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Episode Summary: Dr. Michael Wheeler talks about neuroimmune interactions, exploring how the immune system and brain communicate, particularly through the blood-brain barrier and meninges; how chronic stress and inflammation can alter brain circuits, contributing to mood disorders like depression; how drugs like psilocybin and MDMA may reduce inflammation by modulating immune cells in the meninges, offering potential therapeutic benefits.

About the guest: Michael Wheeler, PhD is an Assistant Professor of Neurology at Harvard Medical School. His lab studies how immune responses influence behavior, mood disorders, and addiction.

Key Conversation Points:

• The blood-brain barrier (BBB) is not as impermeable as once thought, allowing immune signals like cytokines to influence brain function even in healthy states.
• Chronic stress can weaken the BBB, increasing inflammation and affecting mood-regulating circuits, potentially contributing to depression.
• Microglia, the brain’s resident immune cells, help maintain neural circuits by pruning synapses and regulating metabolism.
• Psychedelics like psilocybin and MDMA can reduce inflammation by prompting immune cells (monocytes) to leave the meninges, potentially via vascular effects.
• These psychedelics may act in a context-specific “window,” requiring a dysregulated tissue state to exert anti-inflammatory effects, not as broad-spectrum anti-inflammatories.
• Neuroinflammation may underlie some treatment-resistant depression cases, suggesting immunotherapy could complement traditional psychiatric treatments.
• The brain encodes peripheral immune signals, like gut inflammation, in specific circuits, which can “remember” and recreate inflammatory responses.
• Aging may naturally increase blood-brain barrier leakiness, heightening the brain's susceptibility to peripheral inflammation.
• Future research aims to explore how psychedelics influence plasticity and their potential in treating inflammation-related diseases beyond psychiatry.

Related episode:

• M&M 2: Psilocybin, LSD, Ketamine, Inflammation & Novel Psychedelic Medicines | Charles Nichols

*Not medical advice.

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Episode Summary: New research on how dietary fats, particularly omega-6 fatty acids like linoleic acid, influence triple-negative breast cancer progression by activating the mTOR pathway, a key regulator of cell growth; role of the FABP5 protein in enhancing cancer cells’ sensitivity to omega-6 fats; differences between breast cancer subtypes; broader implications of dietary balance for health.

About the guest: John Blenis, PhD is a Professor of Pharmacology at the Meyer Cancer Center at Weill Cornell Medicine. Nikos Koundouros, PhD is a postdoctoral fellow in Blenis’ lab.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Key  Points:

• mTOR pathway acts as a cellular “brain,” sensing nutrients like amino acids, glucose, and fats to regulate growth. Its dysregulation can drive cancer.
• High dietary omega-6 fatty acids, like linoleic acid found in seed oils, can fuel triple-negative breast cancer growth by activating mTOR.
• FABP5, a lipid chaperone protein, is overexpressed in triple-negative breast cancer, making these tumors more sensitive to omega-6 fats, suggesting its potential as a therapeutic target.
• Modern diets with high omega-6 to omega-3 ratios disrupt inflammation balance, unlike historical 1:1 ratios, potentially increasing cancer risk.
• Genetic variations and cancer subtypes highlight the need for tailored dietary recommendations, as blanket nutrition advice may not suit all patients.
• While omega-6 fats exacerbate existing triple-negative breast cancer, their role in initiating cancer remains unclear, requiring further study.
• High omega-6 intake may influence other cancers (e.g., prostate, colon) and chronic diseases like obesity, linked to FABP5 and inflammation.

Related episode:

• M&M 200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade

*Not medical advice.

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Episode Summary: Dr. Gyorgy Buzsaki discusses the hippocampus’s role beyond memory and spatial navigation, delving into its broader functions in cognition, action planning, and brain-body interactions; how hippocampal rhythms, like sharp wave ripples, influence memory consolidation, glucose regulation, and metabolic health, challenging conventional neuroscience assumptions; the interplay of brain rhythms, sleep, and preconfigured neural dynamics; the history and conceptual foundations of neuroscience; and more.

