From First Principles

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1. What Happens When AI Gets a Lab?

   21 oktober 2026 · 1 uur 39 min

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   What happens when AI moves beyond the chatbot and into the laboratory? From Claude-designed proteins that bind scorpion toxins to robots that assemble optics experiments, we examine what AI can do for science and what still has to be proven in the real world.
   Lester Nare and Krishna Choudhary explore the gap between generating a promising design and demonstrating that it works. We also unpack BrainChat, a research platform that lets epilepsy patients interact with their brain-recording data and contribute feedback to seizure detection, and a 15-year study of orangutan mothers facilitating playdates for their young.
   Along the way: why binding a toxin is not the same as neutralizing it, how patient feedback can help personalize models, and what cloud laboratories and automated experiments could mean for scientific discovery. Which part of science do you think AI will change most?
   CHAPTERS
   00:00 Playdates, brain data and robot labs
   00:29 Hello Internet and Signal Award celebration
   02:40 Orangutan mothers and infant playdates
   15:18 What 15 years of orangutan observations reveal
   25:16 Testing the playdate hypothesis
   39:30 BrainChat and patient-guided learning
   44:57 Putting patients in the feedback loop
   1:02:00 Personalizing seizure detection
   1:05:33 What the BrainChat study does not yet establish
   1:07:59 Anthropic scorpion-toxin binders
   1:15:49 Why a toxin binder is not an antivenom
   1:18:31 Fast AI designs, slower laboratory testing
   1:19:40 Connecting AI to the physical lab
   1:23:22 Robotic optics and automated laboratories
   1:28:04 Cloud laboratories and remote experiments
   1:33:00 Closing the loop with Lila Sciences
   1:37:48 Wrap-up
   RESEARCH & FURTHER READING
   Orangutan maternal ranging and infant social play (PNAS):
   https://pubmed.ncbi.nlm.nih.gov/42837467/
   BrainChat and human-AI collaboration in epilepsy (Nature Medicine):
   https://www.nature.com/articles/s41591-026-04680-4
   Claude-designed scorpion-toxin binders (Anthropic):
   https://www.anthropic.com/research/claude-scorp… Lees meer

2. Nobel Prize 2026: The Science Gets Stranger

   16 oktober 2026 · 1 uur 59 min

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   Can light restore aspects of sight? Can recalling a cold experience change an animal's metabolism? And what can ghost particles and mirror-image molecules tell us about the universe?
   Lester Nare and Krishna Choudhary follow up on our 2026 Nobel Prize episodes with research building on optogenetics, IceCube and molecular handedness. We unpack an early human vision-restoration trial, cold-memory experiments in mice, cosmic neutrino flavors, and a tiny electrical sensor for distinguishing left- and right-handed amino acids.
   Plus: how the Nobels work, our follow-up on the Nobel chemistry illustration, a brief look at neutrino Earth tomography, and why fundamental research matters. Which discovery would you like us to explore next?
   CHAPTERS
   00:00 Cold open: memory, neutrinos and mirror molecules
   00:28 Hello Internet and how the Nobels work
   04:32 Optogenetics recap
   10:23 Restoring aspects of vision
   25:43 Controlling movement in worms
   29:31 Cold memories and metabolism
   41:07 Memory, trauma and ethical questions
   45:44 FFP housekeeping
   48:17 IceCube recap
   56:23 Measuring cosmic neutrino flavors
   1:10:30 A brief look at neutrino Earth tomography
   1:12:20 Why fundamental physics matters
   1:26:58 Chemistry and molecular handedness
   1:29:08 Correcting the Nobel illustration
   1:39:30 Measuring chirality in tiny samples
   1:46:42 Testing the sensor on meteorite and desert samples
   1:51:22 Why these questions matter
   1:57:20 Closing thoughts and signoff
   RESEARCH & FURTHER READING
   Optogenetic therapy for visual function (NEJM, 2026):
   https://doi.org/10.1056/NEJMoa2602215
   Cold memories and thermoregulation (Nature, 2025):
   https://doi.org/10.1038/s41586-025-08902-6
   Three-flavor composition of cosmic neutrinos (PRL, 2026):
   https://doi.org/10.1103/vntd-m133
   Chiral discrimination in meteorite and desert soil extracts (Nature Communications, 2026):
   https://doi.org/10.1038/s41467-026-77947-6
   Further reading, briefly mentioned: neutrino Earth tomography (preprint):
   https://arxiv.org/abs/2607.02644
   … Lees meer

