Reflection

Over the course of this service project,we thought that using grid computing was a unique idea to help researchers find out more about cancer. In our project, we lent our computing power to find drugs to help deactivate proteins associated with neuroblastoma, a common form of childhood cancer. Grid computing is an intelligent idea that uses volunteer devices and deliver information to researchers to use. It was really amazing how we contributed to cancer research without actually physically conducting the research. It was impressive to think that running a program on a computer can help further research in cancer. Also, it was simple because we didn't have to actually do anything on the computer but use it and the grid computing program just uses energy from volunteer devices to power the research. It was a rewarding feeling to know that we are contributing research to cancer without actually taking time out of our lives.

In our interview with Dr. Sirridge, we thought he was amazing to talk to. He answered our questions to the fullest extent and seemed very knowledgeable in cancer. We could tell that he loved his job. He talked a lot about his patients and how they grew as individuals. Many of them got stronger as a result of fighting cancer. We learned so much more about cancer that we hadn't known before. He related cancer to evolution by telling us that cancer has evolved very rapidly. This makes cancer very difficult to treat. But, cancer screenings and cancer treatment have improved. He also enlightened us about childhood cancer and how children's immune systems are better at fighting cancer than adults. Dr. Sirridge was a very nice person to talk to and we enjoyed interviewing him.

Overall, we liked how this project related back to evolution as we read the article on intratumor heterogeneity. We thought it was fascinating applying Darwin's postulates to cancer tumors. Natural selection can act on cancer tumors and make some tumors more resistant to drugs. It was interesting that using phylogenetic trees can map back cancer mutations and allow scientists to track cancer genetic paths. This could lead to treatments to help eliminate cancer. In conclusion, contributing research to childhood cancer was a rewarding feeling and we felt very good to know that we contributed to a great cause and gained more knowledge as a result.

World Community Grid

To help contribute to the research in childhood cancer treatment, we lent our computing power to the World Community Grid. The project's goal is to find drugs to deactivate proteins that are associated with neuroblastoma, one of the most common forms of childhood cancer. These drugs could potentially make neuroblastoma more curable when combined with chemotherapy treatment. Researchers are trying to find a drug that can bind to the protein and inactivate it. They are using a program to see if the shape of the protein and the shape of the drug will fit together enough to disable the protein. The project is expected to be completed in two years.


Below are the project statistics:

Help Fight Childhood Cancer Project Statistics

Statistics Last Updated: 2/13/15 00:06:02 (UTC) [6 hour(s) ago]

	Totals:
	Run Time (y:d:h:m:s)	55874:259:17:42:17
	Points Generated	58,340,545,661
	Results Returned	73,581,917

	Averages:
	Run Time Per Calendar Day (y:d:h:m:s)	38:204:17:17:15
	Run Time Per Result (y:d:h:m:s)	0:000:06:39:07
	Points Per Hour of Run Time	119.19
	Points Per Calendar Day	40,262,626.41
	Points Per Result	792.87
	Results Per Calendar Day	50,781.17

We also decided to lend our computing power to help identify cancer markers. The research being done on cancer was mapping genetic markers to identify various types of cancers. Markers are tissue samples of unique chemical indicators, like DNA or protein. The pattern of markers determine if the individual is more likely to develop a certain type of cancer and what type of treatment is best for the individual. Mapping cancer markers can use tissues in the lungs, ovaries, prostate, pancreas and breast. Millions of data points are analyzed from tissues of healthy humans and cancerous patients. By analyzing this, researchers can analyze patterns of different cancers and test treatments.



Below are the project statistics:

Mapping Cancer Markers Project Statistics

Statistics Last Updated: 2/13/15 00:06:02 (UTC) [6 hour(s) ago]

	Totals:
	Run Time (y:d:h:m:s)	115546:055:08:19:15
	Points Generated	169,325,214,004
	Results Returned	231,844,109

	Averages:
	Run Time Per Calendar Day (y:d:h:m:s)	249:204:07:10:17
	Run Time Per Result (y:d:h:m:s)	0:000:04:21:57
	Points Per Hour of Run Time	167.29
	Points Per Calendar Day	365,713,205.19
	Points Per Result	730.34
	Results Per Calendar Day	500,743.22

Tumor Markers: Analyzing Intratumor Heterogeneity and Branched Evolution

1. a. Name ten other taxa that share some sequence identity with this Rattus gene?

