A new award from the California Institute for Regenerative Medicine (CIRM) will support a team of UC Santa Cruz researchers in exploring the genetic underpinnings of autism spectrum disorder (ASD) and investigating possible treatments, in collaboration with teams at UC San Francisco and UC Berkeley.
ASD affects one in 22 children in California, but there is a wide range of variability in how it presents. Many genetic variants have been linked to autism, but research has not clearly defined how and why these variations affect people differently and result in varying severity of autism.
The SSPsyGene consortium, an effort to study genes linked to neuropsychiatric conditions involving UCSC researchers, recently prioritized 120 gene variants associated with ASD. This work will form the basis of the new project, as the researchers will focus on the gene pathways that most commonly lead to ASD. They will investigate the biological processes that cause ASD using cell culture models of brain development derived from pluripotent stem cells. They will use this information to develop laboratory tests that can be used to investigate targets for treatment.
The researchers will use brain organoids, miniature models of brain tissue grown in the lab, to narrow down the most clinically relevant observable signs of ASD in their models. The Braingeneers group have become leaders in automating the cultivation and measuring the properties of brain organoids as part of their Live Cell Technology Center. This project will be the first time they use their expertise to study neuropsychiatric conditions.
“The Braingeeners group has been working since 2018, and a big part of that has been developing methodologies and platforms for more robust generation and analysis of brain organoids,” said Sofie Salama, Professor of Molecular, Cellular and Developmental Biology who will be an investigator on this project. “This is a really exciting opportunity where the rubber is hitting the road — we can test how these platforms we've developed allow us to study how organoid phenotypes can shed light on the variants that can lead to human diseases.”
CIRM has awarded $12.3 million in total funding for this project through its pilot ReMIND (Research using Multidisciplinary, Innovative Approaches in Neuro Diseases) Program. The project will be led by UCSF Assistant Professor of Neurology Alex Pollen. $4.1 million of this funding will go to UC Santa Cruz, where research will be spearheaded by scientists in the Braingeneers group, including Salama, Research Scientist Mohammed Mostajo-Radji, Associate Professor of Electrical and Computer Engineering Mircea Teodorescu, and Distinguished Professor of Biomolecular Engineering David Haussler.
“We are incredibly excited to combine the scalable technologies developed by our Braingeneers group and our Center for Live Cell Genomics with our experience and collaborations within the neuroscience community to address a critical question: how do genetic perturbations in brain development lead to circuit-level phenotypes in autism?” Mostajo-Radji said. “We are deeply grateful to CIRM and the voters of California who supported Proposition 14 in 2020, making this project possible. We are thrilled to take on this challenge alongside our colleagues at UCSF and UC Berkeley.”
“While we understand through our other funded projects that organoids can develop functional properties resembling those of a developing brain, the exact genetic mechanisms of how autism spectrum disorder (ASD) affects developing brains remain unclear,” Teodorescu said. “To fully grasp these mechanisms, in this project we will conduct a large-scale, automated experimental study. This will generate a vast amount of data, requiring advanced AI-powered data analysis."
The team aims to understand how ASD presents differently across various populations, and what genetic factors might protect certain populations against ASD, by studying these genetic variants in cells from people with diverse ancestral backgrounds. At the end of this project, they will produce a system to classify different types of ASD based on genetic information.
At UC Berkeley, researchers include Associate Professor of Molecular and Cell Biology Helen Bateup; Professor of Chemical and Biomolecular Engineering, Bioengineering, and Neuroscience David Schaffer. At UCSF, researchers include Pollen, Associate Professor of Biochemistry and Biophysics Martin Kampmann, Professor of Neurology Saul Kato, and Professor of Neurology and Pediatrics Elliott Sherr.
The successful collaborative grant writing was the result of the efforts of Lise Barbé, the newly hired grants coordinator at QB3, where investigator Schaffer is the Executive Director, as well as the UC Santa Cruz Genomics Institute grants team.
