To develop effective therapeutics for medical treatments, access to biopsies is essential. Tissue samples are accessible for many organs: skin, liver, kidney. However, this approach is not so simple when it comes to studying or treating neurological conditions. The brain cannot be biopsied in a routine, minimally invasive way. Considering that nearly 1 in 5 Americans experience some form of psychiatric or neurological disorder, finding innovative ways to study and access the brain is not just important: it’s urgent.
The research of Stanford Professor Sergiu Pasca, Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences and Director of the Stanford Brain Organogenesis Program, is at the heart of innovative strategies to access the secrets and pathology of the human brain. The last week of December 2024, I got the opportunity to meet him, two postdoctoral scholars in his lab, and Dr. Spelbrink, a clinical associate professor at Stanford Medicine’s Pediatric Epilepsy Center. Pasca’s work pioneers the use of stem cell-derived brain organoids to model human neurological and psychiatric disorders. His lab creates models that mimic the brain’s development and function and transplants them in rodents, allowing them to study complex neurological and developmental conditions like schizophrenia and autism, including rare genetic causes such as Timothy syndrome, in ways previously impossible. These models provide a powerful, noninvasive tool for understanding brain disorders at the cellular and circuit level, advancing potential treatments.
Reflecting on what drew him to research, Pașca told me that after his medical training in Europe, he dropped everything to come to Prof. Ricardo Dolmetsch’s Lab at Stanford. He was inspired by Nobel Laureate Shinya Yamanaka's discovery that activating specific genes enables the reprogramming of mature skin cells into immature stem cells. These reprogrammed cells are termed induced pluripotent stem cells (iPSCs) and can develop into various cell types. In this way, scientists can ‘direct their fate;’ these cells, having formed new identities, can now be brought together to form organoids. Pașca believed he could reprogram the iPSCs into neurons to learn more about the brain, and conditions like Timothy Syndrome, a genetic cause of autism.
Timothy Syndrome (TS) is a rare and often life-threatening genetic condition affecting less than 100 people worldwide. The disease is characterized by a mutation in the CACNA1C gene that codes for an important protein, one that controls the flow of calcium across cells’ membranes. I had the chance to talk to Dr. Xiaoyu Chen about this and she explained this mutation affects the process of splicing of a particular region of the CACNA1C gene, exon 8a, disrupting the function of the calcium channel CaV1.2. Calcium channels are critical for the function of our nervous, cardiovascular, and musculoskeletal systems, so it’s no wonder such a mutation wreaks havoc on the body. Shockingly, the precise mechanisms by which symptoms arise remain unknown. Pasca knew that if he could figure out the mechanisms by which a defect in a calcium channel causes the neuro-psychiatric effects seen in TS they would further our understanding of other neurological conditions too. In 2011, Pasca published his findings – he had been able to grow neurons in the lab with the same cellular defects associated with TS. He had engineered skin cells from a young TS patient into iPSCs and then into neurons, which still exhibited the phenotype of the neurons in the TS patient. Many neuroscientists believed these characteristics would have been removed when the skin cells were reverted to stem cells. It was a major breakthrough.
Establishing his own group in 2014, the Pașca Lab recreated key aspects of human brain development in a dish, allowing scientists to observe neuronal growth, connectivity, and function in real time. This innovation opened new doors for studying complex neurological and psychiatric disorders at a cellular level. It also set the stage for one of his lab’s most groundbreaking contributions to the field: the creation of assembloids.
Unlike traditional organoids, assembloids fuse different types of brain organoids to mimic the intricate interactions between distinct brain regions, capturing the dynamic communication that occurs in a living brain. In a landmark Nature paper (Birey et al., 2017), Pașca’s team used assembloids to model TS in greater detail than ever before. Until now, one of the major problems in the organoid field was their health and survival. Without essential nutrients and a vascular system, they were inherently limited. In a 2022 Nature paper, Pașca and his team discovered a way to give lab-grown human brain organoids a more natural environment by transplanting them into the brains of young rats. These organoids formed functional connections with the rat’s brain, responding to sensory input—like when the rat’s whiskers were tickled—and helping guide neuron development. The transplanted organoids grew six times larger than in a dish and developed more complex brain activity patterns, increasing their power to help us understand the human brain.
This mechanism enabled the lab to further study TS and potential therapeutics, particularly the use of Antisense Oligonucleotides (ASOs), which work by blocking the abnormal splicing of the CACNA1C gene. In a 2024 Nature paper, first-authored by Dr. Xiaoyu Chen, the Pasca lab demonstrated that ASOs can effectively modulate the expression of the mutant CACNA1C gene associated with Timothy syndrome (Chen et al Nature 2024). By delivering ASOs to patient-derived neurons, they successfully reduced the levels of abnormal splicing, and calcium levels subsequently decreased, leading to a correction of the electrophysiological abnormalities characteristic of TS. This groundbreaking work opens the door to innovative treatments for genetic mutations underlying complex neurodevelopmental disorders.
The work of Professor Pașca and his team highlights the power of innovation in neuroscience while raising profound ethical questions about the future of brain research. The ability to transplant human brain organoids into animals provides a groundbreaking model for studying and developing therapies for neurological disorders, but it also demands careful consideration of ethical boundaries. For instance, as the sophistication of these models increases, we are faced with challenging questions: How ‘human’ is too human? At what point do we risk creating something with cognitive capabilities beyond our intention? When I discussed this with Professor Pașca, he himself emphasized the importance of maintaining clear boundaries – such as avoiding transplantation into primates – to preserve the evolutionary and ethical separation necessary for responsible research.
Reflecting on my conversations with Professor Pașca and his team, I was struck by the compassion driving their work and the broader philosophical and ethical dilemmas it raises. The urgency of advancing therapeutics for devastating conditions like Timothy's Syndrome is undeniable, but so is the need for ethical frameworks to guide these advancements. For me, Pașca’s approach, rooted in deep contemplation and balance—perhaps informed by his practice of transcendental meditation—serves as a model for pursuing scientific innovation with integrity.
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