Biology

bio8.docx

Assignment 1 – 1 ½ page

Please view Case study 7: Sickle cell anemia population screening

(attached). There are question prompts to stimulate further thoughts about each case study and there is also additional interesting information about each category at the end of each group of case studies. After the case studies there is information about 5 Clicker Questions that were presented to students, who then recorded their responses on clicker devices. The results of these audience responses can be found in the attached document.

· First explain why you chose this case study.

· Then present, in your own words, a summary of the case study for your classmates.

· Include your personal comments about the case.

· Look at the audience responses associated with the case study topics and comment on whether you were surprised by the outcome(s) of one or more of the votes.

Assignment 2-

Use the Case study form and fill in the answers together with the Pharmacogenetics: Using genetics to treat disease

This case study delves deeper into personalized medicine, by presenting a scenario based on a wide range of individual responses to the drug used to treat acute lymphocytic leukemia. You will interpret data similar to those initially published in scientific journals in order to learn more about pharmacogenomics and make recommendations about the appropriate medical treatment based on an individual’s genotype.

Assignment 3 – 1 ½ pages

Pretend you are a Genetic Counselor. Invent a patient with symptoms of a real possible genetic problem. Explain what genetic tests you might recommend for the patient. Invent the results of the test(s) and then explain how you would communicate these results to the patient along with your recommendations for any future medical decisions facing the patient. Discuss any ethical dilemmas you might face in your interactions with this patient. (Remember--the patient and test results are fictitious; but the genetic disorder, the genetic tests, the recommended treatments, and ethical considerations are REAL.) there are different ethical considerations for different cultures. Do you anticipate any social justice issues for your patient? Would your advice be different if your patient belonged to a different ethnic group?

Refer to these articles for insights into the importance of cultural considerations in Genetic Counseling:

A GENETIC COUNSELING CULTURAL COMPETENCE TOOLKIT https://www.geneticcounselingtoolkit.com/cross_cultural_communication.htm

Diversity in Genetic Counseling: Past, Present and Future, Mittman https://onlinelibrary.wiley.com/doi/full/10.1007/s10897-008-9160-5

EthicsCasesAudience-ResponseResults.pdf

1. Direct-to-consumer genetic tests have important clinical value to patients and should continue to be widely available.

Agree unconditionally 31 7.71% Agree, if under appropriate guidance 316 78.61%

Disagree 55 13.68% Totals 402 100%

2. Is it acceptable for an airline to test its pilots for genetic susceptibility to disorders affecting motor control?

No, never. 93 32.18% Yes, but only in conjunction with other visible symptoms of loss of motor control. 127 43.94%

Yes, to be used only for assignment decisions (e.g. a “healthy” co-pilot). 30 10.38% Yes, they need to be able to ensure the safety of their passengers. 39 13.49%

Totals 289 100%

3. In the context of whole genome sequencing, which categories of genetic test results do you think are appropriate to report to minors and their families?

Carrier status 66 17.69% Affected status for childhood onset disorders 185 49.60%

Affected status for adult onset disorders 122 32.71% Totals 373 100%

4. Given all of the complexities, do you think whole genome sequencing has a place in modern clinical practice?

Yes, but only within the limited scope of the defined actionable findings. 169 48.70% Yes, but only in highly specialized whole genome testing clinics. 122 35.16%

Yes, it is a powerful approach that should be utilized widely. 43 12.39% No, there are just too many ethical concerns around this strategy currently. 13 3.75%

Totals 347 100%

5. Given that mitochondrial manipulation generates offspring whose genetic alterations can be passed down to future generations, do you think the use of these technologies should be restricted to:

Mothers who have mitochondrial disorders 87 43.50% The engineering of healthy sons 12 6.00%

Families who would otherwise not be able to have biological children 60 30.00% No restrictions should be employed 27 13.50%

Other (tell us!) 14 7.00% Totals 200 100%

Responses

Multiple Answer Responses

Responses

Audience Response Graphical Results By Question (Complied classes 2014-2017)

Ethics in Genomics

Responses

31

316

55

Agree unconditionally Agree, if under appropriate guidance Disagree

169

122

43 13

Yes, but only within the limited scope of the defined actionable findings.

Yes, but only in highly specialized whole genome testing clinics.

Yes, it is a powerful approach that should be utilized widely.

No, there are just too many ethical concerns around this strategy currently.

87

12 60

27 14

Mothers who have mitochondrial disorders

The engineering of healthy sons

Families who would otherwise not be able to have biological children

No restrictions should be employed

Other (tell us!)

66

185

122

Carrier status

Affected status for childhood onset disorders

Affected status for adult onset disorders

93

127

30 39

No, never.

