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Systems Biology of Autism: Cellular Models

The broad range of behaviors seen across the autism spectrum has been more than amply mirrored in the discovery of hundreds of mutated gene candidates proposed to explain their origins. The gap between genes and behavior poses an astonishingly difficult problem, possibly uniquely presented by each individual carrying the label ‘autistic’. Yet, many similarities across the spectrum are seen by neuro-imaging and other non-invasive physiological probes, suggesting that different gene sets might have common final pathways affecting neuronal migration, synaptic plasticity, and electrical signaling across networks. This would imply that there are a few global circuits perhaps that could be modulated in a number of different ways to improve basic neurophysiological processes underlying observed social and motor activity.

In considering how much of the familiar ‘autism pie’ is currently explainable in terms of specific genes it is clear that a large slice is due to rare de novo loss-of-function (LOF) mutations. An attractive approach to studying these cases is to create inducible pluripotent cell lines (IPSC) and induce neuronal cell lines which can be grown to confluence in culture. Remarkably these cultures exhibit electrophysiological and connectivity patterns that seem to reflect normal activity. Interestingly, more than one cell type often appears in these preparations, characterized by surface markers, allowing the application of gene expression analysis. The recent development of facile gene modification technologies (CRISPR), supplementing short hairpin RNA approaches, opens up myriad opportunities for studying the effects of individual LOF mutations on specific cell types in a quasi-circuit context.

In this meeting, participants addressed the question of how best to apply these technologies to close the gap between genes and behavior in autism and perhaps reduce the high degree of apparent heterogeneity. The syndromic forms of autism have provided valuable insights into the general condition of autism and it is possible that each of the rare de novo mutations might do the same.

Staci Bilbo, Ph.D.
Associate Professor of Pediatrics
Harvard Medical School
Director of Research, Lurie Center for Autism
Massachusetts General Hospital

Idiopathic Autism: Characterizing Neurobiological and Molecular Phenotypes using iPSC and “Omic”

Emanuel DiCicco-Bloom, MD
Dept. of Neuroscience and Cell Biology
Rutgers/Robert Wood Johnson Medical School

Convergence in transcriptional effects of suppressing ASD-associated chromatin and transcriptional regulators
James F. Gusella, Ph.D.
Bullard Professor of Neurogenetics
Department of Genetics
Harvard Medical School
Center for Human Genetic Research
Massachusetts General Hospital

Role of metabotropic glutamate receptors (mGluRs) in the etiology and treatment of autism
Hakon Hakonarson, MD, Ph.D.
Professor of Pediatrics
University of Pennsylvania School of Medicine
Center for Applied Genomics
Children’s Hospital of Philadelphia

Elucidating mechanisms of de novo DEAF1 mutations
Philip J. Jensik, Ph.D.
Associate Professor
Southern Illinois University School of Medicine

James Millonig, Ph.D. 
Associate Professor
Dept. of Neuroscience and Cell Biology
Rutgers/Robert Wood Johnson Medical School

iPSC-derived neurons to probe Tuberous Sclerosis and the mTOR pathway
Mustafa Sahin, MD, Ph.D. 
Professor of Neurology
Harvard Medical School
Department of Neurology
Boston Children’s Hospital

Michael Talkowski, Ph.D.
Associate Professor
Massachusetts General Hospital

Autism Genetics: Beyond the Exome
Christopher Walsh, MD, Ph.D. 
Bullard Professor of Neurology
Harvard Medical School
Chief, Division of Genetics
Children’s Hospital Boston


The Nancy Lurie Marks Family Foundation, Wellesley, MA