Mus musculus (House mouse)

Peromyscus maniculatas (Deer Mouse)

Mesocricetus auratus (Golden Hamster)

Cricetulus griseus (Chinese Hamster)

Nannospalax galili (Blind Mole Rat)

Ceratotherium simum (White Rhinoceros)

Saimiri boliviensis (Black-capped squirrel monkey)

Equus caballus (Horse)

Rhinopithecus roxellana (Golden snub-nose monkey)

Homo sapiens (Humans)

b. What is Rattus? In an evolutionary sense, why study the mTOR gene in this animal?

The common name for Rattus  is rat. Rats are medium-size rodents with long tails. These animals prove useful in laboratory research when studying cancer. Their biological, genetic, and even some behavioral characteristics closely resemble Humans. As you can see previously the mTOR gene that is in Rattus closely resembles that of the Homo sapiens, the query coverage is 95% similar. 

It is also easy to replicate experiments done on rats. Cancer can be replicated in rats and studies. Researchers can breed rats to have certain genetic mutations to discover the affects. 

So because rats are genetically similar and are easy to manipulate in a laboratory setting, they are therefore useful organisms to aid in studying the mTOR gene.

c. What does wild type mTOR gene do in these animals? Why is it conserved across so many disparate species?

mTOR is responsible for coding a protein known as the mechanistic target of rapamycin or mammalian target of rapamycin. It is a serine/threonine protein kinase. The wild type mTORgene will code for proteins that function to regulate cell growth and cell proliferation as well as cell motility and cell survival. It also has a key role in protein synthesis and transcription. It is known as the mammalian target of rapamycin because it is conserved across so many mammalian species. It is conserved because it is a mammalian binding protein. That is, it is an important protein across all mammal species and functions in a similar way in each species.

2. Apply Darwin’s postulates to tumor adaptation in drug-resistant clones.

Darwin’s first postulate states that there is variation among individuals of the same species. In the New England Journal of Medicine, intratumor heterogeneity was examined. It is known that intratumor heterogeneity can cause tumors to evolve and adapt to their environment even with drug-resistant clones. So, there is variation in types of tumor. This variation causes tumors to resist drugs. The tumor samples were collected from primary renal carcinomas and metastatic sites. These tumor samples were characterized through the use of immunohistochemical analysis, profiling of messenger RNA, and mutation analysis. The tumor samples also underwent DNA sequencing, exome sequencing, and chromosome analysis. Variation in tumors creates difficulty in researchers to isolate single tumors to create biopsy samples. This leads to difficulty in creating drug-resistant medication. Other evidence for tumor heterogeneity comes from creation of phylogenetic trees of tumor regions. One branch evolved into clones in the metastatic site while other diversified into primary tumor regions.

Darwin’s second postulate states that some variations are hereditary. This means that some variations can be passed down from generation to generation. Results showed that some tumors mutated and underwent branched evolutionary tumor growth. Mutations were seen in tumor suppressing genes SETD2, PTEN, and KDM5C. These genes inactivate mutations with a single tumor suggesting convergent evolution. Gene expression also varied among tumors. Allelic composition was also tested and it was observed that intratumor heterogeneity existed. So, some variations in tumors are passed down to generations. These variations cause tumors to adapt to medications and resist it.

Darwin’s third postulate is that in every generation there are more offspring produced than can survive. In the case of intratumor heterogeneity, some tumor suppressor genes like SETD2, PTEN, and KDM5C prevent tumors from forming. Therefore, only tumors that haven’t been inactivated survive.

Darwin’s fourth postulate is that natural selection operates on populations. In this study, the mutations that were detected in the tumors showed clonal evolution of the tumors. Phylogenetic trees were created to analyze evolutions of tumor regions. Branching evolution of clones at metastatic sites were shown as well as diversified branches in primary tumor regions. This suggests convergent evolution. Other mutations like SETD2 harboring three mutations of missense, R4 (which is a tumor region) carrying a splice-site mutation, and 2-bp frameshift deletion also in R4 support convergent evolution. Convergent evolution in tumors means that tumors become more and more similar. Since SETD2 trimethylates H3K36, tumors become more similar to each other. These tumors are clones that are resistant to particular drugs. Natural selection acts on these mutations to pick out which tumors survive and which don’t.

