Statistics and Reflection

Our BOINC grid completed 725.84 units of work over the semester installed on our computer. We feel that this project has contributed to our learning both of disease pathology and evolution of disease in a very real way. Our opportunity to speak with a professional in the field was an interesting way to see how concepts learned in the classroom can be applied in the real world, especially in the healthcare field. We felt that we made a difference through our small contribution to the grid; we learned a lot about grid computing in general and how we can help a lot just by donating a little of our computer space. This has been a very unique service learning project that we were happy to be a part of.

“Evolutionary Ecology of Human Papillomavirus: Trade-Offs, Coexistence, and Origins of High-Risk and Low-Risk Types” Questions

Questions – Cervical Cancer

These questions address the Journal of Infectious Diseases article entitled “Evolutionary Ecology of Human Papillomavirus: Trade-Offs, Coexistence, and Origins of High-Risk and Low-Risk Types” by Orlando et al. (2011).  Be sure to explain your answers.

1.    On page 1, the authors describe two patterns of selection on the quantitative trait virulence.  Name these two patterns, described below:

a.     “Natural selection often favors intermediate phenotypes”

In the above statement, the authors are describing the pattern of selection known as stabilizing selection in which individuals with intermediate values for the trait virulence have the highest fitness. These individuals are favored by selection.

b.    “…some ecological circumstances may promote extremes of persistence or virulence”

In the above statement, the authors are describing disruptive selection in which individuals with the extreme values of virulence, low or high, have the highest fitness. In this type of selection, the extremes are favored while the intermediate phenotypes are selected against.

2.    Apply Darwin’s postulates to HPV populations in human hosts (see page 2 for guidance).

Postulate 1: There is variation within a population. There are 9 different states, allowing for variation, when dealing with this model of HPV. There are 3 celibate states of people, being susceptible (S), infected (I), and resistant (R). There are 6 other states relating those 3 states; SS, SI, SR, II, IR, RR. This relates to people in relationships. There is also variation in different HPV strands. There are high risk (HR) and low risk (LR) types. HR types produce less virions and have a longer duration of infection, immune response is slower. LR types produce more virions and have a shorter duration of infection, so immune response is quicker. HR types strive in long monogamous relationships while LR types strive in many short relationships.

Postulate 2: Variation is passed from parents to offspring. HPV replicates its DNA within human host cells. LR types create more LR types and HR types create more HR types. 

Postulate 3: Some individuals have greater fitness and results in over reproduction. There are many copies of each type of virus in the human body.

Postulate 4: Selection acts on the population. If the human host is in a long monogamous relationship, HR types will thrive and continue to replicate because there will be more sexual encounters allowing for a longer duration of infection. The LR types will die in that particular human. If the human host is in many short relationships, LR types will thrive and continue to replicate because there are less sexual encounters and the virus needs to be transmitted quickly with each encounter and be able to have a shorter duration of infection with more virions. The HR types will die in that particular human. There is also selection acting in resistant humans. They can no longer contract that particular type of virus, so the virus will not be passed on even if they are in a relationship with an infected person. That particular type of virus will eventually die off either if it has nowhere to move on.

3.    What is an adaptive landscape (sometimes called a Wrightian landscape)?  Please include a 3D figure (with citation).

An adaptive landscape represents the mean fitness of a population. It looks like a mountain and involves multiple dimensions in space. As populations evolve adaptively, they move up the mountain towards the peaks. Multiple gene frequencies are represented on the graph. The high peaks represent high fitness and the low peaks represent low fitness, as illustrated in the figure below. Many loci are represented on an adaptive landscape and contribute to the fitness of a population.

 

Figure represents 2 loci: http://evolution.berkeley.edu/evosite/evo101/images/adaptivelandscape.gif

Source: http://evolution.berkeley.edu/evosite/evo101/VIIC1aComplexNovelties2.shtml

4. The authors define Evolutionarily Stable Strategies on page 4. Can you please explain ESSs in understandable terms?

            Basically, ESSs depend on the simple principle of consumer and resources. Since the amount of susceptible individuals depends on the types of viruses present, different strains have different viral fitness, or the “per-capita growth of infected individuals”. A specific virus has to fight against the other phenotypes to have the highest fitness. An ESS is a form of convergent evolution in which the virus’s “strategy” converges upon several different factors to become most advantageous. Once the ESS is fixed in a population, nothing can disrupt it. Since natural selection acts so strongly on the ESS, no other mutations can be large enough to tilt the strategy of the population to have the best fitness.

