Stanford neuroscientist Sergiu Pasca is leading research that allows scientists to recreate human brain tissue and neural circuits in laboratory settings. This technology offers new ways to study the development of the human brain and could lead to treatments for psychiatric disorders and chronic pain.
Pasca described his motivation, stating, “I encountered my first patient with autism when I was in my second year of medical school – a moment that profoundly changed the course of my career. The disorder was not only devastating in its impact, but also deeply mysterious. From that point on, my mission became understanding the biology of the human brain and how complex mental disorders emerge when that biology goes awry.”
He noted differences in progress between fields where affected organs are accessible versus those like psychiatry, where access is limited. According to Pasca, “The human brain remains the final frontier. For conditions like autism or schizophrenia, the challenge is not just access to tissue, but access to tissue that is functional. While post-mortem studies have offered some insight – especially in neurodegenerative diseases like Parkinson’s or Alzheimer’s – they fall short when it comes to disorders rooted in neural circuit dysfunction. Static, nonliving tissue cannot reveal how brain cells interact in real time or how disruptions in these interactions give rise to complex psychiatric symptoms. To fully harness the potential of molecular biology in psychiatry, we needed a way to study the living human brain at both the molecular and cellular levels.”
A key advance came from research showing skin cells could be reprogrammed into stem cells capable of becoming neurons. Pasca explained, “As I was finishing my clinical training, a breakthrough came from a Japanese scientist who demonstrated that skin cells could be reprogrammed into stem cells. Suddenly, the idea of obtaining living neurons from patients in a noninvasive way became a possibility. We could, in principle, take skin cells from individuals with autism, reprogram them into stem cells, and then differentiate them into neurons in a dish. This would give us direct access to human neurons – and, for the first time, a way to investigate the biology of these complex disorders at a cellular level.”
After joining Stanford University, Pasca generated some of the first human neurons derived from induced pluripotent stem cells on campus and later developed three-dimensional cultures known as neural organoids.
“We can now generate more than two-thirds of the cell types found in the developing human brain,” he said. “But in the brain, function does not arise from individual parts alone – it emerges from how those parts come together into circuits.” His team introduced assembloids—combinations of different lab-grown brain regions—to model how circuits form.
Pasca continued: “We began by modeling interactions between excitatory and inhibitory neurons of the cerebral cortex to explore hypotheses about autism – specifically, the idea that disruptions in the migration and integration of GABAergic neurons may underlie circuit imbalances… From there, we extended the approach to reconstruct long-range circuits… which is now enabling study of disorders like amyotrophic lateral sclerosis and enteroviral-mediated paralysis… We then assembled even more complex pathways… allowing us to begin modeling human pain circuits.”
Stanford Medicine researchers are using this method to better understand pain signaling pathways by replicating them outside the body.
Pasca observed: “Remarkably…neurons in assembloids find each other…forming functional circuits that can trigger muscle contractions or responses to noxious stimuli.” He said this gives researchers new ways to observe dynamic processes involved in brain development.
His group is preparing for what will be one of the first clinical trials for psychiatric disease based entirely on models built from patient-derived stem cell lines: “It took almost 15 years…to reach a point where therapeutic potential became evident,” he said. The trial will focus on Timothy syndrome—a rare genetic form of autism—which may help reveal mechanisms relevant across psychiatric conditions.
Pasca’s lab has trained over 350 laboratories worldwide through immersive courses at Stanford so others can implement these methods.
“I think this is what makes Stanford truly exceptional,” he stated. “The questions we ask here are bold and far-reaching… What enables this is unique proximity and integration of disciplines—the Engineering Quad, Medical School and basic sciences are all just steps apart.” His Brain Organogenesis Center brings together experts across engineering, bioelectronics and law.
He concluded: “I believe this kind of collaboration reflects a new way of doing science…at interface[s] [of] disciplines…with commitment…so others can build on…and expand what we create together.”
Sergiu Pasca holds several positions at Stanford University including Kenneth T. Norris Jr Professor of Psychiatry and Behavioral Sciences; Director of Stanford Brain Organogenesis Program; member or fellow at Bio-X; Maternal & Child Health Research Institute; Wu Tsai Human Performance Alliance; Wu Tsai Neurosciences Institute; Sarafan ChEM-H.
