From First Principles

New Rules For Heredity (Non-Mendelian Inheritance of Epigenetics) (EP 44)

Hosted by Lester Nare and Krishna Choudhary, this episode marks Krishna’s return to the studio after paternity leave — and the timing could not be more fitting. Today’s deep dive is about inheritance: not just the classic Mendelian rules most of us learned in biology class, but the stranger, more dynamic world of non-Mendelian epigenetic inheritance. Starting from Gregor Mendel and his pea plants, Lester and Krishna rebuild the foundations of genetics from first principles: dominant and recessive alleles, Punnett squares, chromosomes, fruit flies, DNA, and the physical mechanism behind inherited traits. Then they move into the “software layer” of biology: epigenetics, DNA methylation, chromatin packaging, RNA interference, and paramutation — cases where the genetic code is present, but the cell’s machinery silences or rewrites how that code is used. The episode centers on a new Nature Genetics paper, “Non-Mendelian inheritance of DNA methylation patterns in mice,” which suggests that non-Mendelian epigenetic inheritance may be more widespread in mammals than previously understood. The conversation also covers why Oxford Nanopore sequencing made this kind of analysis possible, why methylation patterns can be hard to trace across generations, and what all of this could mean for disease risk, drug response, sex differences, evolution, and the long-running nature-versus-nurture debate. Summary Mendel’s rules — how pea plants, true-breeding lines, dominant and recessive traits, and Punnett squares gave us the first mathematical laws of inheritance. The first cracks in Mendel — how chromosomes, fruit flies, sex-linked traits, and linked genes showed that inheritance is more complicated than independent assortment. DNA as hardware, epigenetics as software — why having a gene is not the same thing as expressing it, and how methylation and chromatin packaging can silence parts of the genome. Paramutation — how one allele can change the expression state of another allele across generations, creating inheritance patterns that do not follow standard Mendelian expectations. Oxford Nanopore and the technology shift — why long-read sequencing and direct methylation detection make it possible to trace epigenetic marks back to the parent they came from. The mouse methylation paper — how researchers used collaborative cross mice to show that most methylation inheritance looks Mendelian, but a meaningful fraction appears to follow stranger non-Mendelian rules. Why it matters — potential implications for clinical genetics, disease risk, drug efficacy, sex-specific biology, and the relationship between nature and nurture. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook

Dr. Michael Blanton on Open Data, Galaxy Surveys, and the Future of Astronomy (EP 43)

Hosted by Lester Nare and Krishna Choudhary, this episode is the second interview in our ongoing collaboration series with Carnegie Observatories. Krishna sits down with Dr. Michael Blanton, the new Director of the Carnegie Observatories, for a wide-ranging conversation on how astronomy became one of the most data-rich sciences, how the Sloan Digital Sky Survey helped change the culture around open data, what the next era of astronomical data science and AI could look like, and one of the galaxy mysteries Blanton still wants to solve: why the most massive galaxies in the universe stop forming stars.The conversation starts with Blanton’s Princeton roots and his work connected to the Sloan Digital Sky Survey, then moves into the culture of public astronomical data, the NYU Value-Added Galaxy Catalog, Vera Rubin Observatory, Carnegie’s role in the future of astronomy, the Magellan telescopes, astronomical archives, MaNGA and eBOSS, galaxy formation, dark matter, and even the science behind the black hole visualizations in Interstellar.Audio note: this was one of our first out-of-studio interviews, and there are a few minor audio issues in parts of the conversation. We appreciate your patience, and we’ll be better prepared for future field interviews.Also, if you’re in Los Angeles, Krishna will be giving a talk at Exploring Physics at UCLA, hosted by UCLA’s physics outreach organization Continuum, on Saturday, June 6 at the Fowler Museum. His talk runs from 9:30–10:30 AM.Register here: https://luma.com/3al1hj5h

How Scientists Actually Study Dark Matter (EP 42)

