Ground Truths

Eric Topol

Facts, data, and analytics about biomedical matters.

erictopol.substack.com

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20 episodes
Updated July 20

Episodes20

Newest first

July 20 · 58 min
Patrick Hsu: How Is AI Catalyzing Life Science?
“The future of biology is programmable.” To give you a sense of how important this topic is, Patrick Hsu is the first guest we’ve had back to Ground Truths since the podcast began a few years ago. Nearly 2 years ago we spoke about digital biology but so much has happened since to help unravel the complexities in the language of life. Patrick is a co-founder and core investigator at the Arc Institute. His work is at the intersection of biology, engineering, and AI. At the ripe old age of 33, he’s a pioneer of genome editing technologies and my go-to for tracking progress in digital biology. Besides that he’s a great explainer with frequent use of metaphors and simplification of very complicated stuff. Here’s what we discussed with the relevant links: —Our recent review in Nature Biotechnology on the large language of life models (LLLMs). GBAI-generalist biological artificial intelligence —The 2 multi-agent AI Nature papers in May for accelerating drug discovery: Full House (Robin) and Google Deep Mind (Co-Scientist) Multiple drug candidates were described as an outgrowth of multi-agent AI , with a 200-fold decrease in workflow time. Below Figure from synthesis of the Robin and Co-Scientist papers: “AI devises hypotheses and ways to test them,” Nature News and Views, by Oliver Elemento —Biomni published in Science 9 July An infographic by NotebookLM below helps give you a sense of what—a diversity of important tasks— accomplished by Biomni —New workbench offerings by the AI companies including Anthropic’s Claude Science, Open AI, Google DeepMind and the competition with academic spinoffs —Spud Cells —Virtual Cell project, which it’s such a big deal, and the importance of perturbations —Alzheimer’s disease with OpenAI for finding mechanistic new targets for drug discovery —The Nature Editorial —Mid-Journey’s Ultrasound Imaging of the “Whole-Body” (and we’re not imaginative enough, the need to think big) —Mitigating the worries about humans as lab assistants and nefarious use to produce bioweapons ******************************************************************************* A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 61 summer interns here with us now! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths. Finally, thank you Alan Heldman MD, Bob Fleischman, Jeanie, Maureen Susannah, Mary Powers, and more than 400 others for tuning into my live video with Patrick Hsu! Join me for my next live video in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe
July 3 · 47 min
Aaron Newman: A Breakthrough Blood Test for Cancer
The tumor microenvironment (TME), composed of immune cells, fibroblasts, and endothelial cells, has emerged as critical to pathogenesis, prognosis and treatment for cancer (schematic Figure below). There’s no such thing as TMI (too much information) for TME! Yet there’s still no way of assessing it in the clinic by a blood test, and even by invasive biopsy the sampling bias for TME without broader geographic context can lead to important mistakes. That isn’t used for clinical decision making. The TME field is about to change. Recently, Professor Aaron Newman at Stanford and colleagues from many US leading centers published a landmark paper in Nature. It may ultimately be considered one of the most important leaps in cancer diagnostics in decades. Ground Truths is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. This was a massive undertaking involving 10 million single-cell RNAseq in 10 types of cancer to define 9 TME types by spatial omics which they called “spatial ecotypes”. It was AI-enabled by machine learning (Spatial Ecotyper from biopsy samples) and extrapolating that to knowledge to deep learning AI (Liquid Ecotyper from blood samples). The whole project took several years. Here’s an infographic summary I made with the help of NotebookLM along with the Figures that follow. Some of the key points from our conversation: —TME is the soil in which the cancer cells live. It strongly influences whether the cancer cells will thrive or not, spread, respond to therapy, and determine the fate pf pre-cancerous lesion (as seen in recent important paper in pancreatic cancer evolution and colon cancer development). —Ecotypes, a term coined in 1922, to get at the local environment of tissue and cancer, was repurposed in this new project. Good metaphor: neighborhoods. And emphasis on location , location, location like real estate. —In the clinic today, the only window to TME is via a biopsy. But decisions for treatment are not based on TME, they are based on biomarkers like tumor mutation burden (TMB), PD-L1 levels , or volume of tumor DNA by liquid biopsy. —TME is dynamic and changes over time so a single snapshot won’t cut it. —Spatial 3D maps of TME from 10 million cells, 10 cancer types led to 9 spatial ecotypes (with the Spatial Ecotyper machine learning). Validation across 3D grids (such as Visium) and multiple cohorts. The cell location base within TME is striking. —These 9 neighborhoods are conserved and very different. SE4-immune system is asleep, hypoxic; SE 7/8 are “war zones” rich with immune cells, hot tumor; SE 5 exhibits intense immunosuppression, hostile vs immune system, portends poor survival, SE9 deep in core, driving