Dr. Sergiu Pasca — Professor of psychiatry and behavioral sciences at Stanford and director of the Stanford Brain Organogenesis Program. A pioneer of brain organoids and assembloids who coined the term 'assembloid' and is developing the first therapeutic for a psychiatric disease built entirely from human stem cell models.
The gist
Andrew Huberman and Dr. Sergiu Pasca discuss what autism actually is, why its prevalence has risen to nearly 3%, and why it is a behaviorally-defined spectrum rather than a single disease with no biomarker. Pasca explains the science of stem cells, the Yamanaka factors that let any skin cell be reprogrammed into pluripotent cells, and how his lab grows 3D brain organoids and multi-region assembloids that develop on an intrinsic timer matching real human brain development. They cover gene therapy and CRISPR, the dangers of unregulated stem cell injections, and the ethics of transplanting human neurons into animals. The episode centers on Pasca's work on Timothy syndrome, where understanding a single calcium-channel mutation led to a nucleic-acid therapeutic now heading to a first clinical trial, plus ongoing work on epilepsy, schizophrenia and dystonia.
Big reveals
- Autism prevalence is now close to almost 3% of the population, up from being considered a rare disease when Pasca was in medical school.
- Huberman states on record there is no solid epidemiological evidence that vaccines cause autism.
- Yamanaka discovered that just four genes can reprogram an adult skin cell back into a pluripotent stem cell, likened to alchemy.
- Pasca's lab keeps brain organoids alive for years, with cultures over 800 days old growing in incubators.
- Transplanted human organoids can grow to make up about a third of one hemisphere of a rat brain and respond to the rat's whiskers.
- Every defect described over 15 years of Timothy syndrome research can be reversed with a single tiny piece of nucleic acid, and a clinical trial is being prepared.
- Former NIMH head Bob Desimone told Huberman far more money goes to autism than schizophrenia because schizophrenia patients' parents are often struggling too and don't bring children in.
- The 22q11.2 deletion (60 genes lost) carries a 30% risk of schizophrenia and a 30% risk of autism, yet some carriers are barely affected.
Things worth remembering
- Human brain myelination, especially in frontal areas, continues until roughly the third decade of life (about age 30).
- Autism prevalence is similar across countries (Korea, Scandinavia ~1 in 30 to 1 in 40), undercutting US-specific cause arguments.
- Brain organoids spontaneously switch from a prenatal to a postnatal molecular signature at about nine months in a dish, with no birth event triggering it.
- The human brain has nearly 2,000 cell types, with about 600 already present by the end of the first trimester, versus a couple dozen in the liver.
- The simplest movement circuit, the corticospinal tract, uses just two neurons in humans but has an extra neuron in mice.
- Neurons grown in a dish are about 10 times smaller than real cortical neurons, but grow to six-to-eightfold larger after transplantation into a rat.
- People with mutations that block pain sensation often die because they fail to make the constant postural adjustments that protect the body.
- The field deliberately avoids calling organoids 'mini-brains'; scientists from ~25 labs agreed on standardized nomenclature published in Nature.
- Pasca walks 12,000 to 15,000+ steps a day and generally eats one meal a day, a habit from his medical school days in Romania.