Since the founding of our laboratory, we have committed our research program to determining the mechanisms that cause motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). As our understanding of these mechanisms improves, we gradually seek to translate our discoveries into new therapeutic options for patients.
In order to achieve these goals, we operate at the interface between the fields of stem cell biology, genetics, developmental neuroscience and the neurobiology of disease. Because available rodent models for ALS had not proven to be predictive of clinical outcomes, we conceived and realized an entirely new approach for utilizing stem cell biology and reprogramming technology to study how the many genetic variants causing ALS lead to motor neuron dysfunction. Our demonstrations that this approach can be successfully employed, if its limitations are carefully studied and understood, has induced substantial movement towards this strategy from both those studying ALS, as well as from the broader community interested in neural degeneration.
As we move on from our initial demonstrations of utility, the ability to produce motor neurons harboring the genotype of many distinct individuals is inspiring us to address the central issue of whether there are shared mechanisms that cause neural degeneration in some, or perhaps even all ALS patients. The discovery of one such potential mechanism, apparently exhibited by many patients, has precipitated a clinical trial designed to test if our stem cell models are predictive of the changes occurring in patients.
Based on our initial successes in contributing to the understanding of motor neuron disease, we have now begun to expand our interests, applying similar strategies to the study of psychiatric conditions in collaboration with The Stanley Center at The Broad Institute.
There remains an unmet need to develop improved treatments for debilitating and all to common psychiatric diseases such as schizophrenia (SCZ), bipolar and autism. Improvements in technologies for DNA analysis, coupled with ever scaling collections from affected individuals continue to drive progress in identification of genetic contributors to these conditions. However, our improving understanding of the genetic architecture of these disorders is unlikely to result in new treatments if we cannot determine how predisposing genetic variation damages normal brain function. Unfortunately, high quality brain tissue is generally unavailable from both affected individuals and controls for such studies. To overcome this limitation, we have been using stem cells to produce populations of human brain cell-types with the hope they show utility in determining the functional ramifications of newly discovered genetic variants. While this strategy holds great promise, questions remain concerning how reproducibly stem cells can be used to produce human brain cell-types and how closely they represent those that eventually malfunction in affected individuals. It is our short-term aim to explore the strengths and weaknesses of stem cell technologies. We hope these efforts will lead to improved methods for studying disorders of the nervous system. In the medium term we aim to use stem cell models to assist our efforts to identify the brain cells most impacted by psychiatric disease and provide insight into how they malfunction. In the longer term, we believe these same human stem cells will provide a foundational resource for identifying candidate therapeutics with corrective activities.