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Andrew Huberman asks Dr. Sergiu Pasca about the role of eye contact in autism diagnosis. Dr. Pasca clarifies that while it's an observed feature, it's not a specific diagnostic criterion for autism, noting that some behavioral deficits can be compensated for over time.
Dr. Sergiu Pasca explains that autism is currently diagnosed based on observed behaviors, lacking a specific biological marker, and highlights the puzzling rise in its prevalence to nearly 3% of the population.
Dr. Pasca shares that autism was considered a rare disease when he was in medical school, and he chose to study it partly because it seemed "easier" due to fewer resources, highlighting how much understanding has changed.
Dr. Pașca discusses the future of regenerative medicine, weighing the pros and cons of banking one's own cells for personalized organ replacement against using 'off-the-shelf' cells from generic donors. He explains how immunosuppression or genetic modification could make universal donor cells viable, suggesting this path is more likely for broad therapeutic use.
Dr. Pașca emphasizes the crucial role of clear nomenclature in science, citing the collaborative effort of 25 labs to establish agreed-upon terms for organoids and assembloids. He explains that this proactive approach prevents miscommunication (e.g., avoiding 'sees' or 'intelligence' for organoids) and highlights a new era of scientific collaboration necessary for tackling increasingly complex biological problems.
Andrew Huberman and Dr. Pașca discuss the ethical complexities of advanced biotechnologies, contrasting widely accepted medical treatments (like curing blindness) with more controversial enhancements (like creating 'super memory'). They use the example of the CRISPR baby controversy to highlight the ethical line crossed when genetic modifications are made for non-disease-related traits, sparking outrage in the scientific community.
Dr. Pașca addresses key ethical issues surrounding assembloids, from proper consent for cell use to animal welfare in transplantation. He discusses the complex question of emergent properties like sentience and consciousness in these models, clarifying that emotional components of pain are not present in a dish. He also stresses the critical importance of careful scientific communication, especially avoiding misleading terms like 'mini brains,' to prevent public confusion.
Dr. Pasca explains the pioneering work on organoids and assembloids, which are human brain circuits derived from stem cells, and how they are used to study and develop cures for psychiatric illnesses like profound autism and schizophrenia.
Dr. Sergiu Pasca discusses the higher prevalence of autism in males (1:4 ratio), explaining that girls may be underdiagnosed due to better "masking" of symptoms and highlighting fundamental biological differences in how male and female brains develop and respond to injury.
Dr. Sergiu Pasca explains the anecdotal phenomenon of autism symptoms, particularly non-verbal communication, improving during high fevers, discussing various hypotheses related to nervous system activation and ion channel function, while emphasizing this is not a universal experience.
Dr. Sergiu Pasca reveals that despite advances in genetic understanding, only about 20% of profound autism cases receive a specific genetic diagnosis (like Timothy Syndrome), and even then, targeted therapies are largely unavailable, leaving most cases idiopathic.
Dr. Sergiu Pasca discusses the complex reasons behind the dramatic increase in autism prevalence, attributing it to evolving diagnostic criteria, "diagnostic migration" from other conditions, and high heritability, while also acknowledging the role of environmental factors like thalidomide.
Andrew Huberman addresses the common debate around curing autism, highlighting the spectrum of the condition from functional individuals to those requiring lifelong care, setting the stage for a discussion on novel treatments for severe forms.
Andrew Huberman explores the challenges of relying on correlation in neurological research, referencing past theories like maternal flu causing schizophrenia and the ongoing (debunked) vaccine-autism debate, and uses the Amish population's lower autism incidence to illustrate how correlation can lead to misleading conclusions without understanding causality.
Dr. Pasca explains that proving causality in brain disorders is challenging because, unlike association, it requires being able to reverse a condition by changing a factor, which is impossible to do in the human brain. He also highlights the incredibly long period of human brain development, extending into the third decade of life.
Dr. Sergiu Pasca addresses the hypothesis linking the microbiome to autism, stating that while improving gut health might enhance quality of life, there's no clear causal evidence. He emphasizes that strong genetic factors are now understood to be the primary drivers of autism.
Andrew Huberman questions whether the rise in autism is unique to the US. Dr. Sergiu Pasca confirms it's a global phenomenon, citing similar prevalence rates in countries like Korea and Scandinavia, and emphasizes that the same genetic mutations are found worldwide, suggesting common underlying causes.
Dr. Sergiu Pașca explains the groundbreaking discovery by Shinya Yamanaka, who found a way to reprogram adult skin cells into pluripotent stem cells using just four genetic factors. This innovation bypassed ethical concerns associated with embryonic stem cells and opened new avenues for disease modeling and therapeutic development.
Dr. Sergiu Pasca debunks the outdated "refrigerator mother hypothesis" for autism, explaining how early twin studies in the 70s revealed the strong genetic component that is now widely accepted.
Dr. Pașca explains the fundamental scientific rationale behind the development of assembloids, highlighting that complex brain conditions like autism and schizophrenia are increasingly understood to be issues of faulty neural connections rather than missing cells. This clip details how traditional 'clumps of cells' (organoids) were insufficient for studying these circuit properties, paving the way for assembloids.