Yes, but only in conjunction with other visible symptoms of loss of motor control.

Yes, to be used only for assignment decisions (e.g. a “healthy” co-pilot).

Yes, they need to be able to ensure the safety of their passengers.

M8CaseStudyReportForm-REVISED.docx

M8 Case Study Report Form

Study the case study about leukemia and pharmacogenetics: Pharmacogenetics: Using Genetics to Treat Disease

Add your answers to the following questions from the case study and then submit this completed case study report form.

Part I – Acute Lymphocytic (Lymphoblastic) Leukemia

1a. Suggest a reason why the drug might affect the two girls differently.

1b. What tests might Dr. Ryder order to determine why the two girls are reacting as they are to the drug? Provide two or three appropriate examples of tests.

Part II – Enzyme Activity

2a. If Dr. Ryder had 10 Caucasian patients in the next month, how many would you predict to have each of the TPMT enzyme activity levels, based on the graph above?

Low:

Medium:

High:

2b. Would you expect the actual/observed number of patients to be different? Why might there be differences?

2c. Which bar (low, medium, or high) represents individuals who might be homozygous for a “low enzyme activity’” version of the gene? Which bar represents individuals who might be homozygous for a “high enzyme activity” version of the gene? Which bar represents heterozygotes?

2d. Answer the question: “How does enzyme activity level vary among the patients examined?” In your answer, be sure to include supporting data from the graph above. Explain how these data support your conclusion.

2e. Challenge question: The actual graph (below) showed much more detail. Why do you think that there is more variation between patients than shown in the simplified graph?

Part III – TPMT Enzyme Activity Levels

3a. Why would individuals with the lowest level of enzyme get the sickest when they take the drug? Suggest one possible reason.

3b. Describe the relationship between TPMT enzyme activity levels and TGN levels. Be sure to include supporting data from the graph.

Part IV – Putting It All Together

4. In the paragraphs below, indicate the correct answers (high or low, heterozygous or homozygous) with a different color or by underlining:

From her research, Dr. Ryder hypothesized that patients such as Laura (who became very sick upon receiving the drug) have very high / low TPMT enzyme activity and therefore very high / low levels of TGN nucleotides at normal doses. They easily became sick from the effects of the drug, and could even die. These patients are homozygous / heterozygous for the version of the gene encoding high / low enzyme activity. A better drug dose for these patients is 1/10th the level of other patients.

Patients such as Beth with high / low TPMT enzyme activity had high / low levels of TGN nucleotides. These patients would do well with the drug, and in some cases might even need a larger-than-normal dosage for the treatment to be most effective. These patients were either homozygous for the version of the gene encoding high / low enzyme activity, or were heterozygous.

Based on the graph in Part II, about 10% of the Caucasian population is homozygous / heterozygous .

Part V – SNPs and TPMT

5a. Dr. Ryder now has the ability to conduct a SNP genetic test on her patients to determine what level of drug they should get. A new patient on the ward, Kevin, is homozygous for TPMT 3A*. The graph shown in Part III is reproduced on the next page. Circle (describe) the area of the graph that might likely corresponds to Kevin’s TGN and enzyme activity levels. Explain why you circled that region.

5b. What level of the drug (low, medium, or high) should Dr. Ryder give him? Explain your answer.

5c. In your own words, summarize how knowing someone’s TPMT DNA sequence could be used to determine what kind of medical care they should receive.

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WhenaGeneTurnedOff.pdf

Page 1“When a Gene Turned Off is a Matter of Life or Death” by Tracie M. Addy

When a Gene Turned Off Is a Matter of Life or Death: Epigenetic Influences on Gene Regulation by Tracie M. Addy Yale School of Medicine Teaching and Learning Center Yale University, New Haven, CT

Part I – Jordan’s Health Concerns Jordan had just finished high school and was very excited to start a new chapter in his life. Graduation seemed like just yesterday, with all of the presents, balloons, and celebrations with friends and family. Jordan was bummed that he would not be able to go to school with his high school buddies anymore, but he could not wait to be a college student. The reality was that Jordan had wanted to go to Blake University ever since he was in 10th grade when he had visited there. The campus was amazing, and the students seemed happy. The school also had phenomenal sports teams, and Jordan was certain his chosen academic program would help him attain his career goals.

Unfortunately, a week after graduation Jordan started to feel ill and he did not seem to be getting better after several days. He was often nauseous and at times he would just throw up for what seemed like no apparent reason. Initially he thought he had a stomach virus or food poisoning, but when it persisted and he started having difficulty with his vision, he realized that it could be something more serious. One particular afternoon, Jordan was feeling extremely tired and did not want to get out of bed.