Hosted by Lester Nare, this episode features astrophysicist Dan Gilman for a deep conversation on one of the biggest open questions in modern physics: what dark matter actually is. Starting from first principles, Lester and Dan walk through why the evidence for dark matter is now so strong, how strong gravitational lensing works, why tiny distortions in lensed light can reveal invisible clumps of matter, and how the next generation of surveys may transform the field. Krishna is out on family leave for this one, but the conversation stays fully in the From First Principles lane: grounded, visual, and science-first. Summary What dark matter is — Dan explains the basic case for dark matter, why it appears to interact only through gravity, and why multiple independent observations now point to the same conclusion. How strong gravitational lensing helps — the episode uses intuitive analogies like tides, fish tanks, and flashlights to explain how astronomers can infer the presence and structure of dark matter without seeing it directly. What Dan actually studies — the core of Dan’s work is building and testing simulations of lensed systems to see which dark matter theories best match reality. Why the next few years matter — Rubin, Roman, Euclid, and AI-assisted lens finding could dramatically increase the number of usable lens systems and sharpen the search for dark matter’s fundamental nature. Show Notes Dan Gilman on strong gravitational lensing and dark matter substructure Euclid mission overview Rubin Observatory overview Roman Space Telescope mission context

Dr. John Mulchaey on Carnegie Science and the Future of Astronomy (EP 41)

Hosted by Lester Nare and Krishna Choudhary, this interview features John Mulchaey, the 12th President of Carnegie Science and former Director of the Carnegie Observatories. The conversation starts with his early work on galaxy groups and dark matter, then expands into how Carnegie works as a scientific institution, what the Giant Magellan Telescope could unlock for exoplanets and astronomy, how science funding actually works, and why eclipse chasing is still one of the most magical experiences in science. Summary Galaxy groups and dark matter — Mulchaey explains why small galaxy groups matter more than most people realize, and how X-ray observations of hot gas helped make their masses measurable. Carnegie’s model — the interview gets into what makes Carnegie unusual: scientific freedom, long time horizons, and room to pursue surprising questions. The Giant Magellan Telescope — a look at why bigger telescopes matter, what GMT changes, and why exoplanet atmospheres are one of the biggest goals ahead. The bigger picture — science funding, philanthropy, how astronomy has changed, and why total solar eclipses still inspire so many astronomers. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook Show NotesJohn Mulchaey leadership bio — Carnegie Sciencehttps://carnegiescience.edu/about/leadershipCarnegie Science appoints John Mulchaey as its 12th Presidenthttps://carnegiescience.edu/news/carnegie-science-appoints-john-mulchaey-its-12th-presidentGiant Magellan Telescope — official overviewhttps://giantmagellan.org/about-us/1993 NASA write-up on Mulchaey’s dark matter result in galaxy groupshttps://science.nasa.gov/missions/hubble/dark-matter-found-in-a-typical-cluster-of-galaxies/Carnegie Science Great North American Eclipse outreach recaphttps://carnegiescience.edu/yearbook/2024/science/great-north-american-eclipsePerot Museum eclipse partnership recaphttps://www.perotmuseum.org/events/solar-eclipses/

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Ant Scans, Lunar Chickpeas, Hidden Galaxies & Superconductivity (EP 40)

Hosted by Lester Nare and Krishna Choudhary, this rundown episode covers four new science stories at a high level: a huge new 3D ant imaging database built with synchrotron X-ray microtomography, a lunar agriculture experiment that grew chickpeas in simulated moon soil using fungi and worm waste, AI-assisted discovery of strange objects in the Hubble archive, and a new programmatic roadmap for room-temperature superconductivity. There is also another round of Are You Smarter Than a Scientist? in the middle. Summary Particle accelerators meet biodiversity — researchers built a massive high-resolution ant imaging resource, covering nearly 800 species and thousands of specimens, with AI-assisted 3D reconstruction. Moon farming gets weird — chickpeas were grown in lunar regolith simulant with help from mycorrhizal fungi and worm-derived compost, a first step toward sustainable off-world agriculture. AI found hidden anomalies in Hubble’s archive — AnomalyMatch sifted through roughly 100 million source cutouts in just days and surfaced new candidate lenses, mergers, and other rare objects. The superconductivity long game — a new PNAS perspective argues that room-temperature superconductivity is not ruled out by physics, and calls for a coordinated push to get there. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook Show Notes High-throughput phenomics of global ant biodiversity — Nature Methods Bioremediation of lunar regolith simulant through mycorrhizal fungi and plant symbioses enables chickpea to seed — Scientific Reports Identifying astrophysical anomalies in 99.6 million source cutouts from the Hubble legacy archive using AnomalyMatch — Astronomy & Astrophysics The path to room-temperature superconductivity: A programmatic approach — PNAS