3. The authors assert that intratumor heterogeneity will influence medical decisions and personalized treatments. Why then, might it be important for an oncologist to understand evolution?

“Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection."

When a cancer cell accumulates mutations, it can continuously give the cell a growth advantage over other cells. The cell will occupy the tumor until a stronger cell takes over.  At each stage, cancer cells go through selective pressure that drive their own evolution.

Cancers can also speed reproduction of the cells. They do this by obtaining mutations in genes, which normally fix DNA damage. When cancer cells shut down the cell repair system by shutting down DNA repair, this creates mutations that cannot be fixed. These mutations create more mutations that make the cancer evolve and resist medical drugs. This makes it difficult for oncologists to design medicine or treatments to treat cancer because cancer keeps evolving and mutating into something different. This fuels the evolution of cancer. 

Oncologists should know and understand evolution because knowing the genetic path that a particular cancer followed could one day help them better treat individual patients. When oncologists know how a particular cancer has evolved, they can determine how it will evolve later in the future and analyze patterns. By determining the genetic defects responsible for a specific cancer, physicians might be able to select the therapy that will be most successful at eliminating that cancer.  In addition, cancer-causing genes that are identified can be of use to develop specific therapies to help eliminate cancer. This is done while keeping healthy cells unharmed (Evolution Of Cancer).

Link Evolution of Cancer: http://www.hhmi.org/biointeractive/evolution-cancer

4. Consider Figures 2C and 4B, explain how phylogenetics can contribute to the understanding of tumor heterogeneity and to the generation of better tumor markers.

Phylogenetics allows scientists to construct a tree that shows which mutations are shared among tumor regions and which mutations are unique to each region that branches off. By mapping this, it shows which regions are the most “evolved” from the common “ancestor”, or tumor region that holds all the mutations shared amongst all the tumor regions. This allows scientists to mark the tumors into regions by the type of mutations they hold and which they share with other regions. This allows for the visualization of which tumor regions are the most heterogeneous from other regions.

Link to the article: http://www.nejm.org/doi/full/10.1056/NEJMoa1113205#t=articleBackground

Post Interview Reflection

 We all agreed that Dr. Sirridge was an excellent person to interview, you could tell he was passionate and loved his job. In his body language and his tone, his sincere dedication to helping others was clearly displayed. We were thoroughly impressed with his willingness to share his knowledge with us, and impart some wisdom to us at the end of the interview. He answered our questions in depth and gave his full attention to our questions. He thought about the questions that were asked and answered them in a clear and concise manner. He was very knowledgeable about cancer and had years of experience. Dr. Sirridge seemed like a very respectable man and was very pleasant to talk to. We would also say that a positive vibe came from Dr. Sirridge.

 After the interview, changes did occur as a result. We now looked at cancer patients differently just by the way he spoke. We felt like we had more respect for cancer patients because they have fought so hard and gone through so much. We know more about cancer then we did before. For example, sometimes you can't predict how a tumor will behave. Sometimes, patients have done well with treatments and all was stacked against them to do poorly. We learned that every patient deals with cancer in different ways whether it be with anger or depression. Patients become closer to their family as a result. Also, our research became more of a material thing after the interview. It was harder to become connected to the research solely through the computer program. By speaking to an expert on our topic, we became more involved and personally connected to the topic.

 We wouldn't say we found anything disturbing about the interview more than say emotional. His stories about his past patients were truly touching and helped us connect to the topic on a more personal level. When describing all the different responses that patients can have to cancer, it became clear that Dr. Sirridge cared for each and every one of them because of who they were and how they decided to fight the disease. 