Jordan’s mother entered his room: “Jordan, it’s 2 o’clock in the afternoon and you’re still in bed. Is something wrong?”

“I just don’t feel good. My head is still hurting and I am having trouble seeing,” Jordan replied.

“I’m really worried about you Jordan. This doesn’t seem right.”

Jordan’s mother took him to the hospital that afternoon. Over the course of several days the doctors ran various tests to try to figure out what was going on, including a blood test for normal liver function as well as a CT scan.

Questions 1. Based on his symptoms, what do you hypothesize is wrong with Jordan?

2. What additional information do you need to know in order to support this hypothesis?

2 Case copyright held by the National Center for Case Study Teaching in Science, University at Buffalo, State University of New York. Originally published April 17, 2015. Please see our usage guidelines, which outline our policy concerning permissible reproduction of this work. Licensed image in title block ©Maria Vazquez | Dreamstime.com, id 29778254.

http://sciencecases.lib.buffalo.edu

http://sciencecases.lib.buffalo.edu/cs/collection/uses/

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Page 2“When a Gene Turned Off is a Matter of Life or Death” by Tracie M. Addy

Part II – Jordan’s Diagnosis

Jordan’s blood test results came back negative, a huge relief. However, the CT scan was inconclusive as the doctors were uncertain as to whether the image showed an abnormal fi nding. Th ey decided to order an MRI, which was a much more sensitive test.

Jordan had a feeling that something was not quite right when the technician performing the MRI had a concerned look on his face after the procedure. After a period of waiting, Dr. Kale called Jordan and his mother in to talk with them. Jordan would never forget that day.

“Jordan,” the doctor began. “I am sorry to tell you this, but you have a brain tumor.”

Jordan’s heart sank. He could not believe what he was hearing. His mother gasped for breath and nearly fainted. Jordan tried to calm her and she became less agitated.

“Th e tumor is on your occipital lobe, a part of the brain that plays a role in vision,” continued Dr. Kale as she showed them images from the MRI. “Th is is why you have had trouble seeing.”

Dr. Kale further explained that they would need to perform surgery to remove and further characterize the tumor. At this point they were uncertain if there were additional tumors. Th is news made Jordan become anxious and his mind raced. What type of tumor could it be? Jordan had so many plans in life—he wanted to fi nish college and fi nd a good job. He wanted to go abroad and discover the real world. Why was this happening to him? He was too young to die.

Questions

Access the following National Cancer Institute link (or another reputable source) to answer Questions 1–3: http:// www.cancer.gov/cancertopics/cancerlibrary/what-is-cancer

3. What type of tumor could Jordan have? Explain your reasoning.

4 What is the diff erence between a benign and malignant tumor?

5. How do cancers form?

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Page 3“When a Gene Turned Off is a Matter of Life or Death” by Tracie M. Addy

Part III – Jordan’s Therapy

Th e medical team taking care of Jordan ran further tests on the tumor by taking a biopsy of the tissue to determine whether it was cancerous. Th e biopsy results supported that Jordan had Stage IV glioblastoma multiforme, an aggressive cancer of the brain. Glioblastomas are cancers involving the astrocytes, a type of supporting cell in nervous tissue. Th ey often spread quickly to other parts of the brain, and it is hard for surgeons to be able to fully remove them.

Th e doctors determined that they would perform surgery and attempt to remove the tumor. Th is was tricky as it was associated with the areas in his brain that controlled vision. With some of the top surgeons in the country performing this delicate procedure, Jordan was comforted that the surgery would have good outcomes.

Th e day of the surgery came and the surgeons were able to remove some of the cancer cells, but not all of them—it appeared some had spread. Th e doctor indicated that Jordan would need to undergo adjuvant chemotherapy as well as radiotherapy, and that they would monitor him to see how his body responded. One particular drug he would take was temozolomide. Th is drug damages actively dividing cells. Temozolomide works in most but not all patients with glioblastoma. An individual’s epigenetic markers on a particular gene, MGMT (O-6-methylguanine-DNA methyltransferase), are associated with the eff ectiveness of temozolomide. Epigenetic tags enable genes to be turned on and off . Th e fl ow of genetic information is typically from DNA to RNA to protein. When genes are turned off , they do not express their encoded proteins. Cytosine methylation of DNA and the deacetylation of histones are two ways that genes are switched off .

All of these treatments would mean that Jordan would miss his entire fi rst year at Blake University.

