Photo by Andrew Brodhead.
Stanford Report News - July 24th, 2025
In the “Research Matters” series, we visit labs across campus to hear directly from Stanford scientists about what they’re working on, how it could advance human health and well-being, and why universities are critical players in the nation’s innovation ecosystem. The following are the researchers’ own words, edited and condensed for clarity.
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.
During my time on the oncology ward, I saw treatments that had once seemed impossible begin to change the course of patients’ lives. About 20 years ago, therapies that are now considered routine still felt like small miracles. Reflecting on this transformation, it became clear that much of the progress was being driven by leveraging the power of molecular biology. But this revolution in medicine was not unfolding evenly – it progressed in direct proportion to how accessible the diseased tissue was. Fields where the affected organ was accessible, like oncology, hematology, and dermatology, were advancing rapidly, while those where the tissue remained out of reach, such as psychiatry, were not.
Photo by Andrew Brodhead
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.
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.
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I came to Stanford soon after, drawn by the possibility this discovery opened up, and generated here on campus some of the first human neurons from what are now known as induced pluripotent stem cells. Over time, my lab has developed ever more advanced methods for producing human neurons, including self-organizing three-dimensional cultures that resemble specific domains of the nervous system, which are now known as neural organoids.
We can now generate more than two-thirds of the cell types found in the developing human brain. But in the brain, function does not arise from individual parts alone – it emerges from how those parts come together into circuits. To study this, we introduced a new approach called assembloids, in which we generate distinct brain regions from stem cells and then combine them into two-, three-, or even four-part assemblies.
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. These early assembloids allowed us to observe, for the first time, the migration of these neurons in a human context. From there, we extended the approach to reconstruct long-range circuits, such as the corticospinal pathway – connecting cortex, spinal cord, and muscle – which is now enabling the study of disorders like amyotrophic lateral sclerosis and enteroviral-mediated paralysis. We then assembled even more complex pathways, including those that carry sensory information from the body to the brain, allowing us to begin modeling human pain circuits.
Remarkably, even without fully understanding the rules of assembly, neurons in assembloids find each other in meaningful ways – forming functional circuits that can trigger muscle contractions or responses to noxious stimuli. This approach is gradually giving us unprecedented access to the dynamic processes of human brain development.
Photo by Andrew Brodhead
It took almost 15 years of studying the biology of brain disorders using these models to reach a point where the therapeutic potential became evident. We are now preparing a clinical trial for a rare genetic form of autism called Timothy syndrome. This will be the first clinical trial for a psychiatric disorder developed exclusively using human stem cell-derived brain models. Although ultra-rare, this condition may serve as a kind of Rosetta Stone – offering insights into broader mechanisms underlying other psychiatric disorders. More broadly, it illustrates how we can begin to demystify complex mental conditions by deconstructing their biology in models of the human brain built entirely outside the body.
Initially, our work was focused on specific disease, but I came to realize that the key lies in gaining access to the human brain – specifically, in building tools that let us reconstruct functional neural circuits. Rather than starting with a disorder, we prefer to recreate a fundamental process of brain function and then deconstruct or reverse-engineer it to see how it can be perturbed. That, in turn, reveals insights into disease. For example, we are now developing assembloids that reconstitute the circuitry relevant to Parkinson’s disease, giving us a way to study how this system breaks down in a human model. The beauty of these technologies is the breadth of their applications – some of which I could never have imagined.
In recent years, there has been growing pressure to focus research on projects with immediate clinical applications. But foundational, curiosity-driven science remains essential. The 15 years of work it took to develop these stem cell-based brain models to the point where they can now support a clinical trial is exactly the kind of long-term effort that can only happen in academia.
We are at an inflection point. With new technologies that give us access to the human brain, we are unlocking a cascade of possibilities – for both basic scientific discovery and clinical translation. We have trained or helped implement our methods in over 350 laboratories around the world. Scientists come here for an immersive week-long course, where we guide them through the critical steps, and they return home equipped to implement the techniques and openly train others, helping the field grow exponentially.
I think this is what makes Stanford truly exceptional. The questions we ask here are bold and far-reaching, and the technologies we develop are transformative. What enables this is the unique proximity and integration of disciplines – the Engineering Quad, the Medical School, and the basic sciences are all just steps apart. My Brain Organogenesis Center at Stanford is designed to catalyze this very convergence. For instance, we are bringing together optogenetics developed by Karl Deisseroth, flexible bioelectronics from Zhenan Bao, biomaterials engineered by Sarah Heilshorn, and ethical insight from legal scholar Hank Greely.
I believe this kind of collaboration reflects a new way of doing science in the 21st century – at the interface of disciplines and with a commitment to openness and sharing, so that others can build on and expand what we create together.
Sergiu Pasca is the Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences in the School of Medicine and the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program.
He is a member of Stanford Bio-X, the Maternal & Child Health Research Institute, the Wu Tsai Human Performance Alliance, and the Wu Tsai Neurosciences Institute. He is also a faculty fellow at Sarafan ChEM-H.
