A team at the Novartis Institutes for BioMedical Research grew these human neurons from induced pluripotent stem (iPS) cells derived from the skin cells of a heathy individual. Specifically, the researchers used small molecules to coax the iPS cells to differentiate into cortical excitatory neurons, which are relevant to a variety of diseases, including Alzheimer’s, schizophrenia and autism. The team is scaling up protocols developed in academic labs to facilitate drug discovery in Neuroscience.
“We’re automating the differentiation process,” says Ajamete Kaykas, a senior investigator in Neuroscience at NIBR. “We’re using robots to feed the cells, monitor their confluence and split them as needed.”
The researchers should be able to generate many neurons from different starting material via a standard production line. In some cases, the iPS cells at the beginning of the line will be derived from people who are healthy; in others, they’ll be derived from patients with neuropsychiatric and neurodevelopmental disorders. Presumably, the resulting neurons will behave differently in culture and act as a cellular proxy of disease. Some will be less healthy and die more easily, while others will lack the correct proteins to form synapses and have defects in signaling and connectivity. The researchers plan to characterize such differences in detail with a battery of phenotypic assays.
The iPS program is part of a broader effort to understand the cellular and molecular underpinnings of neuropsychiatric and neurodevelopmental diseases, which seldom stem from a single mutation or variant of a gene. Recent studies suggest a complex model of pathogenesis, with many common variants of genes exerting subtle effects on the brain that add up to trouble. Given this complexity, it’s critical to study neurons derived from many different patients, each with a unique combination of genes, to tease apart the factors that contribute to mental illness and focus drug discovery resources.
“It’s possible to model simple diseases—monogenetic diseases—with a few cell lines, but polygenetic diseases are a different story,” says Kaykas. “That’s when a factory model is required to produce many iPS cell-derived neurons from patients.”
Ultimately, the team plans to conduct massive screening experiments to identify molecules that “rescue” diseased neurons. They’ll apply hundreds of thousands of chemicals—one by one—to the cultures and monitor the cells to see which ones act normal. The hits from these screens could potentially serve as starting points for new drugs.