point at a cellular and molecular level. This article enlightened me and has helped me understand how it enters the body on those levels and I found it extremely fascinating. The thought about a potential cure for the HIV virus will be one of the biggest breakthroughs in medical and genetic history.

Ross Beckner

Pittsburgh researchers single out genes for major depression

I chose to blog about a major problem in today's world known as depression. I found an article that studies the genes and the interactions that may cause depression. Scientists at the University of Pittsburgh wanted to find certain genes that would increase a person's chances of developing depression. The study was done with 81 families that had known depressive disorders. The scientists are trying to gain as much knowledge on depression as possible because it is a very serious disorder. Depression affects 10% of the population, and with more knowledge comes more effective treatments and drugs. Previous studies have shown that between 40% and 70% of depression risks are due to genetics. There have always been issues with discovering the actual genes because they believe that many genes are involved. These scientists believe that the difficulty is due to the fact that many genes may cause depression, and it actually depends on the combination of the genes and the individual that leads to the development of depression. They feel they need to perform this study because people with depression are found to live a shorter lifespan. The study itself found that there are small regions on chromosomes where these genes reside. This is what seems to bring on the actual depressive behaviors. Genetics also has a lot to do with depression in gender. It is believed that due to the differences in gender, depression is more likely in women than in men. There is a gene known as CREB1 that has to do with the regulatory protein known as CREB. This protein is known to have a lot to do with different factors in the body and is thought to be the cause of many depressive disorders, as well as other psychiatric disorders. They have identified 18 new genetic regions that may have a great deal to do with CREB and the influence it has on depression. They believe that identification of susceptibility genes could greatly help the early diagnosis and treatment of depression. This could really help the human lifespan. I have learned a lot from this article. I knew that depression was genetic, but I was not aware that the cause is due to more than one gene. I was interested in this article for personal reasons. I know what it is like to have depression and not understand the direct cause. I did not know about the protein CREB or the gene CREB1. It was very interesting to learn about the genetic regions and how much of the population is actually affected by depression. Magen Deane

RNA Interference used to inhibit Huntington's disease translation

RNA interference is used to prevent the expression of specific genes; hopefully, targeting unique rather than simply abundant sequences. The author’s objective in this article was to use RNA interference to suppress the CAG repeats in the Huntington’s gene that lead to the disease state. This research was initially discouraged as the siRNAs used to originally target genes showed little to no discrimination, as several genes were silenced instead of just the target. However; recent advances have allowed peptide nucleic acid antisense reagents to work with a much higher degree of selectivity than prior studies. The study compares the inhibition of the Huntington’s disease allele with the inhibition of the normal allele and other mRNA’s containing both CAG and CUG repeats.
This study showed that selectivity was not only great in the repeat targeting duplex but that this selectivity could even be further enhanced by specific mutations in which the binding efficiency was reduced. Further it was observed that different RNA duplexes silence gene production in different ways. Duplex 7, which had full complementarity to the mutant allele responsible for Huntington’s disease proved to be the most effective. The RNAi actually decreases the rate of transcription which decreases the prevalence of the mutant phenotype. Lastly the most interesting discovery was that an up-regulation of the wild type Huntington allele resulted when inhibition of the mutant occurred via duplex. This could be a result of the action of the RNAi itself, but most likely is a compensatory mechanism for the inhibition of one of the alleles. Basically in the heterozygote cases when a mutant allele is repressed or inhibited the wild type allele is transcribed, or translated, or both more frequently in order to compensate for the protein shortage. This provides some hope for, not just Huntington’s disease but treatment for any disease caused by an expansion of a repeated three gene sequence in the near future. In conclusion the recent advances in the field have taken a technique that was previously disregarded as too hazardous to a patient’s health and begun to evolve into a specific and targeted technique with the promise of one day treating a series of genetic disorders.
I chose this article because I plan to have a future in drug research and it proposed a treatment for a genetic disease. The entire article was interesting as I did not have much in the way of prior knowledge of RNA interference at all. Further I find it somewhat incredible that RNA, the component use for translation, can also be an inhibitor of the very action the text book teaches as almost its’ sole purpose. Lastly it was interesting to see that even at the DNA level the human body does attempt to compensate whenever it is obstructed, especially in this case. Shutting down or restricting mutant alleles will actually cause the other allele to become more pronounced has huge implications if it applies to more than just this set of genes.

