Chris Rozell - faculty host
"Using the Past to Predict the Future: Applications of High Throughput Longitudinal Single Cell Analysis, Genomics, Stem Cells and Machine Learning to Discovery"
Steve Finkbeiner, M.D., Ph.D.
Department of Neurology
University of California, San Francisco
Clinical trial failure rates for neurological diseases are some of the highest of any indication (~93%), despite showing promise in preclinical disease models. The poor predictive power of preclinical models is a major obstacle to therapeutics development.
To improve matters, we developed an array of human brain cell models differentiated from patient-derived induced pluripotent stem cells (iPSCs), which exhibit disease-associated phenotypes. To fully harness these models to understand mechanisms of disease and screen for therapeutics, we developed systems to perform high throughput longitudinal single cell imaging and analysis, called robotic microscopes. Automated programs find cells within the images and track them longitudinally increasing the sensitivity of screens 2-to-3 orders of magnitude compared with conventional approaches. To expand the power of the platform, we are developing an array of over 270 biosensors that report a variety of biological structures and functions from cells and circuits. Increasingly, deep learning approaches are used to extract features from images, enabling us to achieve super human performance in some cases. We also are using family-based whole genome analysis of patients with neurodegenerative diseases to find new targets and validate then in patient derived human brain cell models. Observational studies in a model of one neurodegenerative disease made it possible to unravel complex cause-and-effect relationships and to identify the autophagy protein clearance pathway as a potential therapeutic target. We then launched a small molecule discovery and development effort that led to brain penetrant orally available autophagy inducers that mitigate disease phenotypes in our human neuron models of neurodegenerative disease. Combining robotic microscopy, biosensors and deep learning, it is becoming possible to develop dynamic predictive models of cell fate at a single cell level that serve as blueprints for therapeutic strategies.
This presentation can be seen via videoconference on the Emory Campus HSRB E160
Dr. Finkbeiner is a Director at the J. David Gladstone Institutes, Director of the Taube/Koret Center for Neurodegenerative Disease, and is a Professor of Neurology and Physiology at the University of California, San Francisco. In 1986 Dr. Finkbeiner earned a bachelor’s degree from Wheaton College. He earned both an MD and a PhD in neuroscience from Yale University in 1991. He completed an internship in internal medicine and chief residency in neurology at the University of California, San Francisco, followed by a research fellowship at Harvard Medical School. Work in his academic research laboratory has focused on studying the molecular mechanisms that are responsible for learning, memory and neurodegeneration. A better understanding of these mechanisms will yield insights into the pathogenesis of neurodegenerative diseases and the memory disorders that often characterize them. A major focus of his work in the area of neurodegenerative disease has been the role of protein dyshomeostasis in HD, PD, ALS, and FTD. In this context, he has developed a unique fully automated high throughput single cell analysis platform called robotic microscopy that provides very sensitive measures of phenotypes. This technology has been used to discover disease-related phenotypes in differentiated neurons from patients with neurodegenerative diseases to better understand mechanisms of disease and to find and develop therapeutic strategies. Dr. Finkbeiner has received numerous awards for his work, including the Lieberman Award, the Taube/Koret Prize, the Award for Outstanding Research Achievement from Nature Biotechnology, and the Javits Neuroscience Investigator Award from the NIH NINDS.