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The Prometheus Constellation: Dramaturgical and Scientific Analysis of the Physicists in Oppenheimer (EP 39)

Hosted by Lester Nare and Krishna Choudhary, this special episode ranks the 26 scientists shown in Christopher Nolan’s Oppenheimer by one standard only: their contribution to fundamental science. Starting with the Manhattan Project figures near the bottom and working up through the giants of quantum mechanics, relativity, nuclear physics, and logic, the episode turns a movie cast list into a surprisingly deep walk through the history of modern physics. Summary A ranking framework that actually means something — this list is based on scientific achievement, not movie prominence, clout, or vibes. A tour of 20th-century science — from nuclear chain reactions and black holes to MRI, GPS, quantum mechanics, and information theory. The great debates — several placements are designed to provoke real argument, especially around how Oppenheimer compares to the physicists around him. A top tier full of monsters — the back half of the episode becomes a speedrun through some of the most influential scientific minds of the modern era. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook

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Harder Than Diamond? The New Hexagonal Diamond Breakthrough (EP 38)

Hosted by Lester Nare and Krishna Choudhary, this episode is a deep dive into one of the strangest and most hard-fought materials science stories in decades: the claim that researchers have finally synthesized bulk hexagonal diamond, also known as lonsdaleite. They break down why this material matters, how it differs from ordinary cubic diamond, why scientists argued about its existence for more than 50 years, and what the new Nature paper actually did to convince skeptical reviewers. Summary Why hexagonal diamond matters — if real, it is a long-sought carbon phase that could be slightly harder than conventional diamond and useful in extreme industrial settings. The first-principles chemistry — carbon allotropes, x-ray crystallography, cubic diamond, and the ABAB stacking that makes hexagonal diamond different. The experimental breakthrough — how the new team engineered around the default pathway to ordinary diamond by controlling graphite orientation and pressure direction. The controversy — why the peer review was intense, and how the new paper relates to an earlier 2025 Nature paper with a similar claim. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook

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Artemis II: Deep Dive on the Moon Flyby, Earthset, and Reentry (EP 37)

Hosted by Lester Nare and Krishna Choudhary, this episode is a full deep dive on Artemis II as the crew returns from humanity’s first crewed lunar flyby in more than 50 years. Lester and Krishna break down the mission photo by photo, from launch and translunar injection to Earthset, Earthrise, the in-space solar eclipse, the science of lunar observations, and the skip-entry reentry profile bringing Orion home. Summary Why Artemis II is historic, what the crew saw on the far side of the Moon, and why this mission matters for the long-term return to the lunar surface.Why NASA relied on the Nikon D5 for deep-space photography, and what camera physics, low-light performance, and radiation tolerance have to do with getting these images home.The standout observations from the flyby: Earthset, Earthrise, a rare in-space solar eclipse, planetary alignment during eclipse, and the first crewed visual observations of meteoroid impact flashes on the Moon.How Orion’s reentry works, why Artemis II uses skip entry, what happened to Artemis I’s heat shield, and what NASA changed for the crewed return. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook

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Artemis II, Claude Code Leak, iPhone Spyware & Project Hail Mary (EP 36)

Hosted by Lester Nare and Krishna Choudhary, this rundown episode covers five new science and tech stories at a high level: NASA’s Artemis 2 moon mission, what actually leaked in the Claude Code incident, a new cancer genomics paper suggesting domesticated cats may be unusually useful real-world models for human cancer, two leaked iPhone spyware toolkits, and a science-focused review of Project Hail Mary. Summary Artemis 2 is finally flying — why this mission matters, why it is not landing yet, and why the moon race is back in geopolitical focus. Claude Code leaked, but not Claude itself — what was exposed, why people got confused, and why the distinction between source code and model weights matters. Cats and cancer — why domesticated cats may offer a more realistic environmental cancer model than traditional lab rodents. iPhone spyware in the wild — what Dark Sword and Coruna are, what they can do, and why this signals a broader shift in cyber risk. Project Hail Mary science review — what the film gets right, what it gets wrong, and which scientific liberties are hardest to buy. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook

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Can AI Help Wake Coma Patients? The Science of Consciousness (EP 35)

