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Michael Lewis is one of the best storytellers of our era. You know and likely have read his books Moneyball, The Big Short, The Blind Side, Flash Boys, Liar’s Poker, and The Undoing Project, to name a few. He has long been one of my favorite authors. This was the first interview that Michael did on his new book, BLOCKERS, published on October 6th, streamed live on Substack Sept 29th. It’s his 21st book and 4 of the last 5 have been about the US government: The Fifth Risk (2019), Premonition (2021), and Who Is Government? (2025). His ability to talk with the silent civil servant heroes of multiple government agencies (the Blockers), members of the DOGE destruction team, and much more from the current US government administration. Here’s a gift link to the exclusive excerpt at WSJ I won’t review all the things we discussed here, but the chapter on the NIH reads like an Agatha Christie murder mystery. We learned a whole different version of what happened that differed from what was previously reported. Thank you jojofinance, Andrew Bowdle, Tracy Paeschke, MD, FACC, Bob Fleischman, Sean Stevenson, and many nearly 500 others for tuning into my live video with Michael Lewis! Join me for my next live video in the app. Ground Truths has 217,000 subscribers from every US state and 214 countries. There are over 300,000 followers of Ground Truths so more than 100,000 folks who can easily convert to be free subscribers. 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! The proceeds from all voluntary paid subscriptions go to support our summer internship program. It enabled us to accept and support a record number of 62 summer interns that joined us 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! Get full access to Ground Truths at erictopol.substack.com/subscribe

In recent weeks the results (announced by press release) of 2 major placebo-controlled randomized trials—ZEUS, testing an interleukin-6 (IL-6) blocker vs inflammation, and HORIZON, testing a drug to lower Lp(a), indicated failure to achieve their primary endpoint. Are we maxxed out for new treatments vs heart disease, as this article in the WSJ (←gift link) today asserts? “Cardiovascular drug development is starting to look a bit like the modern oil industry. The easy wells have been tapped. What’s left is in deep water: expensive, technically perilous and less likely to strike oil.” Or is it more complicated? Are the trial results and reasons for failure different? I wrote a recent Ground Truths —The Coronary Artery Inflammation Controversy— on the data (what has been released to date) and my take. But I wanted to vet this with another physician-scientist who is studying atherosclerosis and turned to Prof Marios Georgakis, from the University of Munich, who as I mentioned in the previous piece, wrote a brilliant analysis of ZEUS and is also doing writing about HORIZON. Many years ago we went through a “CV winter” when the biopharma companies largely shunned doing clinical trials for heart disease. They thought the field had been maxxed out. After a lapse of several years, there have many trials undertaken with positive results and substantial progress for better treatments vs heart disease. Both Marios and I remain optimistic that we are a long way from maxing out, as you’ll learn from the podcast. Heart disease is the number one global killer, for both men and women. That’s despite all the progress that has been made to date. Thanks for your support of Ground Truths and to Dr. Julie Kellogg, Vau Geha, Ralph Horwitz, Jessica Coffman, Michael G. Levin, MD, and mopre than 400 others for tuning into my live video with Marios Georgakis! ********************************** Ground Truths has 215,000 subscribers from every US state and 214 countries. There are over 310,000 followers of Ground Truths so nearly 100,000 folks who can easily convert to be free subscribers. Please consider doing that…it’s free. 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! The proceeds from all voluntary paid subscriptions go to support our summer internship program. It enabled us to accept and support a record number of 62 summer interns that joined us 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! Get full access to Ground Truths at erictopol.substack.com/subscribe

