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

Key Takeaways

Autism diagnoses are increasing globally, with a strong genetic component identified.
Dr. Pașca developed organoids and assembloids to model human brain development and diseases.
Human stem cell models are enabling therapeutic development for conditions like Timothy syndrome.
Ethical frameworks and precise nomenclature are vital for emerging stem cell and gene therapies.
Roughly 20% of profound autism cases have a genetic diagnosis; the majority are idiopathic.

Autism Spectrum Disorder is a complex, behaviorally-defined condition now affecting nearly 3% of the general population.
Twin studies from the 1970s indicated a strong genetic component, refuting the earlier “refrigerator mother hypothesis.”
Autism prevalence is higher in males, with a general ratio of one female to four males, potentially due to underdiagnosis in girls or inherent differences in brain development.
Specific genes have been linked to severe forms of autism, known as profound autism, which often co-occur with intellectual disability and epilepsy.

While factors like microbiome or diet might enhance quality of life, clear causal evidence for them in autism is scarce; most evidence supports a strong genetic component with hundreds of associated genes.
There is no solid evidence that vaccines cause autism, with a lack of epidemiologically supportive papers.
Autism prevalence is consistent globally, typically ranging from 1 in 30 to 1 in 40, dismissing theories linking it solely to specific US environmental factors like glyphosates.

The historical reliance on human embryonic stem cells, obtained from aborted fetuses, generated significant ethical debates.
Around 20 years ago, scientist Shinya Yamanaka pioneered a method to revert mature cells into induced pluripotent stem cells (iPSCs) using four “Yamanaka factors.”
Yamanaka’s discovery enables the creation of patient-specific pluripotent stem cells from skin, which can model human diseases like profound autism outside the body, leading to clinical trials.

Stem cells collected from umbilical cords are restricted primarily to blood disorders and are not a universal solution for future stem cell therapies as sometimes advertised.
Unregulated stem cell injections offered by clinics in the U.S. and abroad, particularly for conditions like autism, carry severe risks including blindness, paralysis, and infection.
The FDA has shut down clinics, like one in Florida for macular degeneration, due to severe adverse outcomes, emphasizing high risks and lack of regulatory oversight.

Assembloids are crucial for replicating brain circuit properties, as conditions like autism and schizophrenia are linked to altered cell connections, not missing cells.
The first assembloid, created in 2015 by fusing two brain regions, demonstrated spontaneous cell migration and desired circuit formation.
The term “assembloid” was coined to denote the assembly of circuits, underscoring the importance of precise nomenclature in scientific fields.

Researchers successfully created a three-part assembloid combining cortical, spinal cord, and human muscle organoids, allowing cortical stimulation to induce muscle contraction.
Scientists recently published findings on the first four-part assembloid, reconstituting the somatosensory pathway (skin to cortex) for processing sensory information.
Sensory assembloids are used to study genetic pain conditions, revealing that specific sodium channel mutations cause hyperactive sensory neurons that fail to synchronize with broader pathways.

Ethical considerations for advanced medical therapies using assembloids include proper consent for human cell use and potential harm in animal transplantation.
While organoids may exhibit pain pathways, they lack the brain regions for emotional pain processing, indicating they are not truly feeling pain.
Calling organoids “mini-brains” is misleading, as scientists have not created an entire human nervous system, only parts, which can confuse the public.
A consortium of 25 labs established precise nomenclature for the organoid field, preventing the misattribution of complex properties like “seeing” or “intelligence” to organoids.

Scientists transplant human cortical organoids into early-born rats’ somatosensory cortex, achieving integration, vascularization, and immune cell population from the host.
These human cells can make up approximately one-third of a rat hemisphere, visible on MRI, with human neurons responding to rat whisker movements.
Neurons from Timothy syndrome patients are significantly smaller in vivo, a defect only observable after transplantation into a living organism, not in a dish.
This interspecies model is critical for identifying disease aspects and testing therapeutics for safety and efficacy before human application.

Assembloids have led to a therapeutic approach for Timothy syndrome, reversing observed defects by correcting how a channel is processed in cells using a specific nucleic acid.
A clinical trial is being prepared for Timothy syndrome, marking the first psychiatric disease therapeutic developed using human stem cell models.
The guest's lab is also developing assembloid models for intractable epilepsy, severe intellectual disability, and forms of schizophrenia, including 22Q11 deletion syndrome.
Research into dystonias involves rebuilding basal ganglia circuitry in ‘loop assembloids’ to study how genetic mutations impact movement circuits.