Using Stem Cells to Cure Autism, Epilepsy & Schizophrenia | Dr. Sergiu Pașca
Dr. Sergiu Pașca, professor of psychiatry and behavioral sciences at Stanford, discusses autism's rising prevalence, genetic basis, and his pioneering work with organoids and assembloids. These human stem cell-derived models are used to understand and develop cures for profound autism, schizophrenia, and other complex brain disorders.
Deep Dive Analysis
15 Topic Outline
Understanding Autism Spectrum Disorder and its Prevalence
Historical Theories and Genetic Basis of Autism
Rising Autism Diagnoses and Environmental Factors
Gene Therapy, CRISPR, and Challenges in Brain Disorders
The Revolution of Induced Pluripotent Stem Cells (iPSCs)
Dangers and Misconceptions of Commercial Stem Cell Injections
Organoids: 3D Human Brain Models in a Dish
Intrinsic Developmental Timing in Organoids
Assembloids: Modeling Brain Circuit Formation and Cell Migration
Self-Organization and Complex Assembloid Circuits
Ethical Considerations of Organoid and Assembloid Research
Nomenclature and Collaboration in Stem Cell Science
Transplantation of Organoids for Enhanced Development and Therapy Testing
Genetic Penetrance and Challenges in Pre-implantation Genetic Testing
Developing Therapeutics for Timothy Syndrome and Other Neurological Disorders
7 Key Concepts
Autism Spectrum Disorder
Autism is a complex, behaviorally defined condition with no single biomarker, diagnosed by observing the presence or absence of specific behaviors. It is not one disease but a spectrum, with varying severities, from fully functional individuals with autistic traits to those with profound autism requiring lifelong care.
Refrigerator Mother Hypothesis
An early, now debunked, psychoanalytic theory from the 1950s and 60s that suggested autism resulted from emotionally cold parents, particularly a cold mother. This theory was later disproven by biological studies, especially twin studies showing a strong genetic component.
Yamanaka Factors (iPS Cells)
A combination of four genetic factors discovered by Shinya Yamanaka that can reprogram adult skin cells (fibroblasts) into induced pluripotent stem cells (iPSCs). This breakthrough allowed scientists to create patient-specific stem cells without using human embryonic stem cells, bypassing significant ethical debates.
Organoids
Three-dimensional self-organizing clumps of human neurons derived from induced pluripotent stem cells, grown in a dish. Organoids can recapitulate fundamental aspects of human brain development, including the intrinsic timing of neuronal maturation, allowing for the study of brain development outside the human body.
Assembloids
Complex models created by fusing two or more organoids together, allowing scientists to study how different brain regions interact, how cells migrate, and how circuits form. Assembloids demonstrate the self-organizing power of biological systems, where parts with the right instructions can assemble into functional circuits.
Intrinsic Development Timer
The inherent ability of human brain cells, particularly neurons, to keep track of developmental time, even when grown in a dish as organoids. This means that cells will progress through developmental stages at a similar pace to in vivo development, such as switching to a postnatal signature around nine months in culture.
Genetic Penetrance
In genetics, penetrance refers to the proportion of individuals carrying a particular genetic mutation who also express the associated clinical symptoms. Variable penetrance means that the same mutation can cause a severe presentation in one person and a very mild one in another, influenced by genetic background and environmental factors.
9 Questions Answered
Autism Spectrum Disorder is a complex, behaviorally defined condition without a single biomarker, diagnosed by observing specific behaviors. It's a spectrum because it encompasses a wide range of severities, from individuals with autistic traits who are fully functional to those with profound autism requiring lifelong care.
The increase in autism prevalence is still puzzling but is partly attributed to changes in diagnostic criteria and a 'diagnostic migration' where conditions previously labeled as intellectual disability now fit autism criteria. While environmental factors are considered, the precise reasons for the increase are not fully understood.
Autism has a strong genetic component, with hundreds of genes now known to be associated with specific forms, particularly profound autism. Many cases involve de novo mutations not present in either parent, highlighting genetic factors as a primary cause for many severe forms.