  Our research and interview intertwined with each other in many ways, which was helpful.  In the interview we asked many of the things we had researched. He confirmed them and added to our knowledge and curiosity of childhood cancer. Dr. Sirridge said many children that came in were more positive than any adult patients. They don't fear cancer because they have got their whole lives ahead of them. He also said that they usually try and get rid of cancer in children because their bodies are still pristine. They treat cancer differently in adults than they do in children. We also asked Dr. Sirridge about grid computing. His answer was very intellectual and made us think of grid computing in a different way. He said that sometimes, we find different types of cancers in different areas of the world. Patterns of these different types of cancers can help contribute to the algorithms and help find out things we didn't know before. We also asked him how evolution and cancer were related to each other. He said that cancer changes very quickly. Some cancers are becoming more common that weren't before and vise versa.

Overall, Dr. Sirridge was an amazing doctor to converse with. He truly was an extraordinary doctor with his years of experience with patients. He knew so much about cancer and had so many stories to tell. We related all of his answers back to what we were doing in class. He made great connections of cancer with evolution and grid computing. He helped us understand more about childhood cancer. In conclusion, Dr. Sirridge was truly an amazing soul and we thank him for taking his time to let us interview him.

The Interview

Dr. Christopher Sirridge, is a doctor who specializes in cancer and hematology. His cancer specialties are in leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome. He works with the University of Kansas Cancer Center in North Kansas City. Christopher knew he wanted to be a cancer doctor since he was nine years old. Dr. Sirridge graduated the University of Kansas at the age of 19 and went on to the University of Missouri- Kansas City’s medical school. graduating medical school at 23. On February 5, 2015, we interviewed Dr. Sirridge.

Question: Why did you choose the field of cancer?

Answer: I chose cancer medicine, because it was just so consistently interesting and so consisting compelling. My mom was a cancer physician so she influenced me. During my career in cancer medicine, there has been advancement and I would like to be part of that. I also like to be around hard fighting patients.

Question: How would you explain cancer?

Answer: In a brief way, every cell in the body that is normal does certain things. Number one, it has programmable cell death, called apoptosis. Every cell has to live, reproduce, and then die. Nearly every cell in the body has a cellular function and these cells stay put where they were destined to be in the first place. And finally, normal cells receive normal blood, nutrients, and oxygen and they share that wealth. Normal cells have programmable cell death keeping normal number of cells constant. The second thing they do is that they stay put. Heart cells stay in the heart and brain cells stay in the brain. Cancer cells often have no programmable cell death. They divide and keep living. They are in fact almost immortal. Cancer cells travel and move wherever they want. As they travel, they grow and wherever they go, they do damage. They are angiogenic. Angio meaning blood vessel. Genic meaning the generation of. They make their own blood cells. They get the blood supply, oxygen, to move to other cells. Cancer cells are a major bad dream because they do whatever normal cells don’t do. They don’t die, they take all the goodies, and they move around. That makes them fatal.

Question: What would you say to person who doesn’t know about cancer?

Answer: They need to know if they have a cancer and if it’s curable. They need to know what is going to be the cost in time, pain, and change in body function. They need to know what our plan is to go about this cure. They need to know: do they have it, is it curable, what is the cost, what they are going to have to endure to get to this point. I always try and tell a patient what the reason is that they have this cancer. They always ask: How did this happen to me? I tell them if it’s related to lifestyle, age, gender, risk factor, and genetics. I try to get rid of misunderstanding that promotes guilt because patients find a way to blame themselves. I always tell the truth because patients want to know what they are up against no matter how tough it may be. They ask me “What do I have? If it’s not curable, how long will I live? What treatments are necessary? What is the cost?” And finally, we talk about why the cancer? After that it becomes a very specific discussion as to what tumor what they have and what we need to do. I sure hate to have a patient leave an initial appointment blaming themselves because that gets in the way of healing.  I think that forgiveness is divine. Without forgiveness, there is no peace. Forgiving yourself will help you find peace.

Question: Do you know anything about grid computing?

Answer: Grid computing? Educate me and then I’ll answer.

Well, for our class, we are running a software called the World Community Grid so it does the research for you. So we picked childhood cancer to help find a cure to cancer. It basically runs algorithms on your computer so we are contributing to help find a cure. So do you think that this is important?