Dr. Pașca shares an engaging anecdote about the surprisingly simple discovery of how to fuse two distinct brain organoids to create the first assembloid. This clip highlights the inherent self-organizing capabilities of brain cells, as they 'smell' chemicals and migrate as expected, leading to a groundbreaking moment in the lab.
Dr. Sergiu Pasca explains that autism-linked genes affect diverse cellular components like synapses, ion channels, and chromatin. He discusses how experiments showing peripheral mutations can impact brain development, suggesting that disruptions outside the brain during critical periods can lead to autism symptoms.
Dr. Pașca recounts the pivotal role of his mentor, Ben Barres, in coining the term 'assembloids.' Barres's insistence on a distinct name, understanding its importance for scientific recognition and clarity, led to a long list of options before 'assembloid' was chosen. This clip emphasizes the significance of nomenclature in scientific progress and immortalizing discoveries.
Dr. Sergiu Pasca explains "profound autism" as the severe end of the autism spectrum, characterized by significant impairment, often accompanied by intellectual disability and epilepsy, requiring lifelong care, and differentiating it from milder autistic traits.
Dr. Pașca details the creation and application of a complex four-part assembloid that reconstitutes the sensory pathway, from skin to cortex. He explains how this model is used to study genetic pain conditions, revealing how specific mutations (e.g., in sodium channels) lead to excessive or lost pain, and how distant cell interactions are crucial for understanding complex disorders like autism.
Andrew Huberman reflects on the miraculous nature of biological self-organization, particularly in brain development, expressing humility at the complexity. He highlights that assembloids are created ethically using patient fibroblasts and Yamanaka factors, completely avoiding the use of aborted tissues. This moment celebrates scientific progress while addressing ethical concerns.
Andrew Huberman shares a heartbreaking story of a child suffering from severe dystonia and passionately advocates for more research into this often-unseen but devastating genetic disorder, highlighting its underrepresentation in public discourse despite its profound impact on patients and families.
Dr. Pasca emphasizes that autism is not a single disease, using the analogy of "fever" in the 19th century—a symptom of many underlying conditions (viral, bacterial, cancer, autoimmune)—to explain why psychiatric conditions, defined behaviorally, lack biological markers and thus unified treatments.
Dr. Sergiu Pasca explains the two major hurdles in treating psychiatric disorders: the lack of clear biological definitions and biomarkers, and the inherent inaccessibility of the human brain, especially during its long development, which hinders direct study and therapeutic development compared to other fields like cancer.
Dr. Sergiu Pasca breaks down gene therapy, explaining how it can involve delivering missing genes or proteins, and then details the revolutionary CRISPR technology that directly edits DNA using guide molecules and enzymes to correct genetic defects, while also touching on the challenges of targeted delivery.
Andrew Huberman and Dr. Sergiu Pașca discuss the severe risks and lack of scientific justification behind unregulated stem cell injections, often sought by patients globally, including parents of autistic children. They highlight cases of blindness, paralysis, and infection, emphasizing the unknown contents and unproven benefits of these procedures.
Dr. Sergiu Pașca shares the astonishing discovery from his lab that human brain organoids maintained in a dish for years beautifully recapitulate developmental timing, including a canonical switch in NNDA receptor subunits that typically occurs around birth. This suggests an intrinsic "timer" within brain cells, offering profound insights into human brain development outside the body.
Dr. Pașca describes the groundbreaking achievement of creating a functional neural circuit in a dish that can cause human muscle contraction. This clip details how they combined brain and spinal cord organoids with a ball of human muscle, overcoming low probabilities to demonstrate that stimulating the cortical organoid leads to muscle contraction, highlighting the power of self-assembly.
Dr. Pașca shares a profound insight from his work: the realization that much of biology's complexity, especially in brain development, stems from 'self-organization.' He explains that the human brain builds itself without a blueprint, with instructions revealed at each step. This clip underscores the idea that by simply creating the right 'parts,' the biological system inherently knows how to assemble itself.
Andrew Huberman and Dr. Pașca engage in a thought experiment about the profound ethical implications of transplanting human neurons into animals or other humans. They discuss the potential impact on identity and the critical need to address such ethical dilemmas during the planning stages of experiments, emphasizing that it's 'never too early' to consider these complex issues.
Dr. Pasca shares the surprising discovery that neurons grown in a dish were 10 times smaller than those in actual human brains, leading to the crucial realization that "in vivo veritas" (truth in life) is essential for accurate disease modeling and benchmarking for therapy.
Dr. Pasca recounts his last conversation with the late Lubert Stryer, who, upon hearing about the Timothy syndrome breakthrough, profoundly declared, "You've demystified the psychiatric disease," validating years of intricate molecular research.
Dr. Pasca explains how the dramatic neuron size defect in Timothy syndrome patients could only be observed when cells were transplanted in vivo, not when grown in a dish, underscoring the necessity of complex biological environments for accurate disease modeling and therapeutic testing.
Dr. Pasca announces that his team is preparing for a clinical trial for Timothy syndrome, having developed the first therapeutic for a psychiatric disease exclusively using human stem cell models, without reliance on traditional animal models.
Andrew Huberman and Dr. Sergiu Pasca discuss the surprising fact that human brain myelination, crucial for efficient neural communication, continues all the way up to the third decade of life, particularly in frontal brain areas.