            A thought experiment given by Cornell University really helps to illustrate this concept. Suppose that one group of people, or population, is using the same strategy in a game, such as poker. The benefit is that everyone is using the same strategy, so all are receiving the same benefits. Now let’s say that one smaller group within the population begins using a different strategy. The minority would win out over the majority if they receive more adaptive benefits. So now, the minority strategy would beat out the majority strategy, which is no longer evolutionarily stable. If the minority has less fitness/survival than the majority, then the majority group has an ESS that is fixed in the population.

Adapted from http://ess.nbb.cornell.edu/ess.html

5. Given the paper’s conclusion (see page 7), what would you predict about the efficacy of HPV vaccines? Why should an OB/GYN know about evolution?

            Since HPV responds to natural selection and other evolutionary forces, getting rid of one strain of the virus would act as an open niche for other strains to fill. This would create even more of a problem due to a larger amount of mutated viruses. HPV strains compete and will evolve at a fairly high rate, so this mutation of virus will occur relatively fast. According to the authors, the vaccine would act as a “strong selective force”. This means that the virus wouldn’t necessarily completely wipe out a selected strain, but it would act as a mechanism of evolution against it. Then, the potentially dangerous viral interactions would be diminished.

            OB/GYNs should definitely have some sort of background in evolution because of the way that the HPV virus can mutate and change with evolutionary forces. HPV is a huge worldwide problem, and OB/GYNs see and treat it almost daily. They need to be able to recognize the strains in order to complete the right testing and treatment if necessary. Also, evolution plays a role in the formation of cervical and breast cancers. People’s individual genetics interact with their environments, and doctors need to be able to understand the risk factors to educate their patients about. 

Interview with a Cervical Cancer Expert- Dr. Brendan B. Mitchell

On January 29, 2013, our group had the privilege of speaking with a cervical cancer expert, Dr. Brendan Mitchell, M.D. Dr. Mitchell graduated St. Louis University School of Medicine in 1990, and he completed his residency in 1994. He is now a specialist in women’s care in obstetrics and gynecology in the Kansas City area. He expressed that he chose this medical specialty because it is a good balance of both the surgical and primary care aspects of medicine, and he said that delivering babies was one of his favorite parts of his job. Dr. Mitchell is active in the pro-life movement, and he expressed that this issue is of great importance to him. Dr. Mitchell cooked a delicious dinner, and we enjoyed lighthearted conversation and conducted our interview while sharing a meal. Before beginning the interview, we explained grid computing and how our project on cervical cancer was involved in the research grid “Mapping Cancer Markers.” Dr. Mitchell expressed that he had read about grid computing, and he was impressed and interested in our project.

            Dr. Mitchell stated that he does not have any current patients with cervical cancer and that cases of cervical cancer are not very common in his practice. However, in the past, he has seen cases of cervical cancer in both practice and residency. He stressed that most of the patients who are diagnosed with cervical cancer are those that have forgone pap smears for numerous years, and all test positive for HPV (Human Papilloma Virus). Because our project is for evolution, we asked Dr. Mitchell for a reason that doctors treating cervical cancer should know about evolution. He responded that there are different strains of HPV that have evolved through time, and evolution helps doctors understand how the virus will affect the host through different processes.

            “Finding a cure is pretty important; however prevention and early detection are the keys to eliminating cervical cancer. Prevention has already helped us immensely,” Dr. Mitchell stated. The primary method of prevention of cervical cancer, according to Dr. Mitchell, is a routine Pap smear. The results are either normal or abnormal, and the “abnormal” range includes many different diagnoses. “The biggest misconception regarding cervical cancer is that an abnormal Pap smear automatically means cancer,” said Dr. Mitchell. The Pap can come back identifying ASCUS, or atypical squamous cells of undetermined significance. This ASCUS can either be positive or negative for high-risk HPV. If negative, a repeat Pap should be performed. If positive, it can be either LGSIL, or low-grade squamous intraepithelial lesion, or HGSIL, high-grade squamous intraepithelial lesion. Dr. Mitchell says that both of these can be further investigated by a colposcopy.