About the guest: Gyorgy Buzsaki, MD, PhD is a professor at NYU. He leads a lab investigating how neural circuits underpin cognition, particularly through oscillations and brain-body interactions. His work has significantly advanced understanding of memory formation and spatial navigation.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Key Conversation Points:

• Hippocampus isn’t just for memory or navigation; it may orchestrate action planning and abstract representations of the world, shaped by evolutionary constraints.
• Brain rhythms, like sharp wave ripples, synchronize neural activity, enabling efficient communication and impacting bodily functions like glucose homeostasis.
• Sharp wave ripples, prominent during non-REM sleep and consummatory states, are critical for memory consolidation and may link sleep disruptions to metabolic disorders.
• Buzsaki challenges the idea of memory as fixed synaptic patterns, proposing it’s more like dynamic, cloud-like sequences, endlessly reconfigurable.
• The brain’s intrinsic dynamics prioritize action generation and learning from consequences over external representations.

Related episode:

• M&M 16: Sleep, Dreams, Memory & the Brain | Bob Stickgold

*Not medical advice.

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The biophysics of life, exploring how light & energy shape biology, with biophysicist Dr. Nirosha Murugan.

Episode Summary: Dr. Murugan discusses the role of biophysics in biology, focusing on how light, particularly biophotons emitted by cells, influences processes like wound healing, neural activity, and cancer detection; how microtubules may act as biological fiber optics, the impact of modern light environments on health; her work inducing limb regeneration in frogs using silk hydrogels and growth factors; cancer as an energetic dysfunction; potential of non-invasive photonic diagnostics; the need for new tools to study these phenomena.

About the guest: Nirosha Murugan, PhD is a biophysicist and assistant professor at Wilfrid Laurier University in Waterloo, Ontario. Her lab investigates the biophysics of life.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Key Conversation Points:

• Cells emit biophotons, ultra-weak light tied to metabolism, which may carry information for processes like immune response and neural communication.
• Microtubules might function as biological fiber optics, potentially guiding light within cells for signaling purposes.
• Red and near-infrared light can accelerate wound healing and reduce inflammation, likely by modulating mitochondrial activity.
• Cancer cells emit distinct photonic signatures, which could enable non-invasive diagnostics by detecting light differences from healthy tissues.
• Modern light environments, unlike natural sunlight, may subtly affect health by altering biological responses to electromagnetic signals.
• Biological systems act as metamaterials, patterning energy flow in ways that constrain and shape molecular and behavioral outcomes.

Related episode:

• M&M 221: Regenerative Energy & the Light Inside You | Jack Kruse

*Not medical advice.

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Short Summary: Dr. Alex Kwan unpacks the latest neuroscience research on how psychedelics like ketamine & psilocybin reshape the brain.

About the guest: Alex Kwan, PhD, is an associate professor of biomedical engineering at Cornell University. His lab employs advanced imaging to study how psychedelics and other drugs affect the mammalian brain.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Episode Summary: Dr. Alex Kwan discusses how psychedelics like ketamine and psilocybin induce rapid neuroplastic changes in the brain, particularly in the prefrontal cortex, contrasting their effects with traditional antidepressants like SSRIs, and exploring their potential for treating depression and chronic pain through structural and functional brain alterations.

Key Takeaways:

• Ketamine & psilocybin rapidly increase dendritic spine density in the prefrontal cortex, enhancing neural connections within days, unlike SSRIs, which take weeks.
• These drugs show sustained neuroplastic changes in mice, lasting weeks to months after a single dose, suggesting long-term brain rewiring.
• Serotonin 2A receptor is critical for psilocybin’s neuroplastic effects, as precise genetic knockouts in adult mice eliminate spine growth.
• Unlike ketamine, psilocybin activates the insula, a brain region linked to chronic pain processing, hinting at new therapeutic potential.
• Both drugs induce similar gene expression patterns in areas like the prefrontal cortex and amygdala, but differ in specific regions like the insula.

Related episode:

• M&M #30: Psilocybin, Ketamine, Neuroplasticity & Imaging the Brain | Alex Kwan

*Not medical advice.

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Short Summary: The flaws of nutrition epidemiology with Dr. John Speakman

About the guest: John Speakman, PhD is a professor at the University of Aberdeen and runs a lab in Shenzhen, China, focusing on energy balance, obesity, and aging. 

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Episode Summary: Dr. John Speakman explores the pitfalls of nutrition epidemiology, a field that links diet to health outcomes like cancer and obesity but often produces contradictory results. They discuss flawed methods like 24-hour recalls and food frequency questionnaires, which rely on memory and are prone to bias, and introduce Speakman’s new tool using doubly labeled water to screen implausible dietary data. The conversation highlights systematic biases, such as under-reporting by heavier individuals, and emerging technologies like photo diaries and AI for better dietary tracking.

