Professor Sergiu P. Pașca is due to visit DPAG on 30 April to deliver the Sir Wilfrid Le Gros Clark Prize Lecture, on ‘Putting the pieces together: Inception of Human Neural Circuits in Assembloids’.
Ahead of his lecture we spoke with Professor Pașca about impact, inspiration and the future of his research.
Professor Pașca is the Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences at Stanford University and the Founding Uytengsu Endoweed Director of the Stanford Brain Organogenesis Program. His laboratory has pioneered the use of human stem-cell-derived models of brain tissue (including organoids and assembloids) to study how the human brain develops, how neural circuits form, and what goes awry in neuropsychiatric disorders. In recognition of these contributions, he has received a number of prizes and honours, including the 2024 International Society for Stem Cell Research (ISSCR) Momentum Award, which honours investigators whose research has shaped emerging fields with tremendous future promise, the IBRO Neuroscience Award, the American Philosophical Society's Daland Prize, the Joseph Altman Award in Developmental Neuroscience, and has been made a Knight of the Order of Merit.
In what ways have you seen the real-world impact of your scientific research?
My team’s work centres on understanding the biological basis of brain disorders. Towards this, we have been creating models of the human brain from pluripotent stem cells, initially as neurons at a bottom of a dish, then spherical organoids representing distinct brain regions, and afterwards in a preparation we named assembloids, where different regions are fused together to model neural circuits. These systems have given researchers unprecedented access to human-specific features of brain development that were previously impossible to observe directly in human tissue.
We have helped hundreds of labs around the world over the past decade to implement these models and witness their application to study mechanisms of neurodevelopment, neuronal migration, circuit formation and dysfunction in conditions such as autism, epilepsy and schizophrenia. Because they are derived from human cells, and in some cases from patients with specific disorders, they allow us to investigate disease mechanisms at cellular and circuit levels, which ultimately represents a bridge between basic developmental neuroscience and clinical questions.
Perhaps most exciting is that these platforms are now being used not only to understand disease, but to test therapeutic strategies directly in human cellular systems as we have recently illustrated for one neuropsychiatric condition. That translational angle, linking discoveries to potential treatments is, for me as a physician and scientist, one of the most tangible impacts of our work.
In what direction do you see your research developing over the next few years?
We are moving toward models that more faithfully recapitulate circuit dynamics and physiological function. This means further refining assembloids to capture not just structural organization but functional patterns of activity, connectivity and plasticity that resemble those in the developing human brain. This also involves integration of some of these models in animals, which is enabling advanced maturation of human cell types as well obtaining complex circuit and behavioural readouts.
Another major direction is integration with CRISPR and high-throughput screening methods. The goal is to create platforms that can reveal how developmental mechanisms go wrong in disease and how they might be corrected.
In parallel, we have been closely developing translational opportunities: using these human-based models not just to study disease but to identify and validate therapeutic approaches. In fact, I am hopeful that the first therapeutic approach developed with human stem cell-based models for a brain disorder is moving towards clinical evaluation.
What first inspired you to become a scientist, and how did you come to choose and specialise in your area of research?
From early on, I was fascinated by chemistry and biology and the question of how complex systems such as the human brain assemble and function. As I pursued medical training and research, that curiosity led me to neuroscience. I became particularly interested in the gap between what we can model in animals and what actually happens in human neural systems.
Twenty years ago, as I was finishing my clinical training, cell reprograming was reported making it possible to derive human induced pluripotent stem cells from patients’ cells. It struck me immediately that we could finally begin building human neural tissues outside of the human body to tackle the biology of brain disorders, such as autism. I immediately shifted gears and moved to the US, where we soon generated some of the initial neuronal models of disease. Afterwards, in my own lab, we continued to create new experimental models that could capture ever more inaccessible aspects of human brain development and disease and deployed them to ask questions about disease.
Is there any advice you would give to an early career research scientist (or to a younger you)?
Science is fun. In fact, I cannot think of another ‘job’ that offers the same freedom to pursue curiosity and explore questions in such depth. There is a special thrill in discovering something that nobody else knows yet.
If I were giving advice to an early career scientist, I would say: choose something that genuinely fascinates you. It may be a question, or it may be a method. But if it truly captures your imagination, you will not have to force yourself to stay motivated through the difficult stretches. Science rarely moves in a straight line. Progress can be slow, and meaningful advances often require patience, and a willingness to follow the data rather than the trends. I would also say: collaborate broadly and build a diverse intellectual community around you. The most important biological questions increasingly require different kinds of expertise and ways of thinking.
We are entering a revolution in human neuroscience, and with it a new era for psychiatry and neurology. For a long time, many of these conditions have remained deeply mysterious because we lacked the tools to study the relevant human biology directly. That is beginning to change and AI advances are going to accelerate and converge with these efforts. So my advice is: get ready for it. This is going to be an extraordinarily exciting time to be in science.