Question

Part II – Nadia’s Aunt Audrey and her partner Andrew sat in the corner of the diner, trying to process the information they had received during their meeting with the team from the research hospital. Many couples planning for a pregnancy have anxieties and questions, but this pair felt they had more than most. During her teenage years, shortness of breath had led to genetic tests that revealed Audrey was heterozygous for a mutation in the dystrophin gene. The dystrophin gene is X-linked; since Audrey had a functional allele on her other X chromosome, the impacts on her health had been minimal. But now she and Andrew wanted to have children and they were concerned about the possibility of having a son with Duchenne Muscular Dystrophy (DMD), a disorder that results when no functional dystrophin is made. At their first meeting with a genetic counselor, they had talked about in vitro fertilization (IVF) and pre-implantation diagnosis (PGD), which would allow them to select only female embryos or embryos that did not carry the altered dystrophin allele. They understood that this would allow for genetic screening of embryos and then a decision would have to be made about which embryo(s) to transfer for Audrey’s uterus hopefully for successful implantation. But then one of Audrey’s friends on Facebook highlighted a report about a new technology that helped mice with muscular dystrophy (<http://www.sciencemag.org/news/2015/12/crispr-helps-heal-mice-muscular-dystrophy>) and the couple realized they had more questions about their possible options. Audrey wished she had been able to schedule this meeting when her niece Nadia was visiting for Thanksgiving. Nadia was studying biology in college and had discussed the genetics underlying this situation with her aunt before. The medical team had shared with the couple the possibility of using new genome editing technology to modify the dystrophin gene in fertilized eggs or even to treat an individual diagnosed with DMD after birth. What was the name of that method? Andrew dug through his backpack and pulled out his notes—CRISPR-Cas9 it was called—and Audrey texted Nadia to ask about it. Questions 1. Why is the couple concerned about having a son with DMD? Are their daughters not at risk? 2. Nadia’s mother Rachel is Audrey’s biological sister. Should Nadia herself be concerned about being a carrier of the DMD allele or having the disorder? 3. (Version A) Conventional gene therapy, described as introducing a functional copy of an allele into an individual that lacks this allele, has been explored as a clinical approach for decades. However, conventional gene therapy is not useful in treating certain genetic conditions. a. Given what you have learned about the dystrophin gene, why is conventional gene therapy difficult for treating DMD? b. When the gene product of a dominant genetic disorder is harmful, why is conventional gene therapy not easily used to treat such disorders? 3. (Version B) Conventional gene therapy, described as introducing a functional copy of a gene into an individual that lacks this allele, has been explored as a clinical approach for decades. Why is the CRISPR-Cas9 system more favorable compared to this conventional type of therapy? 4. (Version A) There are potential technical challenges with genetic modification in general and with CRISPR-Cas9 specifically. a. What challenges might there be in using genome editing to treat an individual diagnosed with DMD after birth? b. The article also refers to ‘‘off-target effects.’’ Explain what you think is meant by this phrase, and why it might be a risk when using CRISPR-Cas9 clinically. 4. (Version B) What challenges might there be in using genome editing to treat an individual diagnosed with DMD after birth? 5. How might the way we think about using these gene editing technologies change if we imagine them being employed for purposes other than clinical disease prevention/treatment?

Part II – Nadia’s Aunt
Audrey and her partner Andrew sat in the corner of the diner, trying to process the information they had received during their meeting with the team from the research hospital. Many couples planning for a pregnancy have anxieties and questions, but this pair felt they had more than most. During her teenage years, shortness of breath had led to genetic tests that revealed Audrey was heterozygous for a mutation in the dystrophin gene. The dystrophin gene is X-linked; since Audrey had a functional allele on her other X chromosome, the impacts on her health had been minimal. But now she and Andrew wanted to have children and they were concerned about the possibility of having a son with Duchenne Muscular Dystrophy (DMD), a disorder that results when no functional dystrophin is made.
At their first meeting with a genetic counselor, they had talked about in vitro fertilization (IVF) and pre-implantation diagnosis (PGD), which would allow them to select only female embryos or embryos that did not carry the altered dystrophin allele. They understood that this would allow for genetic screening of embryos and then a decision would have to be made about which embryo(s) to transfer for Audrey’s uterus hopefully for successful implantation. But then one of Audrey’s friends on Facebook highlighted a report about a new technology that helped mice with muscular dystrophy (<http://www.sciencemag.org/news/2015/12/crispr-helps-heal-mice-muscular-dystrophy>) and the couple realized they had more questions about their possible options. Audrey wished she had been able to schedule this meeting when her niece Nadia was visiting for Thanksgiving. Nadia was studying biology in college and had discussed the genetics underlying this situation with her aunt before. The medical team had shared with the couple the possibility of using new genome editing technology to modify the dystrophin gene in fertilized eggs or even to treat an individual diagnosed with DMD after birth. What was the name of that method? Andrew dug through his backpack and pulled out his notes—CRISPR-Cas9 it was called—and Audrey texted Nadia to ask about it.
Questions
1. Why is the couple concerned about having a son with DMD? Are their daughters not at risk?
2. Nadia’s mother Rachel is Audrey’s biological sister. Should Nadia herself be concerned about being a carrier of the DMD allele or having the disorder?
3. (Version A) Conventional gene therapy, described as introducing a functional copy of an allele into an individual that lacks this allele, has been explored as a clinical approach for decades. However, conventional gene therapy is not useful in treating certain genetic conditions.
a. Given what you have learned about the dystrophin gene, why is conventional gene therapy difficult for treating DMD?
b. When the gene product of a dominant genetic disorder is harmful, why is conventional gene therapy not easily used to treat such disorders?
3. (Version B) Conventional gene therapy, described as introducing a functional copy of a gene into an individual that lacks this allele, has been explored as a clinical approach for decades. Why is the CRISPR-Cas9 system more favorable compared to this conventional type of therapy?
4. (Version A) There are potential technical challenges with genetic modification in general and with CRISPR-Cas9 specifically.
a. What challenges might there be in using genome editing to treat an individual diagnosed with DMD after birth?
b. The article also refers to ‘‘off-target effects.’’ Explain what you think is meant by this phrase, and why it might be a risk when using CRISPR-Cas9 clinically.
4. (Version B) What challenges might there be in using genome editing to treat an individual diagnosed with DMD after birth?
5. How might the way we think about using these gene editing technologies change if we imagine them being employed for purposes other than clinical disease prevention/treatment?

Added by Crystal S.

Question

Please give Ace some feedback