J Harper.

Hereditary Hemorrhagic Telangiectasia

HHT is a genetic disorder that causes abnormalities of blood vessels. Most of the blood vessels in the body of a person with HHT are normal. However, some of the vessels do have an abnormality. There are two types of blood vessels: arteries and veins. An artery does not usually connect directly a vein. Usually there are very small blood vessels called capillaries that connect artery to a vein. A person with HHT has a tendency to form blood vessels that lack the capillaries between an artery and vein. This means that arterial blood under high pressure flows directly into a vein without first having to squeeze through the very small capillaries. This place where an artery is connected directly to a vein tends to be a fragile site that can rupture and result in bleeding. When a blood vessel is abnormal this way, it is called telangiectasia. Telangiectases tend to occur at the surface of the body such as the skin and the mucous membrane that lines the nose. The telangiectases of HHT occur primarily in the nose, skin of the face, hands, and mouth and the lining of the stomach and intestines, lungs, liver and brain. We are still not sure why these abnormalities occur in these specific areas.

The study I picked had to deal with mutations of HHT found in Spanish families. They identified two different mutations, 22 ALK1 mutations and 15 ENG mutations, in independent Spanish families affiliated with HHT. They identified mutations in 37 unrelated families. An analysis of all the symptoms were recorded for each patient that was analyzed. They found there were more abnormalities in HHT1 patients than HHT2 patients. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG.

Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1) in the Spanish population. This data goes along with another previous study that was based on Mediterranean countries such as France and Italy, but different to Northern Europe or North America. There was a significant increase of abnormal blood vessels associated with HHT1 over HHT2 in these families.

Christina Moreno

MicroRNAs involved in transformation of liver cancer stem cells

The existence of cancer stem cells in hepatocellular carcinoma (also known as HCC), which is a cancer of the liver, has been confirmed. This discovery was made possible by characterizing certain cells based on the information gathered from the Hoechst 33342 dye used to stain stem cells. This stain is easy to use on stem cells since it is easily “excited” by ultraviolet light. Recent discoveries in microRNA biology have revealed that these types of RNA's do indeed play an important role in the development of embryos and the formation of tumors. This type of RNA protein is“noncoding”and made up of 19 to 25 nucleotides in length. They regulate gene expression by inhibiting and transforming the layers of mRNAs through base-pairing. However, it is still unclear which microRNAs actually take part in the conversion of normal cells into tumor cells during the production of cancer in the liver.

Cancer stem cells have been identified in cells located in the blood and in solid tumors, including hepatocellular carcinoma (HCC). The isolation and characterization of cancer stem cells are usually based on the presence of stem cell markers. Although, in many tissues, certain markers of bodily stem cells are still unclear. There have been many attempts made to identify cancer stem cells in tumors, based on the results from the use of the Hoechst 33342 dye. The ability to isolate these cells by sorting them, makes it possible to improve both normal bodily stem cells and cancer stem cells without the use of stem cell markers.

Researchers used a gene knockout mouse model to show that microRNAs may be critical regulators of the development of organs in embryonic stem cells. However, data suggests that “dysregulation” of these microRNAs occurs in a many types of cancers, such as lung, colon, and liver. The effects of these specific RNAs in both cancer production and the differences of normal stem cells suggest that microRNA may be involved in the transformation of normal stem cells into cancer stem cells.

Hepatocellular carcinoma is one of the most malignant tumors in existence. However, when researchers divide certain population cells, the presence of liver cancer stem cells in many hepatocellular carcinomas cell lines can be verified using this technique. However, few experiments have focused on the characterization of population cells isolated from HCC cells. The researchers in this study saw that if normal stem cells and liver cancer stem cells could be enriched when the side population cells were isolated, then they could create an in vitro model to determine whether this type of liver cancer could develop through these types of bodily cells.