             In this procedure, the vagina is opened and the cervix is sprayed with vinegar. The vinegar dehydrates the abnormal cells, making them appear white. A biopsy of these cells is then taken, which can be negative or positive for cervical intraepithelial neoplasia. If positive, there are 3 grades of classification. Grades 1 and 2 are things to just watch with the possibility of converting back to normal cells. Grade 3 is referred to as carsinoma “in situ”. This can be further classified into micro- or macro-invasive cervical cancer. From there, Dr. Mitchell would refer the patient to an oncologist. In Dr. Mitchell’s practice, he has only seen about 2 patients with cervical cancer that regularly receive yearly Paps. Those who don’t see a doctor every year and come in without having a Pap in the last ten years are much more likely to present with cervical cancer.

           

            He said he couldn’t stress enough to his patients that yearly checkups and vaccines are what save lives. “New vaccines and implementing new vaccines each year is crucial. It’s difficult to implement these new vaccines because of the social stigma that comes along with the HPV vaccine. Parents don’t want to vaccinate their kids because they think it will influence their behavior and might think it’s alright to be sexually promiscuous,” Dr. Mitchell said. This side of the vaccine has made it less widespread, especially among those with strong religious convictions regarding premarital sex.

            Interviewing Dr. Mitchell was very informative and enjoyable. The interview aspect of this project was beneficial in that we were able to learn about Dr. Mitchell’s first hand experiences with cervical cancer, and we expanded our knowledge of the subject. We were pleasantly surprised to learn that the number of individuals battling cervical cancer is much lower than we initially expected and that he believes the number of cases each year is decreasing. We also learned that yearly exams are key to identifying any problems, and this made us feel more aware and educated about our own health. Our group is very appreciative that Dr. Mitchell was friendly, open, and honest when sharing his time and expertise with us.

Project Description

By Bryna Federspiel, Ashley McGuinness, and Elise Mitchell

In an effort to learn more about cervical cancer and aid research in this area, our group chose to participate in the project Mapping Cancer Markers, found on the World Community Grid. Cancer is a pressing problem worldwide. Currently, early and accurate detection is difficult, rendering treatment less effective. Cancer occurs when damage is done to cellular material, most importantly certain genes within a cell, causing uncontrolled cell growth. Mutations leading to cell malfunction and cancer can be detected in biological samples through indicators such as changes in DNA or proteins; combinations of these markers are unique to various forms of cancer, and individuals diagnosed with the same form of cancer may have different genetic mutations that require different treatments (Jurisica, Cumbaa, Tsay, & Kotylar). This project aims to use the grid to quickly and efficiently analyze data from biological samples from both cancer patients and controls in order to identify multifarious cancer markers. Researchers believe identifying unique cancer markers in various forms of cancer and comparing samples between cancer patients and controls will lead to earlier detection, identification of high-risk patients, and both individualization and optimization of cancer treatments (Jurisica, Cumbaa, Tsay, & Kotylar). Through this project, researchers also hope that markers will be used to lead to more effective treatments for other diseases (Jurisica, Cumbaa, Tsay, & Kotylar).

For more information on grids, see http://www.worldcommunitygrid.org/research/mcm1/overview.do

Cervical (or uterine cervix) cancer is a cancer of the tissues of the cervix, which is the organ that connects the vagina to the uterus (see figure 1 below for the anatomy of the female reproductive system).  It is almost always caused by a previous infection of human papillomavirus, or HPV. There are over 150 HPVs, and more than 40 are transmitted during sexual contact (NIH 2013). This sexually transmitted disease (STD) is the most common STD in the United States, with 42.5% of women having genital infections (NIH 2013).  Low-risk HPVs are those that do not cause cancer, but high-risk HPVs do; types 16 and 18 are the most deadly. These high-risk HPVs are responsible for 5% of cancer worldwide, but some infections can go away within 1-2 years and be asymptomatic (NIH 2013). However, some type of HPV causes 70% of all cervical cancer cases (NIH 2013). HPV infects cells of the epithelium, transcribes its RNA into proteins, and two of these proteins interfere with normal cell function. This makes the cell grow uncontrollably and avoid apoptosis, or spontaneous cell death. These infected cells grow and mutate at a high rate. This leads to high rates of mitosis and tumors in the cervix (NIH 2013).