angiogenesis (new blood vessels) —Now rich information from these 9 SEs needs to be extrapolated to a holistic blood test of TME. It turns out an extension of tapping into methylation as used by some liquid biopsy cell-free DNA tests works very well, providing cell identity from the DNA fragments leaked into the blood. To get to TME spatial biology in a tube of blood. Akin to wastewater surveillance form municipals for detection of infectious disease pathogen sequence variants and circulating levels. A triumph of AI analytics made this possible! —The Liquid Ecotyper was validated in 78 patients with malignant melanoma pre-treatment from Yale University. SE 7/8 benefited from immune checkpoint therapy; SE4 resisted treatment, shorter survival. Matched with tissue biopsy work. —Work beyond publication ongoing in many types of lung cancer, bladder cancer, mesothelioma, and response to other therapies like CAR T and bispecific antibodies. This is critical since we have slew of different cancer immunotherapies (see my pyramid Ground Truths review) and we’re not sure who, when, how to use them to drive optimal cancer outcomes in patients. May also help predict other types of therapy (not just immunotherapy) for cancer. —The blood test can performed serially which is a major advance compared with how we are currently “flying blind” and misled by imaging. —Started a company Liquid Cell Dx to make the TME blood test commercially available. May be available sooner in the academic centers in the current study. —The use of SEs may extend beyond cancer! A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths. Thank you Dr Poonam Desai, Harshi Peiris, Ph.D., YOUR DOCTOR KLOVER, KL, Jessica Coffman, and >400 others for tuning into my live video with Aaron Newman! Join me for my next live video in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe
June 26 · 1 hr 3 min
Elisa Port: Discuss THE BREAST ADVICE Book
“I may be the expert in cancer, but you are the expert in you.”—Elisa Port, MD Ground Truths is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Dr. Elisa Port is Professor of Surgery, Icahn School of Medicine at Mount Sinai; Chief of Breast Surgery for the Mount Sinai Health System; Director of the Dubin Breast Center; and Director of the Center of Excellence for Breast Cancer at the Mount Sinai Tisch Cancer Center, a NCI-Designated Comprehensive Cancer Center. She is remarkably well qualified to provide guidance for prevention and treatment of breast cancer, and runs a model program at Mount Sinai in New York (←we’ll get into why I say that). She has just published a terrific book that centers around the concept of informed optimism. Many of her patient stories are integrated. We tried to cover the waterfront during our conversation including: —4 Ws for reduction of risk: weight, walking, wine, and working out (especially in Nature, “green exercise”) —Only 10-12% of women will ever develop breast cancer during their lives —Role of adipocytes (fat cells), aka estrogen and inflammation factories —Misinformation (underlying the need for this book) —Pervasive myths of magic supplements, with safety issues of unregulated intravenous drips and others when analyzed turned out to be crushed up, dried house plants —Total body MRI: mixed results from her patients —Breast cancer on the rise in young women. Dr. Port relates about recent patients diagnosed in their 20s. Some without BRCA or other pathogenic mutation. Why? —Mammograms in non-dense breasts pick up 80-90% of breast cancer. It’s the 40-50% women with dense breasts, which the scan is trying to find a polar bear in a snowstorm, is a problem. The problem with false-positives. —Use of AI with mammography for increased initial detection, prevention, detect high-risk in women with a “normal” mammogram, and risk of heart disease (see my recent Ground Truths and piece in The Lancet on this important topic) —Mount Sinai provides Transpara AI (the one validated by the big Sweden trial of >100,000 women) to all women getting mammograms FOR FREE. That is the best validated AI tool in medicine today! —How a mammogram saved a patient’s life, not about breast cancer! —Hormone replacement and birth control pills. How to assess benefit and risk in women young and older? Differences in the hormone risks. —Tamoxifen for primary prevention in high-risk people. Reduction of breast cancer in 50% or more in these women. In some subgroups reduction as high as 80%! —GLP-1 drugs may reduce breast cancer risk and this may not just be related to weight loss —Lack of utilization of Genetic testing (it could be your father). I disagreed with respect to use of polygenic risk scores, as I wrote about in SUPER AGERS —“I just wanted to scream out on top of the mountain about genetic testing, family history, and early screening.” Tennis legend Chris Evert —The lack of our ability to assess the immune system in the clinic and how that could change the face of prevention and very early detection of breast cancer An infographic summary I made on Dr. Port’s book with the help of NotebookLM **************************************** Thank you YOUR DOCTOR KLOVER, Diane Romero, Bob Fleischman, Danielle, MagnaAnimus, and 450+ others for tuning into my live video with Elisa Port! Join me for my next live video in the app. A big thanks to all the Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths. Get full access to Ground Truths at erictopol.substack.com/subscribe
June 6 · 51 min
Helen Pearson: What Constitutes Real Medical Evidence?