Biomarkers in Rare Disorders: The Experience with Spinal Muscular Atrophy

Spinal muscular atrophy also known as (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN2 gene. Which means both parents must carry the gene mutation for it to be passed on to their children; however, rarely will either show symptoms. There is a 25% chance having a child that is affected. There are three forms of it, all depending on its severity. All patients with SMA will have at least one copies of the homologous gene (SMN2) which produces insufficient levels of the functional SMN protein. Currently there is no known cure for SMA is available. One possible therapeutic idea is based on attempts at increasing the amount of SMN protein produced by SMN2 genes. Recently, evidence has been provided that SMN2 mutation can be altered many different ways. The availability of participating patients to treat SMA has been an issue, but that doesn’t stop the search for a biomarker. This includes the availability of data on the history of the disease and other variables.

So far, different tools have been proposed as biomarkers in SMA. A biomarker can be simply explained as a molecule that is present or absent from a particular cellular type, which indicates whether a specific disease is there or not. The biomarkers that are used in SMA can be classifiable into two groups: instrumental and molecular. The molecular biomarker consists of the SMN gene products in dosages, either transcripts molecules or protein molecules. And the instrumental biomarkers are the Compound Motor Action Potential, the Motor Unit Number Estimation, and the Dual-energy X-ray absorptiometry. Unfortunately, neither of these biomarkers is even close to being available currently for this specific gene.

The authors stated that since the science community deiced to do clinical studies on SMA then the development of biomarkers must be created to further the understanding of this disease. Also since the topic was brought up none of the biomarkers that were used in this experiment meet the “gold standard” quality. These biomarkers just weren’t the most suitable and reliable measures for SMA. Even though some of the results came back positive for the substances that were being tested for, there are still several crucial issues which should be resolved before that biomarker is even considered being available for SMA research.

The biomarker technology is what is being used in this experiment. The SMN transcripts are the only potential molecular biomarker available. The SMN transcript measures the protein in peripheral blood. There are other possible variations of SMN transcripts/protein levels as evaluated in leukocytes may not reflect the real effect of pharmacological treatment in target tissues, like the spinal cord and, possibly, skeletal muscle. Other tissues are being considered as biomarkers, such as skin tissue or muscle biopsies. Muscle biopsies are simply muscle tissue, which has been removed for another use. Also preclinical studies and double-blind, placebo-controlled studies have been mentioned as approach for treatment. Preclinical studies on SMA positive animal models can provide information on some issues. And a double-blind, placebo- controlled studies are crucial to evaluate the effectiveness of specific biomarkers. Even though there has not been a lot of success with the search of a biomarker for SMA, the search doesn’t stop until that day.

-C. Freycinet

Kartagener Syndrome

Kartagener Syndrome is a recessive autosomal disease. This causes a defect of the cilia lining in the respiratory tract as well as the fallopian tubes in women. Patients with Kartagener Syndrome present chronic inflammation of the nasal passages usually causes by an upper respiratory infection. Another chronic inflammation is the ear passages and gives the middle ear an infection. Pneumonia and bronchiectasis which is widening on the air passages and causes them to become flappy and scarred. Diagnostic test can be done to prove the impaired cilia fuctions and genetic test. In severe cases the likely outcome can fatal if the bilateral lung transplant is delayed. In this case of a 66 year old women is chronic reoccuring upper respriatory infections, pneumonia and bronchiectasis, was also presented with acute respiratory failure. She was diagnosed with Kartagener syndrome based on genetic studies and clinical presentation. This lady passed away on a ventilator with refractory respiratory and multiorgan failure. This lady denied chest pains, nausea, vomiting, urinary symptoms and headaches. Once a physical exam was done, it showed this elderly lady was in moderate respiratory distressed. She also had two sister who died of chronic progressive lung disease.

Megan Rutherford

Bio-305-B

Genetic factors affecting bone marrow transplantation

Nine-year-old Laura Mosley has been battling leukemia for most of her short life. The chemotherapy she underwent destroyed her bone marrow’s ability to produce blood cells, so she had to have a bone marrow transplant. Blood-forming cells from another person were injected straight into her bloodstream. She responded well, and her blood cell counts steadily rose. Then a few months later, her body began to reject the marrow. Despite all the tests that had been done beforehand to make sure that the transplant would be successful, the donor’s cells apparently didn’t match her cells closely enough. Laura is now back on the waiting list. Her family members, friends, and even people in her community gotten tested to see if they might be a match for her, but so far, she has had no luck.