Questions

6. In general, how do cancer chemotherapies work? Use the following source of information for your answer [Informed Health Online]: http://www.ncbi.nlm.nih. gov/pubmedhealth/PMH0072611/

7. Th e promoter region of DNA is where the en- zyme RNA polymerase attaches to start tran- scription of a gene into RNA. Figure 1 shows examples of unmethylated and methylated promoters. What eff ects do you hypothesize that methylation can have on the expression of a gene?

8. Examine Figure 1 and describe how methyla- tion of the MGMT promoter relates to the probability of survival of patients with glio- blastoma.

9. Ignoring whether or not the MGMT promoter is methylated or unmethylated, do these cancer patients generally have a good prognosis?

10. Propose at least two other ways that doctors could treat Jordan’s cancer regardless of whether or not his MGMT promoter is methylated or unmethylated.

Figure 1. Probability of Overall Survival of Glioblastoma Patient. From Th e New England Journal of Medicine, Hegi, M.E. et al., MGMT gene silencing and benefi t from temozolomide in glioblastoma, 352, 997–1003, Figure 2. Copyright © 2005 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

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Page 4“When a Gene Turned Off is a Matter of Life or Death” by Tracie M. Addy

Part IV – Gene Regulation

Not all individuals with glioblastoma respond the same to similar treatment. Th is can at times be attributed to diff erences in their genetic backgrounds. Th e patients who do not respond well to temozolomide chemotherapy and have overall low survival rates are those that have unmethylated MGMT promoters.

Recall from the pre-class videos that chemicals and other agents such as radiation can damage DNA. Typically cells have biochemical helpers to correct such damage, including specifi c proteins that repair DNA.

Th e MGMT gene encodes a protein that is involved in the repair of DNA. When MGMT cytosines are methylated, it is turned off and does not repair the DNA in the cancer cells damaged by temozolomide. As a consequence, the cancer cells undergo apoptosis, and thus, the drug can more successfully kill the cancer cells. However, when the MGMT promoter is unmethylated, the gene is turned on and the protein synthesized repairs the DNA of the cancer cells dam- aged by temozolomide, rendering the treatment ineff ective because the targeted cancer cells do not die by apoptosis.

Questions

11. What role does MGMT play in cancer cell regulation?

12. Is it more favorable for Jordan to have methylated or unmethylated MGMT promoters? Explain why.

13. Examine Figure 2 and describe based on the graphical results the best hypothetical treatment for Jordan if his MGMT promoter is unmethylated.

14. Relate MGMT methylation to what you know about the central dogma/fl ow of genetic information and how genes are expressed.

15. If Jordan had an identical twin, what is the likelihood that his brother would also develop this cancer?

16. Devise a therapy that could potentially circumvent resistance to temozolomide.

Figure 2. Treatment of Glioblastoma as Related to Overall Survival. From Th e New England Journal of Medicine, Hegi, M.E. et al., MGMT gene silencing and benefi t from temozolomide in glioblastoma, 352, 997–1003, Figure 3A. Copyright © 2005 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

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Page 5“When a Gene Turned Off is a Matter of Life or Death” by Tracie M. Addy

Part V – Jordan’s Fate

Jordan was very fortunate. His MGMT promoter was methylated and he responded well to the combined temozolomide and radiotherapy treatment. Two years after his initial diagnosis, the doctors declared his cancer to be in remission. Soon after, Jordan was found smiling, gazing out of his dorm room window at Blake University, excited for what was to come.

•

References

Everhard, S., Tost, J., El Abdalaoui, H., Criniere, E., Busato, F., Marie, Y., Gut, I.G., Sanson, M., Mokhtari, K., Laigle-Donadey, F., Hoang-Xuan, K., Delattre, J-Y, and Th illet, J. 2009. Identifi cation of regions correlating MGMT promoter methylation and gene expression in glioblastomas. Neuro-Oncology 11, 348–356.

Hegi, M.E., Diserens, A-C, Gorlia, T., Hamou, M-F, de Tribolet, N., Weller, M., Kros, J.M., Hainfellner, J.A., Mason, W., Mariana, L., Bromberg, J.E.C., Hau, P., Mirimanoff , R.O., Cairncross, J,G,, Janzxwer, R.C., and Stupp, R. 2005. MGMT gene silencing and benefi t from temozolomide in glioblastoma. Th e New England Journal of Medicine 352, 997–1003.

Ohio State University Medical Center. (2011, May 31). Gene change identifi es brain cancer patients that respond better to treatment. ScienceDaily. Retrieved March 23, 2015 from www.sciencedaily.com/ releases/2011/05/110531155349.htm

Zhang, K., Wang, X., Zhou, B., and Zhang, L. 2013. Th e prognostic value of MGMT promoter methylation in Glioblastoma multiforme: A meta-analysis. Familial Cancer 12, 449–458.