Helen Pearson, PhD, is an award-winning biomedical journalist at Nature, named European Science Journalist of the Year in 2025. She teaches science writing at University College London. BEYOND BELIEF is her second, just published book. THE LIFE PROJECT was her first. The points we covered include: —The evolution of evidence over 8 decades, moving from rationalism, expert opinion, hunches (eminence-based) to empiricism, evidence-based —The enormous devastating adverse impact of Dr. Spock’s Baby and Child Care book from a single sentence change, leading to an epidemic of sudden infant death syndrome. And how it ultimately got corrected. —The term evidence-based medicine was coined in 1991 at McMaster University —Iain Chalmers, Archie Cochrane and the Cochrane Collaboration “The scandalous failure of science to cumulate evidence scientifically”—Iain Chalmers —Systematic reviews —Natural experiments (such as with Shingles) —Resistance to change “Challenging a doctor’s conventional way of practice is like hitting him in the intellectual testicles”—Drummond Rennie, past JAMA editor —Evidence-based practice (and not) in the Covid pandemic —Recent examples of challenging dogma (kindly stones, thymus involution) —AI and misinformation, false evidence Thank you Harshi Peiris, Ph.D., Ageless Mind Project, Anthony Higgins, E West, MagnaAnimus, and many others for tuning into my live video with Helen Pearson! Join me for my next live video in the app. A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in throughGround Truths. Get full access to Ground Truths at erictopol.substack.com/subscribe
May 14 · 52 min
Assessment of the Hantavirus with Prof Donald Milton
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May 13 · 58 min
Joanna Stern: An AI Immersion for 365 Days
Joanna Stern was the Wall Street Journal technology journalist for 12 years. She’s an Emmy award winner for her documentary E-Ternal, and recently started her own company New Things, with added advice from ChatGPT! Over the years at WSJ, I relied on Joanna’s reviews of technology for many purchases (and things I avoided) reflecting her keen and brutal assessments. I also had fun working with her on some of her video assessments of health technologies. Her book I AM NOT A ROBOT is both hilarious and highly informative. It is a terrific primer for those who are not fully grounded in AI getting into the history of AI and right up to date with generative AI’s progress. To get a sense for why AI thought she was the next Tina Fey, check out the back cover! No surprise she got me laughing hard throughout the conversation, no less while reading the book. Here is a short YouTube video she posted on her All In AI year of 2025, referred to during the podcast. Much of her testing of >100 AI products related to medicine and health care, which is what we especially got into during our conversation. She has 3 major rules in her assessment of AI: (1) Ruthless testing; (2) Benchmark vs human; and (3) Costs, which include “compute cost” that we discussed. Here are some of the things we covered: * AI of her blood work * AI of mammogram and breast ultrasound, and overall experience as a person with increased risk of breast cancer * AI at the dentist (and ”Dentist Deep Clean”) * Assessment of Dr. GPT * Bill Gates on health AI * Her AI Trainer (Chris) * Waymo vs Uber * Her AI Therapist (Ash) * Nothing Bot Sex (her 2 digital lovers) * Impact on her children (including 6 F*****g Hamsters, the robodog Sirius) A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths. Thank you Tara Parker-Pope, MPH, Tracy Paeschke, MD, FACC, Chip Hughes, Bob Fleischman, Gretchen Faucett, and >400 others for tuning into my live video with Joanna Stern! Join me for my next live video in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe
April 25 · 51 min
Roxanne Khamsi: We Are All Genetic Mosaics
“You are a slightly different genetic version of yourself today from yesterday, and will be different yet again tomorrow.”—Roxanne Khamsi “Each neuron really is a beautiful and unique snowflake”—Ed Yong Roxanne Khamsi is one of the leading life science journalists, a contributing writer at The Atlantic, recognized with multiple awards for notable publications. Her new book is entitled BEYOND INHERITANCE. It tells the story about us all being genetic mosaics, chock full of somatic (acquired) mutations, and the implications of those mutations for our health. The myth of a single genome, carbon copy, master blueprint, but instead a dynamic, shifting mosaic in constant internal evolution. And here’s the back cover. I was delighted to endorse this book, and reread it to prepare for our podcast. It’s extraordinary and mind-bending. Here are the topics we covered: —The Math. 330 billion cells of our ~37 trillion turnover each day, which yields trillions of mutations per day. —Cellular competition. Winners and losers of an “endoevolution,” Darwinian selection inside us whereby healthy or super-fit mutated cells can crowd out the unfit ones. This was theorized in 1881 in a book THE STRUGGLE OF PARTS, by Wilhelm Roux which led to Friedrich Nietzsche’s famous quote “Uniformity is pure delirium.” —Single-cell sequencing. How this field catapulted forward owing to the ability to zoom in on genomic mutations at the cellular level. —Cancer chemotherapy overkill. The routine scorched