HPV causes hyper proliferative lesions (warts) on infected epithelial surfaces, either mucosal surfaces or keratinized epithelium. It replicates in stratified squamous epithelium. This virus is in the family Papillomaviridae and has unenveloped, circular, double-stranded DNA. It is expressed after the epithelial tissue completes a replication cycle. It begins in the basal epithelial cells and the infected cells are pushed to proliferate faster by non-structural viral proteins in the basal layer. The genome of the virus is now replicated. The epithelial cells ascend as they mature and the viral genes are expressed. In later stages structural viral proteins continue to be produced.  Our immune system can sometimes fight off these infections, however, if the virus does not go away, it can eventually cause cervix cells to change and become pre cancer cells. These pre cancer cells may either turn into cancer or return to normal. See figure 6 for an electron micrograph photo of HPV. 

Scientists are now stating that it can take 10-20 years after an initial infection of HPV for a cervical tumor to form (NIH 2013). Practicing safe sex using condoms is a way to reduce the transmission of HPV. There have been two HPV vaccines approved by the Food and Drug Administration (FDA). Gardisil® is shown to prevent cervical, anal, vulvar, and vaginal cancers, as well as preventing the warts caused by HPV. Cervarix® is strictly to protect against cervical cancer (NIH 2013). Besides HPV, other risk factors for cervical cancer include having many children, having multiple sexual partners, smoking, using birth control pills, being immuno-compromised, or having sexual intercourse for the first time at a relatively young age. Signs of cervical cancer include vaginal bleeding or unusual discharge, pelvic pain, or pain during intercourse (NIH 2013).

It is important to get regular Pap smears since there are usually no signs or symptoms of early cervical cancer, and these tests can detect any cervical cell abnormalities. The vagina is opened with a speculum during the Pap smear, thus exposing the cervix. From there, the physician swabs the cells of the cervix with a cervical brush. These cells are placed into a small container of preservative and sent to the lab for analysis. Most guidelines now say that women should receive their first Pap smear at or before age 21. Women ages 21-29 should be screened every 3 years following normal results of the initial Pap smear. Women ages 30-65 should be screened every five years, again barring any complications (NIH 2013).

Treatment of cervical cancer varies depending on the whether the cancer cells have invaded other parts of the body.  This happens if the cancer has spread to nearby tissue, if it has gone to the lymph nodes, or if it has hit the bloodstream. Stage 1 cervical cancer means that the cancer has not grown past 5 millimeters deep and 7 millimeters wide (see figure 2). Stage 2 cervical cancer implies that the cancer has spread past the cervix, but it has not yet hit the pelvic wall (see figure 3).  Stage 3 cancer means that the disease has spread to the pelvic wall, has become large enough to block the ureters, and is causing kidney problems (see figure 4).  Stage 4 means that the cancer has spread to the body parts away from the cervix (see figure 5). Treatment includes chemotherapy, radiation, hysterectomy, and/or surgery to remove tumors (NIH 2013).

Figure 1- Anatomy of the Female Reproductive System

Figure 2- Stage 1 Cervical Cancer

Figure 3- Stage 2 Cervical Cancer

Figure 4- Stage 3 Cervical Cancer

Figure 5- Stage 4 Cervical Cancer

Figure 6- EM photo of HPV

For more information on cervical cancer, see http://www.cancer.gov/cancertopics/pdq/treatment/cervical/Patient

View our grid at http://www.worldcommunitygrid.org/index.jsp

Works Cited

Jurisica, Igor, et al. Mapping Cancer Markers. n.d. 20 January 2014. <http://www.worldcommunitygrid.org/research/mcm1/overview.do>.

"Lecture Notes: Human Papillomaviruses." - Medical Virology, UCT. N.p., n.d. Web. 22 Jan. 2014.

            <http://www.virology.uct.ac.za/teachhpv.html>.

"National Cancer Institute." Cervical Cancer Home Page -. N.p., n.d. Web. 17 Jan. 2014

            <http://www.cancer.gov/cancertopics/pdq/treatment/cervical/Patient>