Answer: I think grid computing is important because every community, every area of the world, every ethnicity, every different age has its own demographic. Patterns of disease in terms of where you would most likely expect to find it, where you would most likely expect to treat it, and who most likely is to get it gives you the next algorithm on how you screen for it or how you prevent it. So, algorithms and demographics are important. There are some cancers that are more common in the Midwest that are not common in California or New York. There are some cancers more common in the United States than are in China. There are 2 or 3 cancers more common in China than they are in the United States. So, when you get that kind of database through grid computing, it becomes an asset and an accessible piece of information for everybody. These patterns are helpful in helping you find a cure or treatment for cancer.

Question: Do you have any interesting stories about a patient?

Answer: Yeah, we have compelling stories every day. I have one particular patient that because of a cancer she got as a teenager and because of the treatment that she got to cure that cancer and because of her family history and what has happened to her as an adult, she is at risk for any number of malignancies and in fact is likely to get those cancers because of the genetic profile she has and because she is a woman and because she developed another disease that predisposes her to a cancer and she is on treatment for that cancer that predisposes herself to another cancer. So, everyday of her life is a waiting game for the revolver to go off. And everyday is how she handles that amount of stress. I think she is a truly amazing soul and she handles it pretty well. But, we aren’t waiting around for the bomb to drop. We are doing everything we can to prevent these things from happening. But she is truly amazing. I have got hundreds of stories of patients that have lived longer than predicted and responded better to treatment than predicted. I have a remarkable man right now that has presented an aggressive lung cancer. One year mortality from time of diagnosis is 50%, two years is 75%, and three years is 95%. Then, after three years, we don’t even categorize that because there are few people left. This gentleman is 6 years in and still living. So, sometimes we get people that are exceptions to stark realities. Families come together at these times and help each other. It’s nice to see this happen. Any ways that patients express themselves in humor, sadness, and sometimes anger helps them deal with cancer. You never know how a patient will behave in terms of how the tumor behaves. So all of us, and I have been doing this for 36 years, have stories. We have stories of people who have done beautifully and all was stacked against them to do poorly. These are great stories. Stories of how people die gracefully, courageously, meaningfully are some of the most remarkable.

Question: So, why do children get cancer? Why do people get cancer early in life?

Answer: Children with cancer are genetically fated. There are problems as to how they grew. Also, their immune systems are extremely immature. Their immune systems are not capable of turning on to fight viruses and other things. But, no human genome is perfect. Childhood cancer is usually genetic, the result of a poor immune system or a biological accident. We don’t know why but when it happens, it is pretty compelling.

Question: Are children able to come out of cancer better?

Answer: Children’s bodies, despite the fact that they are little, are pristine. They often have good lungs, good heart and bone marrow and are able endure treatment sometimes better than adults. This is because they don’t play the mental game of being defeated. They are the ultimate soldiers. There bodies are in better shape because they don’t have diseases that some of the older people have. So, they can tolerate an incredible amount of treatment because their bodies are pristine. They are amazing human beings.

Question: So, do you go about differently when treating children?

Answer: Yes, you sure do. I think in terms of childhood cancer, you are always trying to find a cure for children or looking for a homerun. In children, you are looking for a big knock. The tumors are completely different in children than in adults. There are more cancers in adults than are in children. In children, we treat their cancers differently than adults. It is different sociologically, psychologically, and physiologically.

Question: How is evolution important in cancer?

Answer: The type of cancers and how they behave have changed even in my 36 years. I’m seeing cancers that are now more common that weren’t once before and I have seen cancers that were once common that aren’t anymore. I guess a deeper question is: has cancer changed? That is one of cancer’s other abilities. They have multiple-resistance genes. Cancers change the way they behave over time. They can be more resistant to treatment and become a different cancer over time. That makes them even more formidable in terms of anatomy. So we are all evolving. Our data evolves. But, lung cancer is still number one and it will probably be this way for the next 25 years. Then colon, breast and prostate are the next most popular cancers. Now, we are better at screening and are curing people more early every day because of this. This has been valuable.

Question: How do you find cancer patients?