earth, carpet bombing approach can promote resistance and deleterious mutations, leading to an adaptive strategy of leaving some cancer cells behind, as has been shown to be effective in prostate cancer for improving survival. —The immune system somatic hypermutation. B cells have the theoretical capacity to produce 1 quintillion unique antibodies (a million trillion). If this weren’t possible, we could die from a common cold. In the Covid pandemic, even before the Omicron variant appeared, Covid booster shots induced hundreds of unique antibodies with neutralization capacity against Omicron. The anticipatory “Red Queen” effect. —Autocorrection of mutations. They can revert, cure a rare genetic disease from within. It can be considered “Natural Gene Therapy.” Example below of a skin condition Epidermolysis Bullosa with revertant mutations (→ normal skin appearance) —Different role of acquired mutations through the lifespan. Examples: At embryonic stage, Lines of Blaschko (Image below). In mid-life endometriosis, and in older adults Loss of the Y chromosome (LOY) and Clonal Hematopoiesis of Indeterminate Potential (CHIP). Note these 2 somatic mutation clone conditions are associated with risk of diseases; CHIP-cardiovascular and cancer; LOY-heart failure and Alzheimer’s. I’ve written about CHIP extensively here and here. —Phenocopy. How a somatic mutation can look the same as a germ-line, inherited mutation, with respect to a disease, and how that is determined. —Environmental effects inducing somatic mutations: UV light, air pollution, plastics —and 3 new papers in the past week! * Somatic mutations in the microglia cells of the brain, same as cancer mutations, drive inflammation and are enriched in the Alzheimer’s brain 2.. The potential of “promolytic drugs” to be used to prevent cancer in people who exhibit precancerous somatic mutations 3. How somatic mutations can be the basis of autoimmune diseases We also spoke about the role of somatic mutations in aging and super aging A related excerpt at The Atlantic A Quick Poll Thank you YOUR DOCTOR KLOVER, Stephen Pribut, Elizabeth J., Maureen Susannah, Gretchen Faucett, and more than 500 others for tuning into my live video with Roxanne Khamsi! Join me for my next live video in the app. And a big thanks to Ground Truths subscribers (> 205,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. We just accepted 51 interns for the 2026 summer, a new record, from thousands of high school, college, and med school student applicants. Our fully loaded cost to do this program is ~$300,000 per year. We’re deeply appreciative for your support of Ground Truths that has enabled this program to prosper and expand. One more thing: SUPER AGERS was featured on the CBS Morning Show this week in a segment with Dr. Jonathan LaPook, Chief Medical Correspondent, on the meaning and measurement of biological aging. Get full access to Ground Truths at erictopol.substack.com/subscribe
April 19 · 53 min
Sebastian Mallaby: The Infinity Machine
This is one of my favorite books over recent years. Sebastian Mallaby is the Paul A. Cocker Senior Fellow for International Economics at the Council of Foreign Relations and author of 6 bestselling books. THE INFINITY MACHINE tells the story of AI’s progress over the past 15 years largely, but not exclusively, from Demis Hassabis as the protagonist and leader of DeepMind’, with its 2010 mission statement to achieve superintelligence by 2030. It’s a rich, informative, page turner. What We Discussed: —What is an Infinity Machine? —Influence of Claude Shannon’s Information Theory and Douglas Hofstadter’s Pulitzer Prize winning book Gödel, Escher, Bach —Origin of DeepMind in 2010. Prescient. Charter, business plan, included use of agents. How Demis Hassabis was made for the mission! —Contrasts with Sam Altman and the other AI leaders, the Oligopoly (cover of The Economist this week). For example, Nature papers vs white papers on company websites. —In March 2016, the same day when DeepMind’s AlphaGo beat Lee Sedol, Hassabis says it’s time to do protein folding (later known as AlphaFold). —Symbolic AI (historic, deductive, rule-based) vs Deep Learning (Toronto tribe) and Reinforcement Learning (Alberta tribe). —The Big Miss: DeepMind’s lack of early recognition of the importance of transformer models (leading to ChatGPT), creating a big opening for OpenAI. And why was this missed? The Comeback Story. Is this happening again with coding (not in the book)? —The AI Arms Race and Hyperscaling —How the complex relationship between Google and DeepMind evolved —The Double Cross —With the dangers anticipated (parallels to Oppenheimer, Manhattan Project, and the atomic bomb), how to promote AI safety? —Is the major build up of data centers justified? Thank you Bob Fleischman, Jeanie, Ruben Max, FelonBroke America, Seitzinator ❌👑, and more than 600 others for tuning into our live video with Sebastian Mallaby! Join me for my next live video in the app. And a big thanks to Ground Truths subscribers (> 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026. And, if you’re interested on extending healthspan, two recent podcasts/TV segments on SUPER AGERS On With Kara Swisher On PBS Get full access to Ground Truths at erictopol.substack.com/subscribe
April 10 · 56 min
Trisha Pasricha: How to Get to Poophoria, Making Your Bowel Movements a Joy!