3. Nobel Prize in Chemistry 2026 Explained: Mirror Molecules (EP 63)

   8 oktober 2026 · 1 uur 21 min

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   Why does life favor one molecular mirror image? The 2026 Nobel Prize in Chemistry honors Henri B. Kagan and Kenso Soai for nonlinear effects and autocatalysis in asymmetric organic synthesis.
   Lester Nare and Krishna Choudhary unpack the science from first principles: chirality, Pasteur's crystals, enantiomeric excess, and how a tiny imbalance can grow into an overwhelming preference for one molecular hand.
   We connect Kagan's catalyst discoveries and the Soai reaction to medicines, the origins of biological handedness, and the serious concerns around hypothetical mirror life. Plus: symmetry in physics, Frances Oldham Kelsey and thalidomide, and our interpretation of a Nobel illustration.
   CHAPTERS
   00:00 Why life has a molecular handedness
   01:33 Hello Internet
   02:49 The 2026 Chemistry laureates
   06:24 Chirality and mirror-image molecules
   12:10 Pasteur and the history of handedness
   19:36 Why is life's chemistry one-handed?
   24:35 Frank and the origin-of-life puzzle
   29:14 Enantiomeric excess explained
   30:30 Kagan and nonlinear effects
   38:58 FFP and symmetry in physics
   42:20 Soai and asymmetric autocatalysis
   51:28 Why chirality matters for medicine
   58:21 What this does and does not explain about life
   1:00:25 Mirror life and biological risk
   1:10:37 Examining the Nobel illustration
   1:14:10 Recap and Nobel week reflections
   RESEARCH & FURTHER READING
   Original papers and supporting context:
   Frank's model (1953): https://doi.org/10.1016/0006-3002(53)90082-1
   Puchot, Kagan et al. (1986): https://doi.org/10.1021/ja00269a036
   Soai et al. (1995): https://doi.org/10.1038/378767a0
   Sato et al., amplification (2003): https://doi.org/10.1002/anie.200390105
   Mirror-life risks (2024): https://doi.org/10.1126/science.ads9158
   Nobel announcement: https://www.nobelprize.org/prizes/chemistry/2026/press-release/
   EDITORIAL NOTES
   Intro: the 50:50 example describes an unbiased synthesis, not all chemistry. The Soai reaction is a clue to amplification, not proof of how life began.
   On-screen clarificati… Lees meer

4. Nobel Prize in Physics 2026 Explained: IceCube & Neutrinos (EP 62)

   6 oktober 2026 · 1 uur 2 min

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   Why build a telescope inside a billion tons of Antarctic ice? The 2026 Nobel Prize in Physics recognizes Francis Halzen's work on IceCube and the discovery of high-energy neutrinos from the cosmos.
   In Episode 62 of From First Principles, Lester Nare and Krishna Choudhary explain neutrinos from the ground up: why these elusive particles make powerful cosmic messengers, how faint flashes of Cherenkov light reveal their interactions, and why detecting them requires an observatory buried deep beneath the South Pole.
   We follow the path from beta decay and the first neutrino experiments to AMANDA, IceCube's construction, the 2013 astrophysical breakthrough, a distant blazar, and a neutrino map of the Milky Way. Along the way: cosmic rays, the Oh-My-God particle, tracks versus cascades, and the international collaboration behind the discovery.
   CHAPTERS
   00:00 Hunting ghost particles beneath Antarctica
   01:16 Hello Internet and Nobel Prize
   05:30 What are neutrinos?
   10:00 Neutrinos as cosmic messengers
   15:02 The Oh-My-God particle
   16:21 Cosmic-ray energies
   19:07 Cosmic particle accelerators
   22:28 Why look for neutrinos?
   25:52 How to detect a neutrino
   29:23 Cherenkov light
   33:13 Building a neutrino observatory
   37:17 From Antarctic ice to AMANDA
   42:21 Building IceCube
   44:59 Reading tracks and cascades
   49:30 Backgrounds and the 2013 discovery
   52:46 Tracing cosmic neutrino sources
   54:16 Mapping the Milky Way
   58:23 IceCube collaboration and Gen2
   1:01:05 Closing and Nobel week
   RESEARCH & FURTHER READING
   AMANDA in Antarctic ice (2001): https://doi.org/10.1038/35068509
   IceCube detector and instrumentation (2017): https://doi.org/10.1088/1748-0221/12/03/P03012
   First PeV neutrinos (2013): https://doi.org/10.1103/PhysRevLett.111.021103
   Astrophysical neutrino evidence (2013): https://doi.org/10.1126/science.1242856
   Blazar TXS 0506+056 (2018): https://doi.org/10.1126/science.aat1378
   Archival blazar neutrino emission (2018): https://doi.org/10.1126/science.aat2890
   Milky Way neutrino map (2… Lees meer

