Modeling Fanconi Anemia and Dyskeratosis Congenita with stem cells.
Maria C. Marchetto, Kristen J. Brennand, Leah F. Boyer and Fred H. Gage. 2011. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises. Human Molecular Genetics, Vol. 20, Review Issue 2. R109-R115.
Maria C. N. Marchetto, Cassiano Carromeu, Allan Acab, Diana Yu, Gene Yeo, Yangling Mu, Gong Chen, Fred H. Gage, and Alysson R. Muotri. 2010. A model for neural development and treatment of Rett Syndrome using human induced pluripotent stem cells. Cell. 143(4): 527–539.
Question 1: About Dr. Carol Marchetto
Dr. Marchetto can you please tell us a bit about yourself, your career path over the years and how you began modeling Neurological diseases and specifically Autism Spectrum Disorders with stem cells?
Question 2: Autism influential factors
Our understanding of Autism Spectrum disorder is that it is a neurodevelopmental disorder that is highly heritable and results in impaired social interaction and repetitive behaviors, but it seems like so many more behaviors and individuals are getting placed in this spectrum. In your expert experience how might you define ASD today? What are the current hypotheses for causes or influential factors? And lastly, how do you think studying ASD in a dish will resolve unanswered questions that may directly help an ASD patient?
Question 3: Epigenetics in cellular reprogramming
What role will epigenetic factors have in reprogramming these cells? Although you use the antibody against me3H3K27 to un-silence the X chromosome, are there other epigenetic factors that could have an effect on the outcome of RTT iPSCs? What hopes do you have for using the me3H3K27 data to provide RTT therapies?
Question 4: Rett’s syndrome and ASD
After briefly touching on this in your paper, you mention some of the challenges that may arise from using RTT models to generalize about ASD. How do you think studying Rett’s syndrome can aid in our understanding of ASD? How applicable is studying a monogenic disease when much of ASDs appear pleiotropic?
Question 5: Disease Modeling
What characteristics of a disease do you need to consider when deciding what method of modeling is the best for that particular disease?
Question 6: IPSC’s vs. Embryonic stem cells for disease modeling
With all the challenges you state in your paper about the variability in iPSC lines, why did you still choose to use iPS cells for your research instead of embryonic stem cells for the modeling of these neurological diseases?
Question 7: Biological markers and iPSC modeling in ASD.
You mention that the lack of early biological markers make ASD an attractive disease for future modeling with iPSCs. What do you mean by “biological markers,” and how do you think modeling with iPSCs can help us discover them and utilize them in treatment of ASD?
Question 8: RTT Screening
It seems that “novel biomarkers that might be exploited as diagnostic tools and that early-intervention may be beneficial” assume that infants would be screened for RTT early on. However, if a child’s family doesn’t have a history of a disease, what would prompt someone to test their child? In other words, why should any parent suspect their child has RTTs? Lastly, how do you plan on extending this work on RTT syndrome to model the more wide spread polygenic causes of ASDs?
Question 9: Biology of RTT
How long have your RTT-iPSC-derived NPCs survived for? How do you think later onset factors involved with RTT will play a role in deriving the eventual RTT model? Do you think that there are later onset biological factors that play a role in the course of RTT?
Question 10: Calcium and MeCP2 in ASD
In the article about the neural development and treatment of Rett syndrome you discuss the possibility of MeCP2 activity is modulated by calcium. Would the mutation of MeCPs affect its ability of being activated by calcium or does the lack of calcium in early neural development affect MeCP2 activity? Could you please further explain the nature of this mutation and the role of Calcium in MeCP2 activity and Autism in general?
Question 11: RTT vs WT iPSCs
Your research explored whether there were significant differences in the proliferation of RTT-iPSCs versus WT-iPSCs or hESCs. Could you first in your words elaborate on the results you found in this area, and then please comment on whether you are attempting to re-create the three dimensional structure of the brain (neural network and supportive glia) to answer this question more confidently? Do you think these results even need to be verified in the context of whole tissue or even the whole organism?