Dr. Trisha Pasricha is a gastroenterologist, Assistant Professor at Harvard Medical School, and the Ask a Doctor columnist for The Washington Post. Her new book gets deep into the stigmatized, taboo, rarely discussed topics of our bowel movements and farts, no less the science that backs that up, with lucid explainers for the mechanisms (such as the gut-brain axis). Her research is on the gut origin of Parkinson’s disease. Here’s a quote from Trisha early in the book: “I’m not a wellness guru. I’m a scientist.” Another quote from a Vanderbilt professor: “An effortless, socially appropriately timed bowel movement is the second greatest bodily pleasure known to man.” The proportion of people with bowel issues is remarkable, a brief summary: Some of the topics covered in our lively, fun and highly informative conversation: —The 3 P’s Propulsion, Pliability, Pelvic Floor —Ten Myths —99% of farts have no odor; the 1% that do are from hydrogen sulfide, Pepto-Bismol substantially reduces the latter (and an incredible experiment of people with rectal tubes and judges smelling their gas) —What is the normal frequency of pooping? —the Bristol Scale of poop appearance and what it means —Transit time —The uselessness and danger of bowel cleanses —Fibermaxxing —5 minutes max on the toilet and positions to help propulsion —Psyllium and laxatives —The art of wiping and bidets —Fecal incontinence —Not to miss urges and the TRPV1 and PIEZO2 receptors —Impact of coffee, alcohol, NSAIDs (Ibuprofen, aspirin, naproxen, etc), and hydration —What are the different definitions of constipation? —What gives poop its color? ******************************************** Thank you YOUR DOCTOR KLOVER, Nickhil Jakatdar, Ph.D., Bob Fleischman, karemm, Jessica Nguyen, and >600 others for tuning into our live video with Trisha Pasricha! Join me for my next live video and newsletters in the app. And a big thanks to Ground Truths subscribers (> 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026. Get full access to Ground Truths at erictopol.substack.com/subscribe
March 29 · 45 min
On the Future of Species
Adrian is a molecular biologist and co-founder and CEO of Genyro, a synthetic biology company. He has published 2 previous books on life science (Life Without Genes and An Intelligent Person’s Guide to Genetics). In this conversation we discussed his new book, cover below and the title of this post. ABI. As Adrian puts it, a monumental shift, a second genesis, the “artivolution,” ability to use a molecular Gutenberg press, it’s post-Darwinian. I made an infographic about the book and our conversation with NotebookLM The expansion of genome sequences beyond “Fred’s library” (referring to Fred Sanger, father of genome sequencing, little green box) We talked about the jump from DNA reading to editing and now writing genomes, with the potential of the latter for both good and harm. I disagreed with Adrian about the bright prospects for curing diseases, but there are many possibilities for positive impact, such as intervening vs the climate crisis and sustainability. We also discussed the large language of life models (LLLMs) and by coincidence my colleagues and I just published a review of these in this Nature Biotechnology (←free access is hyperlinked). “It should be possible to meet most of humanity’s needs through biologically inspired designs—to solve many global problems, revolutionize health care, extend human lifespan, and create other organisms to order.”—Adrian Woolfson If you are into life science, I think you’ll find Adrian’s book thoughtful and provocative, even if you don’t agree with some of his optimism like a disease-free organism. The topic connects with digital biology, a theme that is approached in many editions of Ground Truths, such as this one with Patrick Hsu *************************************************** Thank you Ric Bayly, Kevin Johnson, MD, YOUR DOCTOR KLOVER, Patricia Scott, Anne, and more than 600 others for tuning into my live video with Adrian Woolfson! Join me for my next live video in the app. And a big thanks to Ground Truths subscribers (> 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026. Get full access to Ground Truths at erictopol.substack.com/subscribe
March 6 · 57 min
A Master Class on Sleep
Yo-El Ju is the Barbara Burton and Reuben Morris Professor of Neurology at Washington University, St. Louis. She got her AB from Harvard and MD from Columbia and actively practices sleep medicine and is a prolific researcher, one of the top sleep scientists in the country. Here are some of the topics we discussed and a few related hyperlinked citations: —Importance of Deep Sleep (and her paper on what happens when deep sleep is purposely disrupted, how it is modulated, effect of alcohol —The Orexin Antagonist drugs that promote sleep (and a study that shows they can reduce p-tau217 and other neuroinflammation markers —Link of sleep regularity with less all-cause, cardiovascular, and cancer related mortality Figure 3.9 from SUPER AGERS (SRI-sleep regularity index) More things we discussed: —A sleep foundation model that predicts 130 diseases —Impact of menopause on sleep —Getting to sleep vs staying asleep —Role of naps —Impact of interruptions of sleep —Sleep apnea and new interventions —Vagal nerve stimulation and sleep —Cerebrospinal fluid wave that occurs during attention lapse after poor sleep —cognitive behavioral therapy for improved sleep —Wearables, sleep scores, and effect on sleep —Any supplements that help sleep? —The rare genetically endowed short sleepers Thank you Jeoffry Gordon, MD, MPH, Dr. Sara Wolfson, Lynn L, Vau Geha, Bernie Newman, and more than 600 others for tuning into my live video with Yo-El Ju! Join me for my next live video in the app. ************************************************** Thanks to Ground Truths subscribers (> 200,000) from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026. +++++++++++++++++++++++++++++ I also want to thank the National Academies of Science, Medicine and Engineering for their recent recognition. Get full access to Ground Truths at erictopol.substack.com/subscribe