Hosted by Lester Nare and Krishna Choudhary, this episode is a deep dive into one of the hardest questions in neuroscience: what breaks in the brain during a coma, and can we figure out how to turn consciousness back on? We unpack a new paper from Daniel Toker et al. that uses an interpretable AI framework — not a generic black box chatbot model — to reverse engineer the biological mechanisms of prolonged unconsciousness, recover known features of coma, predict new ones, and propose a possible new target for deep brain stimulation. Summary Why diagnosis is so hard — disorders of consciousness are not just about whether a patient is awake, but whether awareness is still present even when motor output is gone. The mesocircuit hypothesis — the episode explains how the cortex, thalamus, and basal ganglia may work together like an electrical grid to support consciousness. Interpretable AI, not black-box hype — Daniel Toker’s team built a biophysically grounded model that rediscovered known coma features and predicted two new biological mechanisms. A possible stimulation target — the subthalamic nucleus emerged as a standout candidate for deep brain stimulation, suggesting a new path toward restoring wakefulness. Support the show Donate: FFPod.com/donate Follow: @FFPod on X / Instagram / TikTok / Facebook Show Notes Daniel Toker et al. — Adversarial AI reveals mechanisms and treatments for disorders of consciousness Nicholas Schiff et al. — deep brain stimulation in a minimally conscious patient Adrian Owen et al. — fMRI evidence of covert awareness in a patient diagnosed as vegetative

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AI Cancer Vaccines, Strange Fish, Ketamine, and Ancient Life (EP. 34)

Hosted by Lester Nare and Krishna Choudhary, this episode is a fast-moving science rundown covering four remarkable stories from across AI, genetics, neuroscience, and paleontology. We dig into the story of a machine learning engineer who used AI tools to help design a personalized cancer vaccine for his dog, explore how an all-female fish species has survived far longer than evolutionary theory would predict, unpack new brain-scan evidence for how ketamine may rapidly relieve severe depression, and look at new research suggesting life rebounded shockingly fast after the asteroid that killed the dinosaurs. Summary AI and personalized medicine — a striking case study in how AI tools may help accelerate highly customized treatments, starting with a rescue dog named Rosie. Evolution gets weird — the Amazon molly fish appears to challenge the usual assumptions about why asexual reproduction should fail over long time scales. Why ketamine works so fast — new PET imaging research points to brain-region-specific changes in AMPA receptors in treatment-resistant depression. Life after catastrophe — microscopic plankton may have evolved into new species within just a few thousand years after the Chicxulub impact. Support the showDonate: FFPod.com/donateFollow: @FFPod on X / Instagram / TikTok / Facebook Show Notes AI-designed dog cancer vaccine story https://finance.yahoo.com/news/mans-dog-riddled-tumors-dying-210500037.html?guccounter=1 Amazon molly / gene conversion paper https://www.nature.com/articles/s41586-026-10180-9 Ketamine / AMPA receptor PET imaging paper https://www.nature.com/articles/s41380-026-03510-w Post-asteroid plankton recovery paper https://www.yokohama-cu.ac.jp/english/news/20260306takahashi.html

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Can Human Neurons Really Play Doom? The Science Behind Wetware (EP. 33)

Hosted by Lester Nare and Krishna Choudhary, this episode is a deep dive into one of the strangest science stories of the year: a dish of human neurons allegedly learning to play Doom. We go back to the original 2022 DishBrain paper out of Cortical Labs, unpack how biological neurons can be read and written with multi-electrode arrays, and then compare the peer-reviewed Pong result to the much newer Doom claim. The result is a story that is both genuinely impressive and, in places, probably overhyped. Summary Wetware engineering — replacing artificial neurons with real biological neurons plus electronics, and why some people think this could become a new computing paradigm. How DishBrain worked — human stem-cell-derived cortical neurons grown on a multi-electrode array, trained through sensory encoding and a “minimize surprise” feedback loop. Where the Doom story gets messy — the newer system appears to include a reinforcement-learning layer in the loop, raising the key question: are the neurons actually doing the learning? The big idea underneath the hype — even if Doom is overstated, the broader platform is still a remarkable step toward programmable biocomputing. Support the showDonate: FFPod.com/donateFollow: @FFPod on X / Instagram / TikTok / Facebook

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