
Show Notes
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
More from Ground Truths
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.
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.”
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.
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.
“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.