Vilcek Prize for Creative Promise in Biomedical Science
Sergiu P. Pasca
Perseverance might well be Sergiu Pasca’s middle name. The first in his family to attend college, Pasca, now an assistant professor of psychiatry and behavioral sciences at Stanford University, has secured a place on the international neuroscience stage through sheer force of will. At the young age of 35, Pasca has proven himself a force to be reckoned with, developing sophisticated 3D models of the human brain to study an array of psychiatric disorders, including autism and schizophrenia.
Born in Cluj-Napoca, Romania, Pasca was raised in nearby Aiud during the waning years of communism under dictator Nicolae Ceausescu. Growing up in a family of modest means—his mother was a primary-school teacher and his father ran a construction business—Pasca took an early interest in painting and poetry. But in middle school, encouraged by a teacher, he gravitated toward chemistry, poring over textbooks and performing experiments in a basement lab. In the final year of high school, he won a prize in the national chemistry Olympiad, earning a scholarship to attend any university of his choice in Romania.
In 2001, Pasca enrolled in medical school at Cluj-Napoca with a view to pursuing biochemistry. But he soon became dispirited with the scant resources available for research at the school. Unfazed, he teamed up with a biochemistry professor, whom he counts among his mentors, to uncover the biochemical underpinnings of disease. Reasoning that a rare disorder might be amenable to studies in small patient cohorts, unlike common diseases, which often require samples from thousands of patients to draw meaningful biochemical links, he began looking for metabolic defects in autism, which was then considered relatively rare. His resourcefulness paid off; they soon found that children with autism indeed had metabolic alterations. The work resulted in his first publication in a peer-reviewed journal, sparking his interest in neuroscience.
Around this time, while attending a short course in Bucharest, Pasca met Stanford University neurobiologist Jack McMahan, who encouraged him to apply for a postdoctoral position in the United States. Thanks to a fellowship from the International Brain Research Organization, Pasca arrived at Stanford in 2009 to work in the lab of neuroscientist Ricardo Dolmetsch, whose work was motivated by his own son’s diagnosis of autism. “I had been dreaming of investigating patient-derived neurons—ever since medical school,” says Pasca.
With Dolmetsch, Pasca began to explore the molecular underpinnings of Timothy syndrome, a rare form of autism that can be accompanied by heart defects, low blood sugar, and intellectual disability. The syndrome is caused by a genetic mutation in a channel that shuttles calcium ions across cell membranes in the brain and heart. But the precise effects of the mutation at the cellular level remained unclear, partly because obtaining patients’ heart and brain tissues suitable for analysis is challenging.
Pasca used cellular reprogramming technologies to convert patients’ skin cells into stem cells and subsequently into neural cells, furnishing personalized disease models. Neurons derived from Timothy syndrome patients exhibited overactive calcium signaling, altered expression of marker genes, and increased levels of the neurotransmitters dopamine and norepinephrine. What’s more, the channels appeared to control the retraction of the neurons’ dendrites—the slender branches that reach out to make connections with neighboring neurons. “Patients’ heart problems can sometimes be controlled with pacemakers, but we can't do much about the brain defects,” says Pasca.
After five years of training with Dolmetsch, Pasca earned a faculty position at Stanford. Extending his work on developing models for brain disease, Pasca used stem cells to generate self-organizing 3D structures that resemble human brain tissue. Dubbed organoids, these cultures closely resemble the architecture of the brain’s cortical layers and contain functional neurons from different layers as well as neuron-supporting cells called astrocytes. “There are many aspects of brain function that 2D cultures do not capture, and I felt early on that these 3D cultures would prove transformative,” says Pasca. First reported in Nature Methods in 2015, the effort led to a repository of patient-derived brain cultures, representing miniature disease models that are among the most realistic mockups of brain development available to researchers today. Multiple labs around the world have implemented this approach. More recently, Pasca demonstrated in an article in Neuron that brain region-specific organoids can be maintained in culture for years.
Three years later, Pasca bested himself with an even more sophisticated model of the human brain: one that allows precise investigation of the cross-talk between brain regions, including the migration of neurons and assembly of human brain circuits in a dish. (Some types of neurons travel several millimeters from their site of origin in the brain to their destined circuits.) These findings, published in Nature, have paved the way toward insights into human brain development and disorders in which communication between different brain regions goes awry. Using the approach, Pasca uncovered, for example, defects in the migration of so-called interneurons to their final destinations in the brain’s cortex in patients with Timothy syndrome. “With these models, we can finally get access to what we thought was inaccessible brain biology,” Pasca says.
Over the next decade, Pasca hopes that his pioneering efforts to illuminate neuropsychiatric diseases will lead to treatments for patients. Given his contributions to basic neuroscience, that goal appears well within his grasp. He attributes his success to the many opportunities that moving to America made available to him. “I don’t think I would have received this level of support and flexibility anywhere else,” he says.
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