Answer: Actually, screenings are a part of the primary care doctors’ responsibilities. That means examinations and that means working with criteria to do so. This includes doing the right studies. For women, it’s mammograms. For women, it is pelvic exams with pap smears. For men, it’s digital rectal examinations for prostate cancer and a blood test. For colon cancer, it is colonoscopy starting at whatever year you should depending on family history and risk factors. For instance, we start screening for prostate cancer at age 50. So, screening is the responsibility of the patient. However, we still do screenings to see if the cancer recurs.

Question: Are more developed countries more susceptible to more cancers?

Answer: More developed countries have things like tanning beds. More developed countries smoke cigarettes, drink more alcohol; eat more processed and highly genetically altered food. More developed countries have more stress, more competition. Stress is one of causes for illness. Probably one of the biggest risk factor for cancer is age. And in countries that have a long natural survival like the United States, 80 for women and 78 for men, our age is a little different. The reason why we get cancer is sometimes we live long enough to get it.

Question: Do you think there will ever be a cure to cancer?

Answer: I think there will be some cures. I think cancer is a different disease in everybody it comes. But, cancer is more than one disease. There were some cures and will be more. But I don’t think we will ever eradicate this because of the human condition. We are programmed to die and there has to be a reason why we die and one of those reasons is cancer. So, no, I don’t think we are ever going to completely cure it because it is a unique disease.

Question: Do you think we will be able to mutate out of it?

Answer: I think we will have some genetic modifications. Cancer can get better though. I do think that we will continue to increase our average survival. I think we will be able to change the genetic behaviors. We have already done that in some cancers. But I think it will be in baby steps. Cancer is so unpredictable that it changes off of that template and that’s scary. And sometimes, that’s why I fear for the patient and humanity.

After listening to Dr. Sirridge talk about his experiences with cancer, we learned more about our topic of cancer. This knowledge that we gained help us realize our contribution to the World Community Grid. Dr. Sirridge was a very nice person to talk with. He was very knowledgeable in cancer. His experiences have made him very wise and we are thankful that he made time to sit and talk with us. 

Introduction

Childhood Cancer

Unlike adult cancer, childhood cancer is normally a result of DNA changes in cells that takes place early in life. Childhood cancer is also not strongly linked to environmental risk factors.

Childhood treatment has also been shown to respond very well to chemotherapy and their bodies tend to handle chemo treatments better than adults. Though their bodies tend to handle the treatment better, if the child survives, the child might have long term effects from the radiation.

Most children in the US are treated at a children's oncology group. These centers are associated with children's hospitals or universities. As childhood cancer has been more looked into in the past years, it is now more important than ever to have specialist looking into this area.

"What Are the Differences between Cancers in Adults and Children?" What Are the Differences between Cancers in Adults and Children? American Cancer Society, 2015. Web. 22 Jan. 2015.


Grid computing

            Grid computing is a computer system that uses volunteer computer devices to help support scientific causes. Volunteers from around the nation can use grid computing. Grid computing powers cutting edge research in healthcare, poverty, and sustainability. It is used because scientists do not have enough computers to power their research. Thus, volunteers can help by using their computer devices to contribute to the research. The use of multiple computers helps scientists compete a common goal. The data collected from each volunteer goes directly to the scientists. The scientists can then use this data to connect information together, analyze patterns, and come up with results.

                        To set up grid computing software, volunteers simply download the program on to their computers. Once downloaded, the program runs without affecting the volunteer’s daily computer activities. While contributing to the research, volunteers can stay engaged and up-to-date about the causes. Currently, over 600,000 volunteers have helped contribute to research and with this, scientists have made impacting results in just a few short years. For example, research in cancer treatment, HIV/AIDS, and solar energy have been improved with grid computing.

            Grid computing is basically when all the computer’s resources are shared with every other computer system. It uses processing power, memory, and data storage to perform a specific task. Multiple computers are used to perform one task creating a network. This network forms a supercomputer which uses the information collected from volunteer computer devices and delivers the information to scientists. Grid computing is thus, very efficient in that it uses multiple computers to be very cost effective, it does not require an enormous amount of computing power, and the resources of many computers are harnessed to reach a common goal.

http://computer.howstuffworks.com/grid-computing.htm; http://searchdatacenter.techtarget.com/definition/grid-computing

http://www.worldcommunitygrid.org/about_us/viewGridComputingBasics.do