February 4 · 45 min
Robert Wachter & Eric Topol - Discuss a Giant Leap Book
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February 1 · 1 hr 3 min
Vagus Nerve Stimulation and the Immune System
The vagus nerve, also known as the Great Nerve, connects the brain to all parts of the body, like an internet (Figure below). Every week we’re learning more about its importance for health and disease. Until recent years the brain and immune system were thought to be in separate “firewalled” compartments. But that turned out to be far from the truth. Dr. Kevin Tracey, who directs the Feinstein Institute at Northwell Health, has been studying the vagus nerve for more than 3 decades. In the early 1990’s he made the seminal observation that stimulating the vagus reduces the inflammatory cytokine known as tumor necrosis factor (TNF), what he described at the time as a “holy s**t” moment. In 2025 he published the book THE GREAT NERVE with many rich patient anecdotes and the history for how this field developed. I wrote about the brain-immune axis previously on Ground Truths, spotlighting the vagus nerve’s role. That included much more on depth of the pathways if you are interested. We discussed the recent FDA July approval for refractory rheumatoid arthritis (RA)(unresponsive to medications or intolerance to medical therapy) based on a sham-controlled randomized trial published in December 2025 in Nature Medicine. It is striking that the benefits were derived from 1 minute of vagal stimulation per day. That stimulation is barely perceived (tingling, many not at all) by device recipients. The surgery takes one hour to implant the tiny stimulator device along side the vagus nerve in the neck. But this is much bigger than a treatment for RA. It is now being tested for lupus, Crohn’s disease, and other autoimmune conditions. That’s beyond the role vagus nerve stimulation (VNS) has played for epilepsy and depression, independent of VNS’s anti-inflammatory impact (Tracey named it “the inflammatory reflex”). We also discussed handheld VNS devices, potential use for Long Covid and POTS, cold plunges, heart rate variability, stress, and other topics related to the vagus nerve and parasympathetic nervous system (the brakes, “rest and digest” as opposed to the sympathetic nervous system (the gas, “fight or flight”). Most people are not aware of this device approved treatment for an autoimmune disease. Our treatments are so drug-centric but they are immunosuppressive, have important side-effects, and are expensive. It’s good to see a non-drug approach get compelling data as an alternative. Moreover, as I recently wrote about, there’s a shift ongoing from treatment to cures vs autoimmune diseases that will be adding to the mix. Here are some very recent papers about the vagus nerve to give you a sense about how its prominence is getting appreciated more all the time Gut-brain-vagus axis for reward circuit and addiction, 30 Jan 2026, Science Advances Randomized trial of VNS for depression , Int J of Neuropsychopharm 2026 The vagus nerve role in heart function after a heart attack, Cell, February 2026 Vagus receptors and hemorrhage, blood volume, Nature, 28 Jan 2026 A Quick Poll Thank you Harshi Peiris, Ph.D., Tay MacIntyre, David Dansereau, MSPT, Max Manwaring-Mueller, RJ, and over 600 others for tuning into my live video with Kevin J. Tracey, MD! Join me for my next live video with Robert Wachter Feb 4th, 12:30 PM PT in the app. ********************************************** Thanks to Ground Truths subscribers (approaching 200,000) from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026. Get full access to Ground Truths at erictopol.substack.com/subscribe
January 18 · 55 min
A Look Into the Blue Zones
Back in 2005 Dan Buettner patented Blue Zones. He’s written 9 books, of which 5 were NY Times bestsellers, and has another one in the works. His 2023 Netflix documentary series “Live to 100: Secrets of the Blue Zones” won Emmy awards and was widely viewed. Many of the main points that Dan has emphasized over the years—healthy diet (he highlighted whole grains, beans, nuts, greens, and “peasant food” here), physical activity, social engagement, and sense of purpose—are backed up by randomized trials and/or large, prospective studies, as I reviewed in Super Agers. In this interview, I asked Dan about the critique he’s faced, predominantly from Saul Newman, a biologist in the UK, about accuracy of the data for extreme longevity in the blue zones. In December 2025, two of his collaborators published in The Gerontologist a rebuttal response (open-access) entitled “The validity of Blue Zones demography: a response to critiques” on the rigorous demographic work they’ve done. We also discussed the marketing and business operations of Blue Zones LLC, the company he sold to Adventist Health in 2020. His son, Danny, is the EVP of the company and likely successor to Dan’s work in the future. As Dan said, “He’s my genetic upgrade.” I hope you find this conversation informative. An AI-generated transcript is available in the tab at top right above. Some biomedical updates from the past week: * A vaccine to prevent colon cancer in carriers of mutations of Lynch Syndrome looks good for strong immune response and safety, ready for Phase 3 clinical trials * A review of the data of Tylenol during pregnancy reaffirms its safety and lack of increased risk for autism, ADHD, and intellectual disability. * Our perspective/review on how AI and large language models can reduce global health inequities * Another big jump vs refractory autoimmune diseases, this time for hemolytic anemia, using engineered T cells. See my recent review of this topic, from treatment to cures. * A pair of new large prospective cohort studies that reinforce the importance of even small increases in physical activity, along with sleep and diet, for reduction all-cause mortality and improvement in healthspan. Thanks to Ground Truths subscribers (nearly 200,000) from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026 Thank you Annie Fenn, MD, Harshi Peiris, Ph.D., Strategy Shots, Rebecca Moore, Lynn L, and many others for tuning into my live video with Dan Buettner! Join me for my next live video in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe
