Modeling Fanconi Anemia and Dyskeratosis Congenita with stem cells.
Daisy A. Robinton, & George Q. Daley 2012. The promise of induced pluripotent stem cells in research and therapy. Nature. Vol 481: 295-305.
Hao Zhu, M. William Lensch, Patrick Cahan and George Q. Daley. 2011. Investigating monogenic and complex diseases with pluripotent stem cells. Nature reviews genetics. Vol. 12: 266-275.
-Suneet Agarwal, et.al., & George Q. Daley. 2010. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464:292-298.
-Asmin Tulpule, M. William Lensch, Justine D. Miller, Karyn Austin, Alan D’Andrea, Thorsten M. Schlaeger, Akiko Shimamura, and George Q. Daley. 2010. Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage. Blood. 115:17. 3453-3462.
Question 1: About Dr. George Daley
Dr. Daley can you please tell us a bit about yourself, your career path over the years and how you began modeling human diseases with stem cells?
Question 2: ES vs IPSCs response to disease modeling
Why do you think ES and iPS cells have different responses to disease modeling, such as in fragile X syndrome? Do you feel ultimately that iPSCs are the only way to get around the ethical debate surrounding ES cells?
Question 3: Best cells for iPSC treatment
If it is true that most cells have some epigenetic memory and that when “making iPSC-derived beta-cells using cells from a patient with diabetes might not fully erase any deleterious epigenetic signatures related to the pathogenesis of the patient’s diabetes” (Zhu et al), then what are the best cells to use for iPSC treatment in patients? You mention that using “closely related parent cell or tissue types to make iPSCs is likely to be the most efficient way to achieve the direct differentiation of desired tissues” (Zhu et al) but is there really any way to overcome this barrier?
Question 4: iPSC in a culture dish vs. in humans
You have shown that “the RNA component of telomerase is upregulated in the pluripotent state to a degree sufficient to overcome limitations to telomere maintenance in X-linked and autosomal dominant DC” (Agarwal et al), yet this has only shown to be true in a culture dish. Can we assume that the same will be true if these iPSCs are implanted into the human body, or an actual DC patient? What are the complications that may arise, and or will the effects be the same? Or is all this research only leading to the development of a drug that will cure DC?
Question 5: RNAi to model diseases
Your lab has used RNAi against multiple Fanconi Anemia genes in human ESCs instead of using somatic tissues from Fanconi Anemia patients to model this disease. Why did you choose this approach, and what differences in this approach allow you to better model Fanconi Anemia? Does using RNAi pose any problems in the future modeling of Fanconi Anemia or any other diseases it might be used for?
Question 6: Advancing diseases with iPSCs and hESCs
Although the article shows evidence that suggest a successful model for FA, it also states that the molecular mechanisms of FA are not fully known and understood. Without fully understanding the mechanisms underlying a disease, how are scientists advancing in modeling disease with iPSCS and hESCs?
Question 7: FANCD2 gene
In the article, it was stated that the FANCA gene is the most commonly mutated gene in FA, but why was FANCD2 gene specifically chosen for knockdown?
Question 8: How FANCA gradient can lead to formation of different complementation groups
At one point it’s suggested that there might be a gradient of disease that affects the type of FA that a patient may experience. Can you go into more detail about or hypothesize exactly how a FANCA or FANCD2 gradient can lead to different complementation groups forming? Is there any indication that your modeling of the disease supports this gradient idea?
Question 9: Diseases in young people
Some complex diseases have a high mortality rate at a young age. How are these types of diseases going to be understood? Will it not be difficult to obtain the needed cells from such young patients because their parents need to give consent?
Although it seems logical to measure pluripotency against teratomas due to the presence of all three germ layers, does having the standard for pluripotency being a cancerous tumor cause any issues? It seems as if teratomas are the standard, the outcome of much research will just result in cancerous cells?
Question 11: Most pressing questions in the stem cell field
Currently in your opinion what are the most pressing unanswered questions in your field of modeling human diseases with stem cells? What is your lab attempting to do to address these questions.