5. Nobel Prize in Medicine 2026 Explained: Optogenetics (EP 61)

   5 oktober 2026 · 1 uur 11 min

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   How do you prove what a brain cell actually does? The 2026 Nobel Prize in Medicine celebrates a remarkable answer: give cells a light-sensitive protein, then switch their activity on or off with light.
   In Episode 61 of From First Principles, Lester Nare and Krishna Choudhary explain optogenetics from the ground up and trace the discoveries of Peter Hegemann, Georg Nagel and Karl Deisseroth. We follow the story from algae swimming toward light to channelrhodopsins, precisely controlled neurons, and experiments probing memory, reward and behavior. Then we explore heart-brain connections, early attempts to restore vision, and what these experiments can and cannot tell us.
   CHAPTERS
   00:00 The discovery that put brain cells under light control
   02:34 Hello Internet
   03:28 2026 Medicine Nobel and optogenetics
   05:38 Understanding the brain
   08:42 From correlation to causation
   18:13 Controlling neurons with light
   21:25 Early optogenetics and the chARGe system
   24:17 Light-sensitive microbial proteins
   26:26 Algae and phototaxis
   31:42 Discovering channelrhodopsins
   34:42 Nagel and light-gated ion channels
   40:55 Controlling mammalian neurons
   50:19 Expanding the optogenetic toolkit
   56:10 Neural circuits and behavior
   59:02 Memory, reward and reinforcement
   1:02:53 Heart rhythm and emotion
   1:04:02 Beyond the brain and toward medical treatments
   1:06:56 Implications and limits
   1:09:10 Closing and Nobel week
   RESEARCH & FURTHER READING
   Full paper list: https://ffppod.com/episodes/ep61
   Nobel Prize announcement and background:
   https://www.nobelprize.org/prizes/medicine/2026/summary/
   Optical control of neurons: https://doi.org/10.1038/nn1525
   Memory recall in mice: https://doi.org/10.1038/nature11028
   Partial visual recovery: https://doi.org/10.1038/s41591-021-01351-4
   EDITORIAL NOTES
   On-screen clarifications are included at these timestamps:
   13:46 The Jennifer Aniston neuron was recorded in human patients. Selective firing alone did not establish that it causes recognition.
   30:34 Vertebrate rho… Lees meer

6. 2026 Nobel Prize Predictions: Medicine, Physics & Chemistry (EP 60)