Dec 21, 2025 · 56 min
How Our Brain Drains Its Waste Products
Jonathan Kipnis is a neuroscientist, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology and Immunology at Washington University, St. Louis, who discovered meningeal lymphatics and has been a prolific researcher in brain drainage and the continuous immune system surveillance of the brain. I made this infographic with the help of Notebook LM to summarize many of the concepts we discussed. (Notebook LM is free and worth trying) We went over his new review with 24 co-author leading experts in the recent issue of Neuron A Clever Cover The drainage system anatomy on influx and efflux (blue arrows) The 3 ways the flow of glymphatics are modulated. I mentioned the recent studies that show atrial fibrillation, via reduced cardiac pulsation, has an effect on reducing glymphatic flow. We also discussed his recent review on the immune surveillance system in Cell: A schematic of key channels for the “faucet” and “drain” and how the system changes from healthy to central nervous system autoimmune diseases (such as multiple sclerosis) and aging with different immune bar codes. The outsized role of astrocytes in the brain, a subject of recent Nature feature, was also mentioned. Our understanding of the brain’s immune system has been completely revamped. Kipnis’s recent review in Nature Immunology highlights the critical role of the outer layers —the skull, dura and meninges—as an immune reservoir that is ready to detect and react abnormalities in the brain with a continuous “intelligence report.” Notably, Kipnis touched on lymphatic-venous anastomosis (LVA) surgery (Figure below) for Alzheimer’s disease which is popular in China, available at 30 centers in multiple cities, and the subject of multiple randomized trials as a treatment for Alzheimer’s. Trials of LVA surgery are also getting started in the United States for treatment of Alzheimer’s and Parkinson’s diseases. Here is a Figure to show the surgical anastomoses (connections) from the deep cervical lymphatics to external jugular and internal jugular veins This podcast was packed with insights relevant to health, spanning sleep quality, sleep medications, autoimmune diseases, and Alzheimer’s disease. I hope you find it as informative and engaging as I did. A Poll ************************************ This is my 4-year anniversary of writing Ground Truths. Post number 250! That’s an average of more than 1 per week, nearly 5 per month. Hard for me to believe. Thanks to Ground Truths subscribers (approaching 200,000) from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026 Thank you EG, Alan, Lynn L, Stacy Mattison, Jackie, and many others for tuning into my live video with Jonathan Kipnis! Join me for my next live video in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe
Dec 7, 2025 · 59 min
The Story of Francis Crick, a new masterpiece biography by Matthew Cobb
A recording from my enthralling conversation with Prof Matthew Cobb about the life and science contributions of Francis Crick, regarded as one of the most influential biologists of all times, along with Darwin and Mendel. As you’ll see, there’s so much more to Crick’s story than cracking DNA’s double helix structure in a matter of weeks with James Watson. Matthew Cobb, Emeritus Professor of the University of Manchester, has written several award-winning books on life science, but I think this is his most important one to date, deeply researched and a thrilling account of Crick’s life, clearing up, as best as one can, many questions, and presenting some surprises. The transcript is available (A.I. generated) by clicking at the top right. A few things we discussed —Crick’s reaction to James Watson’s book Crick contrasted his own approach to science writing with Watson’s memoir: “The difference between my lecture and your book is that my lecture had a lot more intellectual content and nothing like so much gossip. (...) Your book on the other hand, is mainly gossip and I think it a pity in this way that there is so much of it that it obscures some of the important conclusions which can be drawn of what we did at the time”. —The Peyote Poem, by Michael McClure (part 1) that had a big influence on Crick —Crick’s 1994 neuroscience book “The Astonishing Hypothesis” “You, your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free Weill, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules.”—Crick The book has been reviewed at Science, Nature, The Economist and many other journals. Here is a gift link to The Economist It has deservedly been named a best book of 2025 by The Guardian, The Economist, and many other media. Thank you Bruce Lanphear, Harshi Peiris, Ph.D., Elisabetta Pilotti, Allan Konopka, Stephen B. Thomas, PhD, and over 500 others for tuning into my live video with Matthew Cobb! ********************* Upcoming, this Wednesday 9AM PT, live podcast I will be interviewing Dan Buettner founder of the Blue Zones Join us! ********************** Thanks to US News for recently being named one of the 25 best leaders in the United States https://www.usnews.com/news/leaders/articles/best-leaders-2025-eric-topol ^^^^^^^^^^^^^^^^^^^^^^ Thanks to >190,000 Ground Truths subscribers from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026. Get full access to Ground Truths at erictopol.substack.com/subscribe
Nov 28, 2025 · 1 hr
Jennifer Gunter & Eric Topol: Discuss Women’s Health and Recent Changes by FDA for MHT
