Scientists have linked neuropsychiatric disorders, such as schizophrenia and autism, to changes in many genes involved in early brain development. However, more research is needed to understand how these gene variants influence the biological mechanisms that underlie these disorders.
Anne Bang, PhD, director of Cell Biology at the institute’s Conrad Prebys Center for Chemical Genomics, is part of an interdisciplinary team of scientists and clinicians working to establish clearer connections between the implicated genes and their effects on brain function and mental health.
Bang’s lab is equipped with extensive instrumentation necessary for high-throughput screening. This technology allows scientists to automate experiments on multiple samples at once using robotics, precise fluid handling technologies and automated imaging.
Under the leadership of Jonathan Sebat, PhD, a professor in the departments of Psychiatry and Cellular & Molecular Medicine at UC San Diego School of Medicine, the group was awarded a $12.7 million grant from the California Institute for Regenerative Medicine (CIRM) to create a new research center to support this work. The UC San Diego Verge Center: Convergence and Divergence of Genes on Neurodevelopment and Mental Health is one of five collaborations supported through CIRM’s pilot ReMIND (Research Using Multidisciplinary, Innovative Approaches in Neuro Diseases) program.
“Through large-scale efforts to understand the genetic underpinnings of complex psychiatric conditions, tens of thousands of individuals across the world have had their genomes sequenced, leading to the identification of gene variants that place individuals at risk for disorders such as schizophrenia and autism,” said Bang.
“That incredible effort has brought the field to the place we are today, and, with this support from CIRM, we are poised to study these risk genes more closely than ever before.”
The new research center will strengthen collaborations between experts from UC San Diego, Sanford Burnham Prebys, the University of California Los Angeles (UCLA) and the University of Montréal. By integrating clinical data, genetic analyses and functional studies of neurons and brain organoids, the researchers aim to uncover biological mechanisms that drive schizophrenia and autism.
Bang will co-lead the center’s high-throughput screening team with Gene Yeo, PhD, MBA, a professor in the Department of Cellular & Molecular Medicine at UC San Diego. Their group will study the function of more than 100 genes in brain cells using the Prebys Center’s extensive instrumentation to conduct high-throughput biology.
Bang, Yeo and their collaborators will employ genetic engineering techniques to silence or restore the function of certain genes and investigate how these genetic changes affect neurons grown from patient samples that are transformed into stem cells in the lab.
“We’re using CRISPR technology to upregulate and downregulate the activity of risk genes in stem cell-derived neurons to map out subsequent changes in the cells,” said Bang. “Everything we learn will be shared with the data coordinating center to integrate data from all the teams.”
The other UC San Diego Verge Center projects are:
- Organoids team: Lilia Iakoucheva, PhD, a professor in the Department of Psychiatry at UC San Diego, and Alysson Muotri, PhD, a professor in the departments of Pediatrics and Cellular & Molecular Medicine at UC San Diego, are leading the study of genetic risk factors for autism and schizophrenia through the use of brain organoids and assembloids — three-dimensional cell culture models that mimic human brain structure and function.
- Clinical team: Carrie Bearden, PhD, a professor in the departments of Psychiatry and Psychology at UCLA, and Sébastien Jacquemont, MD, a medical geneticist from the University of Montréal, will use large datasets to convert samples from patients carrying specific gene mutations into stem cells and neurons. Researchers will then compare characteristics in patient-derived neurons with clinical outcomes in the same patients.
- Genomics team: Sebat will lead a data coordinating center, and will work with Trey Ideker, PhD, a professor in the departments of Medicine and Bioengineering, to evaluate data on genes, pathways, neuronal function and neurodevelopmental traits, with the goal of finding new explanations for how gene mutations influence behaviors and cognitive function.
“I’m a big believer in this multidisciplinary approach that emphasizes team science,” said Bang. “By bringing together many perspectives, you can create a synergy that is far greater than what any of us could accomplish alone.
“The need for innovation in treating neuropsychiatric diseases is vast. Patients and families often experience treatment odysseys of trying drug after drug until one hopefully helps. Our hope is that understanding these genetic factors may in the future lead to better diagnostic tools, improved treatments and potentially new therapeutic targets for these conditions.”