   3 oktober 2026 · 41 min

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   Who could win the 2026 Nobel Prizes? From the science behind Ozempic to quantum interference and droplets inside living cells, Lester Nare and Krishna Choudhary make their picks for Medicine, Physics and Chemistry, and explain the discoveries behind them.
   In Episode 60 of From First Principles, we explore seven research areas with a case for Nobel recognition: GLP-1, optogenetics, optical coherence tomography, the Aharonov–Bohm effect, atomic force microscopy, biomolecular condensates and Buchwald–Hartwig coupling. We also discuss Michael Berry’s geometric phase and the awkward question of how a prize limited to three people recognizes discoveries built by larger teams.
   These are our predictions, recorded before the 2026 announcements. Medicine, Physics and Chemistry will be announced October 5–7. Which discovery, and which researchers, would you pick? Tell us in the comments, then join us for our Nobel week breakdowns.
   CHAPTERS
   00:00 The science that could win a Nobel Prize
   00:57 Hello Internet: our 2026 predictions
   02:03 Medicine: GLP-1 and the science behind Ozempic
   07:41 Medicine: optogenetics and controlling neurons with light
   13:16 Medicine: optical coherence tomography
   16:28 Golden Goose Awards and FFP updates
   18:39 Physics: the Aharonov–Bohm effect and geometric phase
   27:37 Physics: atomic force microscopy
   32:04 Chemistry: biomolecular condensates
   36:36 Chemistry: Buchwald–Hartwig coupling
   38:42 Your predictions and our Nobel week plans
   RESEARCH & FURTHER READING
   Foundational papers and background for the discoveries discussed:
   GLP-1: Mojsov, Weir & Habener (1987)
   https://doi.org/10.1172/JCI112855
   Optogenetics: Boyden et al. (2005)
   https://doi.org/10.1038/nn1525
   Optical coherence tomography: Huang et al. (1991)
   https://doi.org/10.1126/science.1957169
   Aharonov–Bohm effect (1959)
   https://doi.org/10.1103/PhysRev.115.485
   Berry’s geometric phase (1984)
   https://doi.org/10.1098/rspa.1984.0023
   Atomic force microscopy: Binnig, Quate & Gerber (1986)
   https://doi.org/1… Lees meer

7. Golden Goose Awards 2026: The Science Behind the Winners (Part 1) (EP 59)

   29 september 2026 · 2 uur 7 min

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   What connects a noise complaint, holiday lights seen from space, and the physics of a coffee stain? Three unexpected paths from basic research to discoveries with real-world impact.
   Krishna Choudhary and Lester Nare explore the science behind the 2026 Golden Goose Awards: Zhen Xu's work on histotripsy, NASA's Black Marble nighttime satellite data, and Sidney Nagel's discoveries in soft matter physics.
   We start with focused ultrasound and the tiny bubbles that can break apart targeted tissue, tracing the journey from early laboratory experiments to clinical research on liver tumors. Then we look at how Earth's nighttime lights reveal power outages, disaster recovery, and changing human activity. Finally, falling drops, coffee stains, and jammed grains open up a world of robotic grippers and materials that can be trained and retrained.
   The thread connecting all three stories is the unexpected value of federally funded basic research. Part 2 will feature conversations with the award-winning researchers and AAAS CEO Sudip Parikh.
   CHAPTERS
   00:00 Golden Goose Awards trailer
   01:19 Introducing our Golden Goose special
   02:42 Zhen Xu: From a noise complaint to histotripsy
   05:57 The early ultrasound experiments
   13:42 Controlling cavitation with microtripsy
   20:29 Tumor destruction and the immune response
   28:33 Histotripsy through the skull
   37:23 The HOPE4LIVER clinical trial
   43:55 Why basic research needs time
   47:17 FFP updates and supporting the show
   49:20 NASA Black Marble: Holiday lights from space
   55:29 Turning night lights into reliable data
   1:01:36 Hurricane Maria and unequal recovery
   1:08:12 COVID-19 and changing nighttime activity
   1:10:16 Mapping access to electricity
   1:15:20 Where Earth is brightening and dimming
   1:32:57 Sidney Nagel and the physics of everyday life
   1:37:07 The science of a falling drop
   1:46:02 Why coffee leaves a ring
   1:51:04 Jamming: When grains become rigid
   1:53:35 A robotic gripper filled with grains
   1:55:39 Why air pressure changes a splash
   1:58:… Lees meer

