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Can Using Stem Cells to Recreate Part of the Human Brain Reveal the Causes of Schizophrenia?
Principal investigator: Dr Sergiu Pasca
Institution: Stanford University School of Medicine
Location: USA
Research award: Fellows Award
Funding Period: 2015-2018
Serious mental illnesses (SMI’s) such as schizophrenia can impact how people interact with the world around them, how they feel, think and behave and lead to premature mortality in the most serious cases.
Understanding what happens in the brain cells of people with SMI’s could provide vital information about how to identify and treat those problems.
The project
To simulate and study the ways that cells interact Dr Sergiu Pasca and his team used state-of-the-art stem cell technology to recreate parts of a functioning human brain in the lab.
The goal was to identify cellular mechanisms of disease and novel therapeutic targets by studying neurons derived from patients, enabling direct investigation of disease-related changes at the cellular and molecular level.
The process
Sergiu and his team used a new technique for creating 3D cell cultures in lab conditions. This technique creates cells that more closely mimic natural tissues than cells grown in traditional flat petri dishes.
By taking stem cells from people with schizophrenia who have specific genetic mutations, the team created tiny ‘minibrains’ – each smaller than a pea – that emulated parts of a foetal human brain.
It’s was then possible to study the molecular and cellular processes that could contribute to schizophrenia.
The outcome
This ground-breaking work enabled Sergiu and his team to study individual cells – and their growth into fully-functioning circuits – in detail we’ve never been able to see before. Previously we could only study individual cells in a test and the only way to study circuits was to use rodents’ brains.
They found that robust transcriptional changes and defects in calcium and potassium channel signalling were identified in patient-derived neurons. The DGCR8 gene and a downstream microRNA were found to be responsible for these defects.
As a result, they can now begin to answer fundamental questions about the formation of the cerebral cortex, the outer layer of the brain responsible for our most advanced functions and linked to mental illnesses like schizophrenia.
Papers published
- Sun Y, Paşca SP, et al, A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. Elife. 2016
- Marton RM, Paşca SP. Neural Differentiation in the Third Dimension: Generating a Human Midbrain. Cell Stem Cell. 2016
- Paşca SP, Personalized Human Cortical Spheroids, Imaged in Neuroscience, 2016
- Deverman BE, et al, Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol. 2016
- Khan, T., Paşca, S. The Zika threat to the periphery. Nat Neurosci 2017
- Madelaine R, Paşca SP, et al, MicroRNA-9 Couples Brain Neurogenesis and Angiogenesis. Cell Rep. 2017
- Birey F, Paşca SP, et al, Assembly of functionally integrated human forebrain spheroids. Nature. 2017
- Cao Y et al, Nondestructive nanostraw intracellular sampling for longitudinal cell monitoring. Proc Natl Acad Sci U S A. 2017
- Sloan SA, Andersen J, Pașca AM, Birey F, Pașca SP. Generation and assembly of human brain region-specific three-dimensional cultures. Nat Protoc. 2018
- Farahany NA, Paşca SP, et al The ethics of experimenting with human brain tissue. Nature. 2018
- Marton RM, Paşca SP. A human cellular model of amyotrophic lateral sclerosis. Nat Med. 2018
- Pașca SP. The rise of three-dimensional human brain cultures. Nature. 2018
The impact
This ground breaking work could transform our understanding of schizophrenia, potentially leading to therapeutic treatments that target the condition more precisely.
The project established a new platform for studying schizophrenia and related neuropsychiatric disorders at the cellular level, enabling direct investigation of disease mechanisms and potential therapeutics.
Sergiu’s model can also now be replicated to build different brain circuits, helping improve our understanding of other conditions associated with the brain and informing vital treatments. This could have a profound effect on future studies.
Data from the MQ award helped secure additional private and federal funding for ongoing research whilst the team’s methods and cell lines have been shared with multiple groups worldwide, enabling broader adoption and future research.
Dr Sergiu Pasca
Dr Sergiu Pasca is a PKenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences and Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program.
He is also the Director of the Pasca Lab at Stanford University.
He focuses on understanding the molecular and cellular mechanisms of neuropsychotic disorders.
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