Key Takeaways:

• Nutrition epidemiology studies often contradict each other due to unreliable methods.
• Common techniques like 24-hour recalls & food frequency questionnaires suffer from memory issues, portion size issues, and systematic biases, often underestimating food intake.
• Heavier individuals (higher BMI) under-report food intake more, skewing associations between diet & obesity.
• Speakman’s tool, based on 6,500 doubly labeled water measurements, predicts energy expenditure to flag implausible dietary survey data.
• Emerging technologies, like smartphone photo diaries and AI food identification, promise more accurate dietary tracking than traditional surveys.
• Randomized controlled trials, not surveys, provide the most reliable dietary insights; single-day intake surveys linked to outcomes years later are dubious.
• Speakman advises ignoring most nutrition epidemiology headlines due to their inconsistency and lack of prognostic value for behavior change.

Related episode:

• M&M #132: Obesity Epidemic, Diet, Metabolism, Saturated Fat vs. PUFAs, Energy Expenditure, Weight Gain & Feeding Behavior | John Speakman

*Not medical advice.

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Short Summary: Cancer’s metabolic roots with Dr. Thomas Seyfried.

About the guest: Thomas Seyfried, PhD is a professor of biology at Boston College. He has researched cancer metabolism, epilepsy, and lipid biochemistry for over 40 years.

Note: Podcast episodes are fully available on the M&M Substack and YouTube. Transcript and other information on Substack.

Episode Summary: Dr. Thomas Seyfried discusses the mitochondrial metabolic theory of cancer, challenging the dominant somatic mutation theory. He explores how cancer cells rely on fermentation due to defective oxidative phosphorylation, drawing on Otto Warburg’s work. Seyfried explains how ketogenic diets and nutritional ketosis can starve cancer cells by limiting glucose and glutamine, while sharing evidence from nuclear transfer experiments and clinical studies. The conversation also covers environmental factors driving cancer and the importance of metabolic flexibility for prevention.

Key Takeaways:

• Cancer is characterized by dysregulated cell growth, but Seyfried argues it stems from mitochondrial dysfunction, not just genetic mutations.
• Cancer cells ferment glucose & glutamine, unable to use fatty acids or ketones, making ketogenic diets a potential therapeutic tool.
• Nuclear transfer experiments show cancer traits reside in the cytoplasm, not the nucleus, challenging the somatic mutation theory.
• Environmental factors like processed foods, stress, and poor sleep disrupt mitochondrial function, increasing cancer risk.
• Seyfried’s glucose-ketone index helps monitor metabolic states to manage cancer & chronic diseases.
• Cancer rates are rising in younger people, possibly due to obesity, inflammation, and environmental toxins.
• Metabolic flexibility, cycling between ketosis and carb-based states, may mimic ancestral patterns and reduce chronic disease risk.

Related episode:

• M&M #215: Cancer Metabolism: Sugar, Fructose, Lipids & Fasting | Gary Patti

*Not medical advice.

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• Good Chemistry: Personalized, science-based health consulting. Work with Dr. Nick Jikomes directly.
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Short Summary: Heart health and the ketogenic diet, with expert insights from a cardiologist and researcher.

About the guest: Matthew Budoff, MD, is a preventive cardiologist and professor of medicine at UCLA School of Medicine.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Episode Summary: Dr. Matthew Budoff discusses cholesterol, heart disease, and his study on the ketogenic diet’s impact on lean, metabolically healthy individuals with high LDL cholesterol. He explains LDL, HDL, and triglycerides, debunking myths about their direct link to heart disease, and emphasizes the importance of coronary calcium scans to assess plaque buildup. Budoff also covers statins, dietary cholesterol, and personalized heart health strategies.

Key Takeaways:

• LDL cholesterol is not a definitive predictor of heart disease; plaque buildup, assessed via coronary calcium scans, is a better indicator.
• Lean metabolically healthy people on a ketogenic diet may have high LDL without increased plaque progression after one year.
• Coronary calcium scans, costing ~$100, are recommended for men around age 40 and women around 45-50 to evaluate heart disease risk.
• Statins effectively lower LDL and can reverse soft plaque, but may be overprescribed for those without plaque buildup.
• Dietary cholesterol has minimal impact on blood cholesterol, as the liver produces ~85% of it.
• Ketogenic diet can aid weight loss & diabetes control but may cause high LDL in some lean individuals, known as lean mass hyper-responders.
• Plaque progression depends more on existing plaque than LDL levels in metabolically healthy ketogenic diet followers.
• Heart health varies widely due to genetics and other unknown factors, underscoring the need for personalized assessments.

