Using Stem Cells to Cure Autism, Epilepsy & Schizophrenia | Dr. Sergiu Pașca

The rise in autism prevalence, now approaching nearly 3% of the population, fuels much public debate and misunderstanding. Dr. Pașca emphasizes that autism is not a single disease but a constellation of disorders with diverse causes and outcomes. Although many individuals with autism thrive independently, there remain those who require lifelong care, underscoring the need for targeted research and treatments for these severe forms.

Gender Differences and Diagnostic Challenges in Autism

One notable aspect of autism prevalence discussed is the consistent finding that males are diagnosed more often than females, with an approximate male-to-female ratio of four to one. The reasons behind this disparity are multifaceted. Part of the difference likely stems from biological variation, including the influence of genes like SRY that determine male sex development, potentially altering brain resilience to injury or maturation pace. However, diagnostic biases also exist, as females might mask or compensate for their symptoms better, making diagnosis more difficult.

Dr. Pașca highlights that male and female brains differ in their developmental trajectories, which influences vulnerability to developmental disturbances such as premature birth—females tend to have better outcomes. This dimorphism could contribute to the disparity in autism rates but does not fully explain all differences, considering autism's heterogeneity.

Biological Basis, Early Diagnosis, and Behavioral Features

Although joint attention deficits and reduced eye contact are often observed in autistic children, these features are not formal diagnostic criteria, since they lack specificity and universality. Observational behavioral assessment remains the cornerstone of autism diagnosis. Dr. Pașca also addresses anecdotes, such as the temporary improvement of autistic symptoms during febrile episodes. While some children show transient gains in communication during fevers—a phenomenon linked to immune activation and nervous system excitation—this is anecdotal and not a universal feature of autism.

The challenge of correlating behavioral features with precise biological abnormalities is a significant barrier to understanding autism and many psychiatric conditions, primarily because of the lack of clear biomarkers and the complexity of brain development.

The Role of Genetics and Environmental Factors

With advancements in genetics, researchers have identified hundreds of genes associated with various forms of autism, ranging from channelopathies affecting ion channels to chromatinopathies influencing DNA packaging. Many of these genes also have expression outside the brain, highlighting the systemic nature of some disease processes. Intriguing animal experiments demonstrate that peripheral mutations alone can influence nervous system wiring, suggesting a complex interplay between the brain and body.

Nonetheless, environmental factors cannot be discounted entirely, even though major identified risk factors such as thalidomide exposure have been eliminated. The increase in autism incidence is partially explained by shifting diagnostic criteria and awareness but remains incompletely understood. The overall picture is one of multifactorial causation involving genetics, biology, and environment.

Current Treatment Paradigms for Autism

In clinical practice, autism treatment is multifaceted but lacks a single cure. Approximately 20% of individuals receive a genetic diagnosis, yet specific targeted therapies remain limited. Typically, treatment focuses on managing symptoms and co-occurring conditions such as epilepsy, alongside behavioral interventions designed to improve communication and social skills. Infinite resources would augment multidisciplinary approaches but would still face challenges due to the disorder's complexity.

Dr. Pașca notes the hope that stem cell-based and genetic therapies may eventually allow for direct interventions at the cellular or molecular level, particularly for those rare, genetically defined autism subtypes such as Timothy syndrome.

The Promise and Challenges of Gene Therapy

Gene therapy, including CRISPR gene editing, holds promise for treating monogenic neurological disorders. The technology can function at different levels: delivering functional copies of genes using viral vectors, supplying proteins directly, or precisely editing DNA sequences. However, significant practical challenges exist, especially for targeting the brain. The blood-brain barrier, the need for cell-type specificity, immune responses to viral vectors, and gene size limitations complicate therapy delivery.

Adeno-associated viruses are commonly engineered as vectors to ferry therapeutic genes but have packaging limits and may trigger immune reactions. Moreover, timing is critical; for neurodevelopmental disorders, earlier intervention likely yields better outcomes. Adult brains are less plastic, and some mutations have irreversible effects if treatment comes too late.

