CIRM Funds new UCSD VERGE Center to Better Understand Schizophrenia and Autism

This blog is part of a series highlighting our ReMIND program and the researchers it's supporting. To explore all features in the series, click here.

As outlined in Proposition 14, one of the goals of the California Institute for Regenerative Medicine (CIRM) is to help accelerate discoveries that enhance our understanding of central nervous system (CNS) disorders. As part of this goal, CIRM launched the Research using Multidisciplinary, Innovative approaches in Neuro Diseases (ReMIND) Program in 2023 with the ReMIND-L (DISC4) awards.

Through the 2024 ReMIND-L awards, CIRM is supporting large, collaborative research teams conducting expansive, integrated research projects, utilizing recent advancements in stem cell and genetic research, to address critical gaps in the study of neuropsychiatric disorders, including schizophrenia, autism spectrum disorder, and other conditions that significantly affect patients and caregivers throughout California.

One of these teams includes principal investigator Jonathan Sebat, PhD, of UC San Diego, and his co-investigators, who were recently awarded $12.5 million to drive this research forward.

CIRM connected with Dr. Sebat and the team to learn more about the project and how it could advance our understanding of CNS disorders that affect millions of people in California and worldwide.

Some responses have been edited for clarity and brevity:

CIRM: Please share a summary of your research project. Is there a particular disease focus? Is there a broader question that this project is hoping to address?

Dr. Sebat: Our new UC San Diego Verge Center will take a data-driven approach to defining the mechanisms underlying psychiatric traits. Researchers will use cutting-edge stem cell and brain organoid technologies to investigate how specific genetic mutations influence brain development. Uniting research teams in genetics, neuroscience, and clinical psychiatry from UC San Diego and partner institutions, the center will collaborate on four major projects (clinical, high-throughput screening, organoids, and data science) that build on strong research programs in the genetics of psychiatric disorders.

CIRM: What are some of the discoveries you're hoping to achieve through this research project? What are some research challenges you'd like to overcome through this project?

Dr. Sebat: The central goal of the Verge Center is to determine how genes that have been linked to schizophrenia or autism converge upon molecular pathways, cellular function and neurocognitive traits.

Key to our approach will be a careful integration of genetics, neuroscience and data science. Experts in stem cell technology will apply scalable analysis platforms to study neural functions of more than 100 genes and copy number variants (CNVs). Experts in clinical neuroscience will investigate the effects of genetic factors on cognitive and psychiatric traits and brain activity in the clinic. Our data scientists will work closely with the lab to integrate cellular, clinical, and genetic data to define core pathways and neurodevelopmental processes that influence early brain development.

The clinical teams, led by Carrie Bearden, PhD, of UCLA and Sébastien Jacquemont of University of Montreal will take advantage of large clinical, neurocognitive, and neuroimaging datasets on patients that carry specific gene mutations. Their teams will also collect samples from patients which will be converted into stem cells and neurons. This will enable neuroscientist to correlate clinical features in patients with molecular and cellular function in patient-derived neurons in the laboratory.

Gene Yeo, PhD, and Anne Bang, PhD of Sanford Burnham Prebys will use high-throughput screening platforms to investigate the functions more than 100 genes in brain cells. They will study how loss of function or gain of function of genes affect neurons grown from stem cells in the lab.

Lilia Iakoucheva, PhD, and Alysson Muotri, PhD, will study how genetic risk factors for autism and schizophrenia impact brain development using brain organoids-three-dimensional cell culture models that mimic human brain structure and function.

Trey Ideker, PhD and I will analyze data on genes, pathways and neuronal function. Using a variety of statistical and machine-learning approaches, they will identify convergent pathways and neurodevelopmental traits between hundreds of genes associated with conditions like schizophrenia and autism.

By integrating clinical data, genetic analysis and functional studies of neurons and brain organoids, the researchers aim to uncover the biological mechanisms that drive schizophrenia and autism. These discoveries could pave the way for improved diagnosis and treatment of psychiatric disorders in the future.

CIRM: What are some ways this research project can positively impact patients across California and the world? Alternatively, what are the ways in which this research could change the way this disease is considered or studied by other scientists?

Dr. Sebat: In order to have evidence-based psychiatric medicine, we need to have a mechanistic understanding of psychosis, depression and anxiety that is currently lacking. The Verge Center will take a data-driven gene-first approach to defining the molecular and cellular mechanisms that influence cognitive traits. This knowledge will enable a more complete understanding of how specific neural processes in the developing brain influence mental health and will guide the development of new pharmacologic therapies.

CIRM: In your words, can you share why research for neuropsychiatric disorders and diseases affecting the Central Nervous System (CNS) is so important?

Dr. Sebat: Mental health is critical to the well-being of people from all walks of life. Like other health conditions, susceptibility to psychiatric disorders has a biological basis. Research in genetics and neuroscience is needed to have a basic understanding of how brain function relates to psychiatric traits and how this knowledge can be applied in mental health care.

CIRM: The ReMIND program is a pilot for collaborative, multi-investigator funding for foundational basic discovery research. Could you speak to the timeliness and impact of such funding structures more broadly and why you think such funding structures will be impactful for CIRM's mission?

Dr. Sebat: One of CIRM's mandates is to advance research in diseases of the brain and that includes mental health disorders. Given the many genes involved and the scientific questions at multiple levels, many aspects of basic and clinical neuroscience come to bear. However, traditional mechanisms that fund one investigator at a time do not facilitate the rigorous integration of basic genetics, neuroscience, and clinical psychiatry. It is essential to have coordinated collaborations across disciplines and institutions.

CIRM: CIRM is celebrating its 20-year anniversary this year. In your words, can you describe CIRM's impact over the last 20 years?

Dr. Sebat: As a researcher in neuroscience in San Diego, I have been deeply impressed by how stem cell technologies have transformed the field, and I'm keenly aware of the central role that CIRM has played in building the research.

Learn more about the ReMIND program at cirm.ca.gov/remind.