This podcast is meant to complement my recent Ground Truths post Why Our Memory Slips After Age 50 which has all the relevant links to the 2 papers, key graphics, and other related publications. If you haven’t had a chance to read that, it would be helpful to spend a few minutes to do so before listening to this podcast. Links to the 2 papers for those who don’t want to look back Zemke et al in Science https://www.science.org/doi/10.1126/science.adt8307 Belk et al in Nature https://www.nature.com/articles/s41586-026-10939-0 It’s a major and fascinating discovery. We’re talking about a “hostile takeover” of blood monocyte cells that invade the brain and ultimately completely replace the brain microglia. The problem is these new microglia are pro-inflammatory. A surprising finding is about CHIP (blood stem cells with mutations known as clonal hematopoiesis of indeterminate potential) that was shown to be protective. It’s surprising because CHIP is common with age and until now it has been linked to bad things such as cardiovascular disease, clotting, and cancer. If this pans out, it introduces the concept of immunotherapy of the blood (“brain immunotherapy”). We discussed recent studies of microglia replacement and ways to keep our brain microglia intact, such as prevention any breakdown of the blood brain barrier. The role of latent viruses and the mechanism of benefit of the Shingles vaccine were touched on. Our conversation provides far more color and perspective about why their independent, complementary, and convergent findings are so important, debunking our longstanding belief that the microglia, the immune cells in the brain, are exclusively derived from the brain. Technology driven discovery. And what are the next steps in this line of research. I hope you found this podcast illuminating and fun. If you did, plus share it with your network. Thanks for supporting Ground Truths and your help in spreading the word. And thank to jojofinance, Elisabetta Pilotti, Daniel Rench, Dr. Sara Wolfson, Bob Fleischman, and hundreds of others for tuning into the live video with Julia Belk and Nathan Zemke! Join me for my next live video in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe

Deb Cohen is an award winning investigative journalist and correspondent who trained as a physician and has worked with the BBC and BMJ. She just published BAD INFLUENCE, a book which takes us deep into the wellness-industrial complex—the confluence of the supplement, testing, tech, and pharma industries, and how they sell health anxiety to healthy people. Here are some of the points we discussed: —The big market in healthy, well people. Tests, wearables, imaging, supplements, etc —Algorithms feed the health anxiety in an amplifying, vicious loop on the social media platforms. When the algorithm knows you better than you. —The special qualities of influencers, likable, relatable, vulnerable, appearance as friends, certainty, cultivating parasocial relationships. “I understand you, I see you, I hear you.” Often with financial conflicts of interest. Plus hidden financial benefits. —The inverted pyramid of evidence and displacement of trust. Anecdotes believed and accepted as best evidence instead of rigorous randomized trials. A big flip, doctors losing trust to influencers and the sponsors of influencers. —The Nocebo effect of harm through expectations —The epidemic of neurologic tics during the pandemic traced back to TikTok, a viral contagion with 5.8 billion views (Figure made with Notebook LM) —Potential for regulation of patient/consumers/prosumer influencers —Celebrity influencers and the recent NEJM paper —Many ideas for how we can mitigate this mess (Graphic by Notebook LM) —Many illuminating patient examples: Femtech, silicon breast implant illness (BII), beta blocker experiment, a bogus bioresonance of hair test in a woman with GI symptoms, full-body MRI of brain lesions (transmitted to the patient by an automated message) that were a false positive. —The term “wellness” —Concierge physicians Thank you jojofinance, Vote Against Billionaires, Gretchen Faucett, Mary Powers, Jessica Coffman, and hundreds of others for tuning into my live video with Bad Influence! Join me for my next live video in the app. Ground Truths has subscribers from every US state and 214 countries. There are over 302,000 followers of Ground Truths so nearly 90,000 folks who can easily convert to be free subscribers. 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! A couple of other things to note: —Thanks to the voluntary paid subscribers who support our summer internship program for high school, college, and grad school students. On August 6th, we had a poster session with our SRTI summer interns (pictured below) which was an extraordinary event with about 100 posters! —I hit a publication milestone that I had not ever envisioned. More than 400,000 citations with an h-index of 259, as tallied by Google Scholar Thanks to all for your support of Ground Truths. Get full access to Ground Truths at erictopol.substack.com/subscribe

