Tomasz Nowakowski, PhD
University of California, San Francisco
Biography:
Tomasz Nowakowski, Ph.D., is an Associate Professor of Neurological Surgery, Anatomy and Psychiatry and Behavioral Sciences at the University of California, San Francisco, and a member of the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research. Trained in physiology, life sciences, and biomedical sciences at the University of Edinburgh, he completed postdoctoral research with Arnold Kriegstein in 2017. His research focuses understanding how the human brain develops and how genetic mutations interfere with the processes of normal brain development to give rise to neurodevelopmental disorders. His lab pioneered molecular tools for single-cell and spatial genomics, lineage tracing, and circuit mapping, leading to discoveries on progenitor fate competence, human-specific neurodevelopmental programs, astrocyte and vascular diversity, and mechanisms underlying autism and psychiatric risk variants.
Nowakowski has received major recognition including the Joseph Altman Award in Developmental Neuroscience, the Vilcek Prize for Creative Promise in Biomedical Sciences, and the Robertson Neuroscience Investigator Award. He plays leading roles in the NIH BRAIN Initiative Cell Atlas Network the Simons Foundation consortia. Dr. Nowakowski holds a CR Muthukrishnan Distinguished Chair at IIT Madras, India. He is a co-founder of two startups: Voltagen Inc. and Mreza Therapeutics.
Abstract:
Autism spectrum disorder affects roughly 1 in 36 people and is defined by differences in social communication and behavior. Despite decades of research and the identification of hundreds of genetic risk factors, we still do not understand why those genetic differences lead to the brain changes underlying autism — or why some individuals are more severely affected than others. Answering these questions requires looking directly at the human brain. Our lab studies postmortem brain tissue donated to research by individuals with autism and unaffected controls. Using a technology called single-nucleus RNA sequencing, we can measure which genes are active in each individual brain cell — across thousands of cells at once — to build a detailed molecular portrait of how the autistic brain differs at the cellular level. We focused on two brain regions that have received relatively little attention in autism research. The first is the striatum, a deep brain structure involved in movement, reward, and habit formation. Genetic studies have long suggested that a specific cell type in the striatum — called medium spiny neurons — may be particularly relevant to autism, but this had never been directly examined in human tissue. We found that these neurons show clear molecular differences in people with autism, especially those with a confirmed genetic diagnosis. Unexpectedly, the pattern of changes resembles what is seen in aging brains and in neurodegenerative conditions like Parkinson's disease — consistent with recent reports that autistic individuals are diagnosed with these conditions at higher rates and earlier ages than the general population. The second region is the language cortex, the area of the brain responsible for producing and understanding speech. This matters because up to 40% of autistic individuals experience significant language impairment, and approximately 25% never develop functional spoken language. We found that the language cortex in autism shows molecular changes concentrated in neurons, driven in part by altered activity of a gene regulatory protein called RFX3. Strikingly, the degree of molecular disruption tracked with whether an individual was verbal or non-verbal — suggesting that measurable differences in gene activity in specific brain cells may underlie one of the most impactful and least understood features of autism. Together, these findings identify specific cell types and molecular pathways that are disrupted in the autistic brain, point to unexpected connections with aging and neurodegeneration, and bring us closer to understanding — and eventually targeting — the biological basis of communication differences in autism.
Tomasz Nowakowski, Ph.D., is an Associate Professor of Neurological Surgery, Anatomy and Psychiatry and Behavioral Sciences at the University of California, San Francisco, and a member of the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research. Trained in physiology, life sciences, and biomedical sciences at the University of Edinburgh, he completed postdoctoral research with Arnold Kriegstein in 2017. His research focuses understanding how the human brain develops and how genetic mutations interfere with the processes of normal brain development to give rise to neurodevelopmental disorders. His lab pioneered molecular tools for single-cell and spatial genomics, lineage tracing, and circuit mapping, leading to discoveries on progenitor fate competence, human-specific neurodevelopmental programs, astrocyte and vascular diversity, and mechanisms underlying autism and psychiatric risk variants.
Nowakowski has received major recognition including the Joseph Altman Award in Developmental Neuroscience, the Vilcek Prize for Creative Promise in Biomedical Sciences, and the Robertson Neuroscience Investigator Award. He plays leading roles in the NIH BRAIN Initiative Cell Atlas Network the Simons Foundation consortia. Dr. Nowakowski holds a CR Muthukrishnan Distinguished Chair at IIT Madras, India. He is a co-founder of two startups: Voltagen Inc. and Mreza Therapeutics.
Abstract:
Autism spectrum disorder affects roughly 1 in 36 people and is defined by differences in social communication and behavior. Despite decades of research and the identification of hundreds of genetic risk factors, we still do not understand why those genetic differences lead to the brain changes underlying autism — or why some individuals are more severely affected than others. Answering these questions requires looking directly at the human brain. Our lab studies postmortem brain tissue donated to research by individuals with autism and unaffected controls. Using a technology called single-nucleus RNA sequencing, we can measure which genes are active in each individual brain cell — across thousands of cells at once — to build a detailed molecular portrait of how the autistic brain differs at the cellular level. We focused on two brain regions that have received relatively little attention in autism research. The first is the striatum, a deep brain structure involved in movement, reward, and habit formation. Genetic studies have long suggested that a specific cell type in the striatum — called medium spiny neurons — may be particularly relevant to autism, but this had never been directly examined in human tissue. We found that these neurons show clear molecular differences in people with autism, especially those with a confirmed genetic diagnosis. Unexpectedly, the pattern of changes resembles what is seen in aging brains and in neurodegenerative conditions like Parkinson's disease — consistent with recent reports that autistic individuals are diagnosed with these conditions at higher rates and earlier ages than the general population. The second region is the language cortex, the area of the brain responsible for producing and understanding speech. This matters because up to 40% of autistic individuals experience significant language impairment, and approximately 25% never develop functional spoken language. We found that the language cortex in autism shows molecular changes concentrated in neurons, driven in part by altered activity of a gene regulatory protein called RFX3. Strikingly, the degree of molecular disruption tracked with whether an individual was verbal or non-verbal — suggesting that measurable differences in gene activity in specific brain cells may underlie one of the most impactful and least understood features of autism. Together, these findings identify specific cell types and molecular pathways that are disrupted in the autistic brain, point to unexpected connections with aging and neurodegeneration, and bring us closer to understanding — and eventually targeting — the biological basis of communication differences in autism.