A couple of weeks ago, the FDA Commissioner published a WSJ oped “The FDA Liberates Women’s Hormone Replacement Therapy” (←gift link) and, with other FDA colleagues, a JAMA essay entitled “Updated Labeling for Menopausal Hormone Therapy” (open-access). That change, and the data cited, led to a series of articles in the days that followed, such as at STAT News “FDA reverses decades-old warning on hormone therapy products for menopause. Agency says the treatments o!fer heart, brain, and bone health benefits” and at the Washington Post “The FDA finally corrects its error on menopause hormone therapy. Women have been needlessly scared away from effective treatments.” If you read through these links, you’ll be confused. Does MHT have proven cognitive benefits? What about a study from 1991 that showed ~50% reduction of fatal heart events with MHT? Or the 35% decreased risk of Alzheimer’s disease? Or the breast cancer increased risk attributed to medroxyprogesterone acetate? I turned to my go-to gynecologist truth teller, Dr. Jen Gunter, to get her review of the evidence. This is a complex topic, with old data from the 2002 Women’s Heath Initiative (WHI), new reports since, population level analysis, changes in preparations of MHT including local delivery, and much more. Here is our conversation which isn’t just about MHT but includes “Big Wellness” marketing direct to middle aged women, the new FDA approved drug for hot flashes, the $14 million cut of the NIH’s Office of Women’s Health , marked increase in philanthropic support of women’s health research, the Surgeon General nominee, ovarian failure, and a lightning round on proven benefits of MHT. Here’s a brief clip on her views of the women’s health “wellness” predators We also discussed the reasons for Dr. Gunter’s planned move next year back to Canada after practicing gynecology for 3 decades in the United States. I referred to a recent GT I wrote about the WHI and the potential favorable impact of MHT on the immune system, as suggested by new data on organ clocks. That finding, which has been replicated, may be linked to healthy aging, extending healthspan. **************************** Thanks to the >190,000 Ground Truths subscribers from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you found this interesting PLEASE share it! Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.Thank you Debbie Weil, Cynthia Brumfield, Sara Garcia, Harshi Peiris, Ph.D., Liane Moccia, and over 1,000 others for tuning into my live video with Dr. Jen Gunter! Join me for my next live video in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe
Nov 8, 2025 · 54 min
Dr. Susan Monarez—Former CDC Director, First Live Interview
Dr. Susan Monarez was the first CDC Director to be confirmed by the Senate and served from July 31, 2025 – August 27, 2025. Because she refused to give approval to new vaccine recommendations without ever seeing them or their evidence and firing scientists without cause, she was fired. In my view, she’s a hero for standing up for science and speaking truth to power. In her first live interview since leaving the CDC, we review her background. That includes growing up in rural Wisconsin and getting her college and PhD education at UW-Madison, the latter in microbiology and immunology. She then went on to 18 years of government service with an extensive portfolio of jobs and management at BARDA, the White House, ARPA-H, and others, before becoming Acting Director of the CDC in early 2025. We discussed the horrific CDC shooting on August 8th, days after she started. Then we reviewed a conversation that we had on August 19th in which she laid out her exciting vision for the future of CDC, emphasizing the goal of prevention (BTW, CDC stands for Centers for Disease Control and Prevention) and asked me to help as an advisor. At the time, she was well aware, with growing tension, that her tenure at CDC might be limited. I asked about her perspective for the jobs of 4,300 people at CDC who have been terminated, which account for more than 1/3rd of the workforce, no less the gutting of the budget. Then we got into what she learned from this ordeal and her plans for the future, which includes a very ambitious initiative: 90/90/2035. As you’ll see from our conversation, Dr. Monarez is exceptionally resilient and an optimist. She’s got lots to do in the years ahead to carry out her mission of promoting human health! Dr. Monarez just started a Substack The Road Best Traveled so you can follow her there. It was a real privilege for me to do this interview with her. In deep admiration of her willingness to not only take on the job of CDC Director in tough circumstances, her professionalism during testimony at the Senate committee hearing, her impressive yet unrealized vision for transforming the CDC, and refusing to cave to immense pressure from the HHS Secretary to move ahead with his agenda. Thank you Julie, Stephen B. Thomas, PhD, David Dansereau, MSPT, Dr. Sara Wolfson, Vau Geha, and >500 others for tuning into my live video with The Road Best Traveled! Thanks for being a Ground Truths subscriber! Please spread the word. Get full access to Ground Truths at erictopol.substack.com/subscribe
Nov 5, 2025 · 47 min
Seth Berkley & Eric Topol - Discuss Fair Doses Book
Get full access to Ground Truths at erictopol.substack.com/subscribe
Oct 1, 2025 · 35 min
Tom Frieden & Eric Topol - Discuss the Formula for Better Health Book
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Vagus Nerve Stimulation and the Immune System

A Look Into the Blue Zones

How Our Brain Drains Its Waste Products

The Story of Francis Crick, a new masterpiece biography by Matthew Cobb

Jennifer Gunter & Eric Topol: Discuss Women’s Health and Recent Changes by FDA for MHT

Dr. Susan Monarez—Former CDC Director, First Live Interview

Seth Berkley & Eric Topol - Discuss Fair Doses Book

Tom Frieden & Eric Topol - Discuss the Formula for Better Health Book