We now know that somatic cells can be reprogrammed to a state resembling embryonic stem cells. These reprogrammed cells (induced pluripotent stem cells, or iPS) not only have potential widespread clinical use, but also serve as a demonstration that cell identity is malleable. Indeed, since the iPS discovery, other types of cell engineering have been described, for example, converting fibroblasts to neurons. A possible barrier to the clinical application of engineered cells (iPS or otherwise) is their acquisition of oncogenic mutations during the in vitro culture and reprogramming process. My research involves both cell engineering and determining the genomic integrity of engineered cells.
Using a mouse model system, I am assaying for genes that efficiently reprogram cells into engraftable hematopoietic stem cells, the parent cells of the blood system. Any genes identified in this screen will be tested in human cells, with the goal of designing novel therapies to treat blood-related diseases.
Recent advances in sequence capture technology coupled with deep sequencing allow the direct examination of genomic coding regions for point mutations. In addition, alterations to gene regulatory regions or to gene expression machinery can now be sought by deep sequencing the transcriptome to assay for imbalanced alleles. Using these techniques, I am assaying the genomes of induced pluripotent stem cells to determine the load of mutations that is acquired from culture or during reprogramming and whether the observed load can be reduced by lowering the cells’ exposure to oxygen.