Finding someone with a matching tissue type is very difficult, much more so than finding someone with a matching blood type. Tissue type depends on a set of proteins called Human Leukocyte Antigens, or HLA. These antigens can be found on the surface of nearly every cell in the body, including blood cells. They serve as “self” markers, meaning that they allow the body’s immune cells to differentiate between the body’s own cells and foreign cells, like bacteria or viruses. If the free-floating immune cells ever encounter a cell without the right HLA markers, they recognize the cell as foreign and attack it. Thus, HLA is an indispensible component of the immune system. Unfortunately, it also complicates tissue transplants. If the donor HLA type is not similar enough to the recipient’s HLA type, the recipient’s immune cells will attack the blood cells that have formed from the donor’s marrow.

The oldest way to type potential donors’ tissue is serotyping, a technique based on antibody-antigen recognition. Antibodies are proteins produced by the body. These proteins are designed to bind specific antigens, almost like a lock (the antibody) and a key (the antigen). Once the antigen-antibody complex is formed, the antigen is marked for destruction. A person with a specific antigen on their cells will not produce the antibody that binds with it; otherwise the antibodies would attack the body’s own cells! So let’s say that we are looking for a donor with the antigen HLA-B21. We would take a sample of the potential donor’s serum, which is what you get when you take the cells and clotting factors out of the blood. Then we would add an antibody that is known to bind with antigen HLA-B21 to the serum. If we observed evidence of binding, like clumping of the sample or a color change, then we would know that HLA-A is present in the sample. If it is present in the sample, then it is present on all of potential donor’s cells.

Serotyping antibodies have become more and more refined over time, and are increasingly sensitive to slight differences between different types of antigen. But there are limitations to this technique. Serotyping does not preclude the possibility that the transplant will be rejected, as was the case with Laura. The differences between antigens are often so minute that they will bind with the same antibody. Thus, the donor and recipient antigens appear to be the same, when in fact they are “subtypes” of a particular antigen. The differences between the two subtypes may be enough to activate the recipient’s immune response.

Another higher-resolution technique based on DNA matching is now the preferred method for tissue typing. Three or more different loci (or regions) on the gene that codes for HLA are examined. A perfect match at these loci is ideal, though nearly impossible to find, unless the patient has an identical twin. Of course, most people do not have a twin, so they look for a match among their relatives. According to the National Marrow Donor Program, however, the chance that a patient will find a match this way is only 35 percent, so most patients rely on unrelated volunteers. Sadly, only four out of ten people looking for an unrelated donor actually get a transplant. Part of the reason that it’s so difficult to find a suitable match is that there are many different forms of the HLA gene. These forms, or alleles as they are called, arose when the DNA sequence that makes up the HLA gene mutated. These mutations may have occurred long ago or recently. Perhaps the gene is still mutating. Whatever the case, new alleles continue to be identified. It is these different alleles that account for the antigen subtypes. For instance, if a certain allele is found at loci A, then the individual has a particular subtype of HLA-A.

Of the 40 percent of patients who do get find an unrelated donor, practically none of them manage to find a perfect match. Some of these recipients survive; others do not survive or they require a second transplant. The question now is, how much mismatching can the body tolerate? The National Marrow Donor Program conducted a study in order to answer this question. Data was obtained from 3857 transplantations. It was found that mismatches at a single HLA-A, -B, -C, or –DRB1 locus (7/8) was associated with lower survival rate. Of the patients who had a single mismatch at these loci (7/8), 43% survived, compared with a 54% survival rate for perfect matches (8/8). Mismatching (7/8) at these loci is also associated with complications, like “treatment-related mortality” or and Graft-Versus-Host-Disease. Mismatched alleles at the HLA-DQ or –DP loci did not appear to have an effect on survival rate. There were no differences in the survival rates of patients whose donors had been selected using high-resolution DNA typing, or low-resolution serological typing. indicating that allele matching is just as valid a method of tissue typing as antigen matching, contrary to many researchers' opinions.

By AB