Sarah Urbut is a physician-scientist at Harvard Medical School and the Massachusetts General Research Institute. She and her colleagues published a landmark paper in Nature on patient health journeys for 3 different cohorts—the Mass General Brigham patients, the UK Biobank, and the All of Us research program—with a cumulative 683,000 individuals, 348 diseases, and up to 52 years of follow-up. Integrating electronic medical records and polygenic risk scores (N=36). An AI model was developed and validated called ALADYNOULLI, with each individual represented latent disease signatures (N=21), mathematically and biologically driven. An example of a patient’s dynamic life journey (health arc) is provided in the Figure below (adapted from the paper, made with NotebookLM). The longitudinal story for each individual is key here. Using a Gaussian process, the risk continually shifts like a GPS navigation when you make a wrong turn and you are re-routed. Considerable effort was dedicated to addressing selection bias with inverse probability weighting. Here are 20 temporal pattern signatures for the UK Biobank cohort, which help to provide the biologic mechanism of a person’s disease, as shown for multiple conditions like heart attack, breast cancer, and depression. That is, the same disease phenotype can link to different genomic pathway underpinnings. An example for breast cancer could be related to signature 8 or signature 7; the latter tied to inflammation and metabolic abnormalities. This biological pattern could also be used to detect likely medication failure (such as SSRI treatment for depression) and predict rare diseases. In fact, the model was used to discover genomic signatures for different diseases, as shown below. This model predicted 1 and 10-year risk of diseases at the individual level and far surpassed routinely used clinical prediction calculators such as the pooled cohort equation (PCE) for coronary artery disease (0.89 vs 0.68, respectively, 1-year risk ) and the GAIL model for breast cancer (0.783 vs 0.54, respectively). ALADYNOULLI also surpassed accuracy for precision when compared with the recent Delphi-2M model that I wrote about here The ALADYNOULLI paper is packed with information and equations and is not easy to get through without a sophisticated math background. That’s why the summary infographic below (made by Notebook LM) may be helpful to grasp its main findings Prediction of Your Health Trajectory in Context The new model substantively adds to many other recent reports that include Delphi 2M, APOLLO, and AURORA that predict future health events up to 20 years out. Each of these models were different with respect to inputs, how patient data were represented (tokens, embeddings, or latent states), and prediction outputs as briefly summarized in the Table I made below. Notably, the inputs are complementary and likely additive, such that the deeper and longer (longitudinally) the data re for each individual, the better predictive accuracy will be possible. Adding to these models are many specific disease prediction (e.g. cancer, asthma, diabetes, neurodegenerative diseases) and sources of data (such as sleep lab, wearables, or high-throughput proteomics). We are now seeing intense efforts at medical forecasting which will continue to evolve and something that was not previously possible in patient care. What I mean is that we could provide a rough sense of a patient’s risk for, let’s say Alzhiemer’s disease, but could not temporally place when it might occur. Age 65 or 95? It makes a huge difference. And so does the ability to apply counterfactuals, what-if scenarios for the individuals to reduce the risk, markedly defer a condition’s appearance, or even fully prevent it. That’s why ALADYNOULLI adds yet another dimension, different methodology, multiple patient cohorts, and novel findings that further add to a new prediction and prevention dimension of medical practice. It couldn’t have been done with multimodal AI. Note to readers: I wrote this post entirely. There was no AI used except to generate 3 Figures by Notebook LM (Figure 1,3 and 4) as noted. Figure 2 above is from the Supplemental information of the paper. I have no COI related to this post. ****************************** 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. And thank you Harshi Peiris, Ph.D., DOCTOR KLOVER 🍀, William Joseph Turner, Barry R. Davis, Robert Taylor, and hundreds of others for tuning into my live video with Sarah Urbut, MD PhD! Join me for my next live video or newsletter in the app. Get full access to Ground Truths at erictopol.substack.com/subscribe

“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

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

“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

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

Get full access to Ground Truths at erictopol.substack.com/subscribe

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

“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

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

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

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