A UC San Francisco research team funded by the California Institute for Regenerative Medicine (CIRM) is using AI models to explore potential stem cell and gene therapy treatments for schizophrenia.

The project is part of CIRM’s Research using Multidisciplinary, Innovative approaches in Neuro Diseases (ReMIND) program. Led by Tomasz Nowakowski, PhD, of UCSF’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, the team includes investigators from several University of California campuses. Their goal is to understand how schizophrenia‑associated genetic mutations affect protein function and brain development.

Dr. Nowakowski and his co‑investigators—Alice Ting, PhD (Stanford); Nevan Krogan, PhD, and Willow Coyote‑Maestas, PhD (UCSF); Aparna Bhaduri, PhD (UCLA); Matthew State, PhD (Langley Porter Psychiatric Institute); and Trey Ideker, PhD (UC San Diego)—will use stem cell technologies and AI‑driven models to map the biochemical processes influenced by these mutations. They also plan to build public resources to advance research and treatment for neuropsychiatric disorders.

Dr. Nowakowski answered a few questions about the work. Some responses have been edited for clarity and brevity.

Can you summarize your research?

Dr. Nowakowski: This project seeks to advance our understanding of how mutations in genes causally linked to schizophrenia diagnosis impact protein structure and function, as well as human brain development. We will leverage stem cell technologies to create research resources and foundational datasets. We will harness advances in artificial intelligence to develop computational models that use a biologically informed approach for predicting the risk of severe neuropsychiatric phenotypes from genetic variants identified through genome and exome sequencing, establishing a public resource of variant-to-function relationships in schizophrenia.

What are some research challenges you’d like to overcome through this project?

Dr. Nowakowski: Although hundreds of genetic mutations have been identified, it is unclear how these variants lead to neuropsychiatric symptoms.

We have decided to focus our efforts on proteins, which are encoded by genes and disrupted by mutations, as biological ‘mediators’ of genetic risk. By studying how genetic mutations affect protein structure, function, localization, and interactions, we hope to pinpoint biochemical processes that could present new drug targets for these disorders.

We are also excited to work with researchers who develop new technologies that will allow us to probe deeper into the inner workings of the brain to better understand how and why neurodevelopmental disorders and schizophrenia arise in the first place.

Alternatively, what are the ways in which this research could change the way this disease is considered or studied by other scientists?

Dr. Nowakowski: There is a growing number of neuropsychiatric patients who are diagnosed with genetic mutations, but currently very little of that information subsequently impacts treatment options. Fundamental studies of how these mutations affect protein structure and function has the potential to reveal novel targets for pharmacological intervention.

Our research has the potential to directly facilitate the development of precision interventions for these patients. Our team will develop new technologies to more easily study the effects of genetic mutations on protein structure, localization, and function. This is important, because proteins mediate the pathogenic effects of mutations, and their role has been vastly understudied. By taking advantage of emerging artificial intelligence models, our team seeks to accelerate our ability to predict the risk for neuropsychiatric symptoms from genetic data alone.

Why is research of neuropsychiatric disorders and diseases is so important?

Dr. Nowakowski: Neuropsychiatric disorders present a major source of socioeconomic burden in California. These conditions are highly heritable, and can result in significant social, communicative, cognitive, and behavioral challenges to individuals affected. In some cases they require lifelong medical support, and disproportionately affect disadvantaged communities. Neuropsychiatric disorders are especially difficult to predict, manage, and urgently require progress in novel therapeutic development.

The ReMIND program is a pilot for collaborative. Why you think such funding structures will be impactful for CIRM’s mission?

Dr. Nowakowski: Collaborative, multi‑investigator projects create unique opportunities for cross‑disciplinary research that single‑investigator grants cannot support. This approach is especially important in neurological and neuropsychiatric research, where the complexity of these conditions demands expertise in genetics, molecular biology, biochemistry, and bioinformatics working toward a common goal.

A well‑designed multi‑investigator collaboration can accomplish far more than individual labs working alone. It strengthens reproducibility and produces a coherent, integrated body of knowledge that is better at identifying translational opportunities. By supporting these collaborations, CIRM is building an innovative research ecosystem that is far more likely to generate translational projects than traditional research models.

What has been CIRM’s impact over the last 20 years?

Dr. Nowakowski: Over the past 20 years, CIRM has had an outsized impact on research in California. It created a cutting‑edge scientific environment by investing in infrastructure and training programs that opened doors for many scientists to enter stem cell research.

I came to California after completing my PhD abroad to take advantage of these opportunities as a postdoctoral scholar. I joined CIRM‑funded projects, including the CIRM Center of Excellence in Stem Cell Genomics (CESCG), which was transformative for my career. Collaborations that began through these programs led to some of my most exciting discoveries and sparked long‑term partnerships that continue to advance my research into the causes of neuropsychiatric disorders.

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