Stem Cells and Modeling Human Brain Development

Central to Dr. Pașca's work is the use of induced pluripotent stem cells (iPSCs), a breakthrough discovery enabling scientists to revert adult cells such as skin fibroblasts to a pluripotent state. This technique bypasses ethical issues surrounding embryonic stem cells by generating patient-specific stem cells in vitro. iPSCs retain the genetic information from the donor and can differentiate into almost any cell type.

These cells provide an unprecedented window into human brain development and pathology by allowing researchers to study live human neurons and brain tissue analogs derived from affected individuals. The ability to effectively model neural development in a lab dish offers crucial insights into psychiatric and neurodevelopmental disorders that have historically been inaccessible due to ethical and practical constraints.

Organoids and Assemblids

While neurons derived from iPSCs provide individual cellular models, Dr. Pașca and colleagues have pioneered organoids—three-dimensional self-organizing clusters of brain cells that recapitulate key cortical features. These organoids preserve intrinsic developmental timing and molecular changes analogous to in vivo brain development, such as the perinatal switch in NMDA receptor subunits. Their ability to mature over months to years allows study of neurodevelopmental milestones otherwise impossible in model systems.

Building on this, "assemblids" are constructed by combining different organoids representing distinct brain regions, enabling neurons to migrate and form synaptic circuits resembling long-range brain connectivity. An example includes fusing cortical and subcortical organoids to study inhibitory neuron migration. More complex assemblies mimic sensorimotor circuits with the eventual goal of reproducing functional outputs like muscle contraction, providing exquisite models for neurological diseases.

Transplantation of Organoids into Animal Models

To overcome limitations of in vitro culturing, the lab has also transplanted human cortical organoids into neonatal rodent brains. Being grafted early enables human cells to vascularize, integrate with host tissue, and mature significantly, showing growth and morphological features closer to native human neurons. Functionally, transplanted neurons respond to sensory stimuli experienced by the host animal, providing a physiological milieu unattainable in dish cultures alone.

These chimeric models bridge the gap between simplistic in vitro systems and the complexity of living brains, facilitating the study of human neuron behavior in vivo and enabling preclinical therapeutic testing with patient-derived cells in an environment approximating normal brain circuitry.

Ethical Considerations in Brain Organoids and Assemblids

The technology raises ethical questions due to the potential for emergent properties such as sensory processing or neural activity. Dr. Pașca emphasizes careful nomenclature—avoiding misleading terms like "mini-brains"—to prevent misrepresentation. Ongoing discussions with ethicists and legal experts focus on obtaining informed consent for cell use, defining humane treatment in animal chimeras, and addressing concerns about sentience or consciousness.

Stanford and other institutions have convened consortia to establish guidelines and frameworks governing this research. Ethical discourse is vital at the early stages of experimentation to anticipate future dilemmas, ensure responsible communication with the public, and guide the development of therapeutic applications.

Application to Neurodevelopmental and Psychiatric Disorders

Dr. Pașca's research has directly impacted understanding and therapy development for monogenic conditions linked to psychiatric and neurological illness. Timothy syndrome, caused by a mutation in a calcium channel, was among the first modeled using patient-derived neurons and organoids, leading to promising nucleic acid therapeutics now approaching clinical trials. Other targets include severe epilepsies and 22q11.2 deletion syndrome, a major genetic risk factor for schizophrenia.

Assemblids enable investigation into brain circuit dysfunctions underlying these disorders and offer platforms to test novel treatments. However, diseases with predominant environmental or psychosocial components, such as depression or anxiety, remain more challenging to model due to complexities in replicating those factors in vitro.

Future Perspectives, and Scientific Culture

Throughout the discussion, Dr. Pașca shares a profound fascination with the intricacies of human brain development and a dedication to translating fundamental discoveries into treatments. He attributes part of his success to an intense passion for research and a collaborative scientific community that embraces complexity and ethical rigor.

Looking forward, he hopes to refine the understanding of human neural timers, accelerate aging interventions, and expand the therapeutic repertoire for profound autism and other severe brain disorders. The intersection of stem cell biology, genetics, and neurotechnology is reshaping neuroscience, with organoids and assemblids at the forefront of this revolution, promising new avenues for curing devastating neurodevelopmental and psychiatric diseases.