Related episode:

• M&M #158: Ketosis & Ketogenic Diet: Brain & Mental Health, Metabolism, Diet & Exercise, Cancer, Diabetes | Dominic D'Agostino

*Not medical advice.

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Short Summary: The science of obesity and appetite regulation, blending genetics and neurobiology with practical insights

About the guest: Giles Yeo, PhD is a professor of molecular neuroendocrinology at the University of Cambridge. He leads a lab studying obesity and appetite regulation.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Full transcript and other information on Substack.

Episode Summary: Nick interviews Dr. Giles Yeo about the genetics and neurobiology of obesity, starting with the discovery of leptin in the obese mouse model, detailing its role in appetite regulation via the hypothalamus, and discussing GLP-1 drugs like Ozempic for weight loss. It delves into how genetic factors, like the leptin-melanocortin pathway, influence hunger, the heritability of body weight, and societal factors driving the obesity epidemic, emphasizing the interplay of biology and environment.

Key Takeaways:

• Leptin, discovered through the obese mouse, signals fat levels to the brain, but its absence causes severe obesity and infertility, as seen in rare human mutations.
• The hypothalamus, a key brain region, senses hormones like leptin and GLP-1, balancing hunger and satiety through POMC (anorexigenic) and AgRP (orexigenic) neurons.
• Body weight heritability is 40-70% at the population level, but this does not mean that 40-70% of someone’s body fat composition is due to genetic factors outside human control. Dr. Yeo unpacks how to think about it.
• GLP-1 drugs (e.g., Ozempic) mimic gut hormones to reduce appetite, offering some people 15-25% weight loss, but require long-term safety monitoring.
• According to Dr. Yeo, obesity reflects energy imbalance, but nutritional density matters more than calorie counting for health, and societal changes are needed to prevent it.

Related episode:

• M&M #132: Obesity Epidemic, Diet, Metabolism, Saturated Fat vs. PUFAs, Energy Expenditure, Weight Gain & Feeding Behavior | John Speakman

*Not medical advice.

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• Good Chemistry: Personalized, science-based health consulting. Work with Dr. Nick Jikomes directly.
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Short Summary: A mind-bending dive into evolutionary biology and health through a biophysicist’s lens, with Dr. Jack Kruse delivering provocative insights about biology, medicine, and health.

About the guest: Jack Kruse, MD, is a neurosurgeon known for integrating biophysics into medicine. He challenges conventional biochemistry with his “leptin prescription” and decentralized health approach.

Episode Summary: Dr. Jack Kruse joins host Nick Jikomes to explore the Great Oxygenation Event’s role in shaping life, linking it to modern health via biophysics over biochemistry. They discuss oxygen’s impact on metabolism, the significance of deuterium-depleted water, and sunlight’s influence on the leptin-melanocortin pathway. Kruse shares his dramatic weight loss journey using sunlight and cold therapy, critiques modern tech-driven obesity, and unveils a controversial history of SV40 in vaccines, tying it to cancer spikes.

Key Takeaways:

• The Great Oxygenation Event (2.1-2.4 billion years ago) drove life’s shift to oxygen-based metabolism, with cyanobacteria as key players.
• Kruse argues biophysics, not biochemistry, explains evolution, spotlighting light as life’s fundamental driver.
• Deuterium-depleted water is important for enabling our cells and mitochondria to use energy from the TCA cycle without “shocking” the body.
• Sunlight exposure boosts nitric oxide, reducing food needs via the leptin pathway, challenging diet norms.
• Kruse lost 133 pounds in 11 months using sunlight and cold therapy, inspiring his “leptin prescription.”
• He links obesity to indoor tech lifestyles, disrupting heme proteins and mitochondrial function.
• SV40, a virus in 1950s polio vaccines, may connect to cancer rises, a story Kruse says was buried by centralized science.

Related episode:

• M&M #196: Vaccine Contamination & Fiat Science | Kevin McKernan

*Not medical advice.

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