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Our laboratory focuses on translational, high-throughput research to model disease and develop drugs using stem cells. We have established an extensive range of complex image based assays that have been used to probe various properties of stem cells and of many cells derived from them. To accomplish this we use automated high content screening imagers, associated robotic equipment, and selected small molecule libraries. We combine our high throughput approach with detailed molecular studies to further our understanding of the mechanisms of disease and determine which compounds are most likely to be of therapeutic value.

A primary focus of the lab is diseases of motor neuron degeneration, including spinal muscular atrophy (SMA) and amyotrophic lateral scleroris (ALS).  SMA is genetic disorder caused by the decrease in the level of Survival of Motor Neuron protein (SMN) leading to neuromuscular degeneration in children. We have carried out quantitative high content measurements in patient fibroblasts to discover small molecules that increase the level of SMN. (Makhortova et al. Nature Chemical Biology, 2011). Prolonging motor neuron survival is a major therapeutic goal for treatment of both SMA and ALS. We have executed a variety of survival assays using motor neurons generated in large numbers from mouse and human ES cells as well as patient derived iPS cells to identify compounds that prevent motor neuron death.

Another important aim of our lab is to develop new stem cell based disease models using small molecule screens.  One project has applied this approach to improve the differentiation of stem cell derived dopaminergic neurons, the same cell type that is specifically lost in Parkinson’s disease. We are also working to identify small molecules that enhance transdifferentiation, which is the direct conversion of one differentiated cell type into another. 

Our expertise in developing stem cell based disease models and high content screening allows us to contribute to a large number of collaborations with members of the Harvard Stem Cell Institute.