Yamanaka factors are four specific genetic factors that can reprogram adult skin cells into induced pluripotent stem cells (iPSCs). This discovery allowed scientists to create patient-specific stem cells without using human embryonic stem cells, bypassing significant ethical concerns and enabling new research avenues.
Commercial stem cell injections, often sought outside regulated medical systems, are generally not supported by scientific rationale and carry significant risks, including infection and tumor growth. There is no clear evidence of their efficacy for autism, and reported improvements are often temporary and possibly due to strong placebo effects.
Organoids are 3D self-organizing clumps of human neurons grown in a dish, modeling brain development. Assembloids are formed by fusing multiple organoids to study complex brain circuits and cell migration. They allow researchers to observe molecular defects, test therapeutics, and understand emergent properties of brain interactions outside the human body.
The brain possesses an intrinsic developmental timer, meaning that even in organoids grown in a dish, cells track developmental time similarly to in vivo. For example, specific protein subunits (NMDA receptors) that typically switch around birth in a human brain also switch at the equivalent time in organoids maintained in culture.
Genetic penetrance describes the variability in how severely a genetic mutation manifests clinically. It's important because a mutation might cause severe symptoms in one individual but mild or no symptoms in another, influenced by complex genetic backgrounds and environmental factors, making genetic counseling and prediction challenging.
Ethical considerations include proper consent for cell use, potential harm to animals receiving transplants, and emergent properties like sentience or consciousness in complex circuits. Careful nomenclature is crucial to avoid misrepresenting these models as 'mini-brains' and to ensure responsible communication with the public.
14 Actionable Insights
1. Avoid Unregulated Stem Cell Injections
Exercise extreme caution and avoid unregulated stem cell injection procedures, especially those offered outside of established clinical trials, as the contents are often unknown, lack scientific rationale, and carry significant risks, including infection, paralysis, or tumor growth.
2. Regular Therapy for Health
Consider engaging in regular professional therapy as an essential component of overall health, on par with physical exercise. Therapy can provide support, guidance, and useful insights for improving work, relationships, and self-relationship.
3. Comprehensive Lab Testing for Health
Undergo comprehensive lab testing, such as Function Health’s 100+ advanced tests, to gain insights into heart, hormone, immune health, nutrient levels, and toxin exposure. This provides a detailed snapshot of your bodily health and can guide personalized health improvements.
4. Reduce Mercury, Boost Detox
If elevated mercury levels are detected, reduce consumption of high-mercury foods like tuna. Support detoxification by increasing intake of leafy greens and supplementing with N-acetylcysteine (NAC) to boost glutathione production.
5. Tailor Mattress to Sleep Needs
Select a mattress (softness, firmness) that is customized to your unique sleep needs, as this significantly impacts the quality of sleep, which is foundational for mental health, physical health, and performance. Use a sleep quiz to match to the ideal mattress for your back, side, or stomach sleeping preference and temperature regulation.
6. Improve Sleep for Social Skills
Recognize that severe sleep disturbances can impair social skills and overall function. Prioritize and improve the quality of sleep, as even a few nights of poor sleep can negatively impact social interactions and general well-being for anyone.
7. Meet Protein Goals Efficiently
Consume high-protein, low-calorie snacks like David protein bars (28g protein, 150 calories) to easily achieve a daily protein intake of one gram per pound of body weight without ingesting too many calories. Integrate them as afternoon snacks or for on-the-go nutrition.
8. Walk 12,000+ Steps Daily
Aim to walk more than 12,000 to 15,000 steps daily, as Dr. Pasca does, to maintain physical fitness and support overall well-being. Incorporate walking into daily routines like commuting or exploring new places.
9. Practice One Meal Daily (OMAD)
Consider adopting a one-meal-a-day eating pattern, a practice Dr. Pasca has maintained for years, potentially for health or practical reasons.
10. Pursue Genetic Autism Diagnosis
If a child receives an autism diagnosis, pursue genetic testing to identify specific mutations, as about 20% of cases have a genetic diagnosis. While specific therapies are currently limited, being part of the community for that genetic form can be beneficial for future individual treatments.
