Mind & Matter

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How genomics is used to study what makes a human brain, and how genetically damaged neurons get removed.
TOPICS DISCUSSED:
Scale & Size: A human brain is about three times a chimpanzee brain by mass, but the larger change is extra association cortex and extra upper-layer circuits that talk mostly to other cortex.
When Development Ends: Most cortical neurons are born before birth. Myelin and other glia keep forming into the twenties. Synapses keep changing after that.
Broken Genomes Get Edited: Walsh describes forthcoming work in which ~25–30% of late-fetal cortical neurons carry genetic defects, falling to ~5% by birth, with smaller defects still being removed through adult life.
Regulation vs. New Genes: Humans and mice both have ~20,000 genes. Most human-specific change is in when and where those genes turn on, not in inventing new proteins.
Human Accelerated Regions: About half of HARs involve the brain. Rare mutations in them show up more often in kids with intellectual disability and autism.
ASPM & Microcephaly: Loss of one conserved cell-division gene can shrink a human brain toward chimpanzee volume and shape. The same knockout barely shrinks a mouse.
Heritability of Genetic Disorders: Autism is highly heritable in twin studies. A whole-genome test today still finds a specific cause in only about a quarter to a third of kids.
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The biology of endogenous cannabinoids & history of cannabinoid-based therapeutics
TOPICS DISCUSSED:
Anandamide vs 2-AG: The two major endocannabinoids with a shared arachidonic acid backbone but distinct head groups biological roles.
On-demand production: Calcium-dependent enzymes release cannabinoids from membranes in response to neuronal activity patterns.
Trafficking: Fatty acid binding proteins and extracellular microvesicles traffic endocannabinoids within and between cells.
Adolescent THC: Global receptor activation during circuit wiring may contribute to cannabis use disorder and psychosis vulnerability in susceptible individuals.
Enzyme inhibitors: Early FAAH clinical trial halted by off-target toxicity; MAGL inhibitors advancing in phase 2 for anxiety and addiction.
Peripheral CB1: Liver receptors regulate metabolism; restricted antagonists aim to reduce weight without central psychiatric risks of the weight loss drug rimonabant.
ABOUT THE GUEST: Nephi Stella, PhD is a professor at the University of Washington School of Medicine. He has studied endocannabinoid signaling for more than 25 years, focusing on therapeutic strategies that separate beneficial effects from side effects of cannabinoid-system modulation.
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Mitochondrial peptides act as stress signals that regulate metabolism, muscle mass, and neurodegeneration.
TOPICS DISCUSSED:
Mitochondria as Communication Hubs: Beyond ATP production, mitochondria encode peptides that regulate cell death, immunity, and inter-organ communication.
Humanin Discovery: Identified independently by three labs; neuroprotective, longevity-linked, and capable of neutralizing APOE4 effects via a rare Jewish variant.
Ethnic Genetic Variants: Ancestry-specific mutations in MOTS-c, MENTSH, and SHMOOSE influence diabetes, obesity, sarcopenia, and Alzheimer’s risk.
MOTS-c & Muscle Preservation: Exercise-induced peptide prevents atrophy and may offset muscle loss seen with GLP-1 drugs.
Peptide Classes: Fragments of larger proteins, endogenous microproteins from small genes, and emerging AI-designed artificial peptides.
Diet Modulation: Mediterranean diet adherence raises circulating levels of the peptides humanin and SHMOOSE.
Clinical Reality Check: Early MOTS-c trials showed metabolic benefits; unregulated products often contain inaccurate doses.
ABOUT THE GUEST: Pinchas Cohen, MD is Dean of the USC Leonard Davis School of Gerontology and a leading researcher on mitochondrial peptides in aging, metabolism, and neurodegeneration.
RELATED CONTENT:
Article | Metabolic Stress & the Peptide MOTS-c: How Much is Too Much?
Podcast | MOTS-c & Mitochondrial Peptides in Health & Aging | David Lee

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How the nervous and immune systems communicate, using peptides and other signals, to regulate pain, itch, and inflammation.
TOPICS DISCUSSED:
Nociception & Pathogens: Sensory neurons detect bacterial toxins within seconds, enabling rapid host-defense coordination ahead of immune-cell recruitment.
CGRP & neutrophils: Nociceptor-release the peptide CGRP, which blocks neutrophil (immune cell) recruitment; pathogens exploit this in necrotizing fasciitis and meningitis.
Pain sensitization: Inflammation can lower neuronal thresholds for pain, which sometimes becomes a chronic problem.
Gut barrier protection: CGRP from gut nociceptors drives goblet-cell mucus secretion, supporting the protective “weep and sweep” response.
Skin-to-gut allergy priming: Early skin exposure to allergens plus scratching may promote food allergies.
Vagus nerve circuits: Distinct vagal sensory neurons selectively suppress TNF or induce IL-10, allowing precise inflammatory control.
Brain inflammatory memory: Insular neurons encode site-specific immune responses that can later be recalled by reactivating those circuits. The brain remembers past inflammatory events.
ABOUT THE GUEST: Isaac Chiu, PhD is a professor in the Department of Immunology at Harvard Medical School. His lab studies nervous-immune system crosstalk in pain, itch, infection, and inflammatory disease.
RELATED CONTENT:
Article | Inflammation Regulation by Omega Fats: How High ω-6 Intake Impacts ω-3 Levels
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Mitochondrial peptide MOTS-c is a stress-induced signal that reprograms cell metabolism.
TOPICS DISCUSSED:
Mitochondrial Roles: Not just ATP production, but “speaker of the house” via communication molecules that “talk” to the rest of the cell.
Origin of Communication: Mitochondrial peptides were likely co-opted from ancient antimicrobial factors to synchronize nuclear and mitochondrial genomes.
MOTC Discovery: Identified in mitochondrial ribosomal RNA regions linked to interferon responses.
Stress Induction: MOTS-c is produced in response to exercise, immune activation, and nutrient withdrawal; circulates as a mitokine.
Nuclear Regulation: MOTS-c translocates to the nucleus under stress and acts as a nonspecific cofactor that shapes chromatin accessibility and gene expression.
Metabolic Effects: Prevents diet-induced obesity and fatty liver in mice without altering baseline weight; engages AMPK and suppresses anabolic pathways.
Immune Modulation: Shifts immune cell programs to reduce autoimmune attack in type 1 diabetes models.
Aging Phenotypes: Daily or intermittent dosing doubles running capacity and preserves walking ability in old mice.
ABOUT THE GUEST: Changhan David Lee, PhD is Associate Professor at the University of Southern California Leonard Davis School of Gerontology. His laboratory investigates mitochondrial communication and microproteins in the biology of aging. 
RELATED CONTENT:
Article | MOTS-c & Cellular Energy Homeostasis
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