11. Distinguish Profound Autism
Understand that research for autism treatments primarily targets profound forms of the condition, which involve severe impairment and lifelong care needs, distinct from the broader autism spectrum that includes high-functioning individuals. This distinction is crucial for appropriate terminology and focus.
12. Umbilical Cord Stem Cell Limits
Be aware that umbilical cord stem cells are restricted in their potential, primarily useful for blood disorders, and are not a universal solution for all future stem cell therapies. They differ from pluripotent stem cells in their capabilities.
13. Precise Science Communication
Scientists should use precise language when communicating research, especially to the public, to avoid trivializing complex topics or creating confusion (e.g., avoiding terms like ‘mini-brains’ for organoids). This ensures accurate understanding and manages public perception.
14. Explain Science Simply, Acknowledge Change
When explaining science to the general public, assume zero prior knowledge but infinite intelligence, allowing for simple yet accurate explanations without trivialization. Also, communicate that scientific understanding evolves and self-corrects over time.
6 Key Quotes
Autism is not one disease. And I think, you know, no psychiatrist or even biologist who's studying autism would ever consider that this is one single disease.
Dr. Sergiu Pașca
The unbearable inaccessibility of the human brain.
Dr. Sergiu Pașca
The human nervous system has done everything possible to slow down that process, right? I mean, we myelinate all the way to the third decade.
Dr. Sergiu Pașca
I think what we also started to learn from this was that all we need to do is make the parts. And if we make the parts right, then the parts will come with the instructions and then the circuits will assemble on their own.
Dr. Sergiu Pașca
I always sort of like assume, and that is sort of like being my, you know, my mantra, that somebody really has, when you explain even to the general public, that, you know, they have zero knowledge and yet, you know, infinite intelligence, right?
Dr. Sergiu Pașca
Not all superheroes wear capes. You're doing God's work. So thank you.
Dr. Andrew Huberman
5 Protocols
Making Induced Pluripotent Stem Cells (iPSCs)
Dr. Sergiu Pașca- Take skin cells (fibroblasts) from an individual.
- Introduce a combination of four specific genetic factors (Yamanaka factors) into these cells.
- Allow the cells to reprogram and revert to a pluripotent stem cell state, almost identical to embryonic stem cells.
Creating Cortical Organoids
Dr. Sergiu Pașca- Plate induced pluripotent stem cells (iPSCs) in a dish.
- Remove factors that maintain pluripotency, allowing cells to differentiate.
- Aggregate the differentiating cells into balls and keep them floating in a dish (e.g., using non-stick plates).
- Maintain and feed the cultures for months or years, allowing them to self-organize into 3D structures resembling parts of the cerebral cortex and recapitulating developmental timing.
Assembling a Corticospinal Tract Model (Three-Part Assembloid)
Dr. Sergiu Pașca- Create an organoid resembling the cortex, containing cortical neurons.
- Create an organoid resembling the spinal cord, containing motor neurons.
- Create a ball of human muscle cells from a biopsy.
- Place the three parts together in a tiny tube overnight to allow them to fuse and self-assemble.
- Stimulate the cortical organoid to observe muscle contraction, indicating circuit formation.
Assembling a Somatosensory Pathway Model (Four-Part Assembloid)
Dr. Sergiu Pașca- Create four distinct organoids representing sensory neurons, spinal cord, thalamus, and cortex.
- Assemble the four parts in a specific order: sensory neurons, then spinal cord, then thalamus, then cortex.
- Allow the parts to fuse and self-organize over several weeks, forming connections that reconstitute the sensory information processing pathway.
- Observe spontaneous synchronized activity across the entire pathway.
Transplanting Organoids for Enhanced Development and Therapeutic Testing
Dr. Sergiu Pașca- Create cortical organoids from human induced pluripotent stem cells.
- Transplant the organoids into the somatosensory cortex of an early-born rat (within the first few days after birth).
- Wait for several months for the graft to grow, become vascularized by the rat, and integrate with host microglia.
- Record activity of human neurons while stimulating the rat's whiskers to observe functional integration.
- Analyze the transplanted human neurons, which grow significantly larger and acquire more physiological properties than those in a dish, to study disease defects and test therapeutics in an in vivo environment.