8. What OpenAI Actually Did to Navier-Stokes (EP 58)

   24 september 2026 · 4 uur 9 min

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   What does it mean to solve an equation that describes almost every fluid around us, from the air over a wing to the water swirling down a drain?
   In Episode 58 of From First Principles, Lester Nare and Krishna Choudhary build the Navier-Stokes equations from the ground up before digging into OpenAI’s claimed breakthrough and the debate surrounding it.
   Summary
   How Newton’s laws become equations for a moving fluid
   Velocity fields, incompressibility, pressure and the nonlinear convective term
   Why viscosity smooths a fluid while nonlinear motion can create finer structure
   What finite-time blowup means, and why simulation is different from proof
   How forced and unforced equations differ, and why those assumptions matter
   Earlier work on Euler, Boussinesq and related fluid equations
   OpenAI’s claimed result, Lean verification and the scope of the theorem
   The dispute over scientific credit and the human research behind AI-assisted work
   The METR investigation of the Hugging Face incident
   Emergence World and long-running multi-agent experiments
   AI-assisted biological discovery, oversight and recursive self-improvement
   Separating demonstrated capabilities from claims and future scenarios
   Chapters
   00:00 Can AI solve Navier-Stokes?
   00:34 Episode introduction
   02:20 Navier-Stokes: Mathematics Meets AI
   10:20 Building the Equations of Fluid Motion
   21:34 Velocity fields, divergence and incompressibility
   34:33 Acceleration and the convective term
   52:18 Why Fluid Motion Is Nonlinear
   1:02:08 Pressure, Euler and the Missing Physics
   1:14:50 How Viscosity Changes Everything
   1:33:36 Solving Equations vs. Simulating Fluids
   1:44:59 Can a Smooth Fluid Blow Up?
   2:13:52 The Road to the Claimed Breakthrough
   2:31:13 Inside the Claimed Navier-Stokes Proof
   2:48:26 The Dispute Over Scientific Credit
   3:07:23 From Chatbots to Agents
   3:08:57 The METR report and Hugging Face incident
   3:23:23 AI Risk, Oversight and the Race Ahead
   3:38:51 AI Discovery Beyond Mathematics
   3:52:47 Why “just turn it off” gets co… Lees meer

9. What’s Next in Science? Nobel Prizes, Space Missions & More (EP 57)

   14 september 2026 · 1 uur 4 min

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   What science should you be watching this fall? From Nobel Prize season to NASA’s Roman Space Telescope, Mars’ moons and Mercury, Lester Nare and Krishna Choudhary take a relaxed tour of the discoveries and missions on their radar.
   In Episode 57 of From First Principles, we explore why curiosity-driven research matters, what the Golden Goose Awards celebrate, and how questions that once sounded impractical can lead to unexpected breakthroughs. Then we turn to space: Roman’s search for dark energy and exoplanets, JAXA’s Martian Moons eXploration (MMX) mission, and the mysteries ESA and JAXA’s BepiColombo mission will investigate at Mercury.
   Along the way, we tour the updated FFP website, revisit some favorite episodes, and ask which stories you want us to cover in depth next.
   A note before we begin: the main conversation was recorded before Labor Day weekend. The opening announcement addresses your requests for a separate episode on OpenAI, Navier–Stokes and the wider AI conversation. This episode is our fall science rundown; that deep dive is still to come.
   CHAPTERS
   00:00 Update on our upcoming Navier–Stokes and AI coverage
   03:43 Episode intro and football banter
   05:47 FFP intro
   06:01 Nobel Prize season and our coverage plans
   10:45 Golden Goose Awards: why basic research matters
   21:02 FFP website tour and favorite episodes
   42:24 Nancy Grace Roman Space Telescope
   46:20 Microlensing, exoplanets and dark matter
   51:25 MMX: where did Mars’ moons come from?
   54:40 BepiColombo and the mysteries of Mercury
   1:02:17 Your questions, future deep dives and sign-off
   1:05:40 Outro
   SHOW NOTES
   NASA’s Nancy Grace Roman Space Telescope:
   https://science.nasa.gov/mission/roman-space-telescope/
   JAXA’s Martian Moons eXploration (MMX):
   https://www.mmx.jaxa.jp/en/mission/
   ESA / JAXA BepiColombo:
   https://www.esa.int/Science_Exploration/Space_Science/BepiColombo
   Explore the research and episodes we cover:
   https://ffppod.com
   Science R&D Funding Tracker:
   https://ffppod.com/funding
   Science Transf… Lees meer

10. The Yak Mutation That Could Help Repair the Brain (EP 56)

    7 september 2026 · 1 uur 36 min

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    What can a yak living thousands of meters above sea level teach us about repairing the human brain?
    In Episode 56 of From First Principles, Lester Nare and Krishna Choudhary break down a new Neuron paper that traces an evolutionary adaptation found in high-altitude animals to a previously hidden pathway involved in building and repairing myelin.
    Summary
    What myelin actually does and why losing it disrupts neural communication
    How multiple sclerosis damages myelin and why the brain’s natural repair process eventually fails
    Why oligodendrocyte precursor cells can remain present in damaged tissue without successfully rebuilding myelin
    Why current therapies are better at slowing further damage than restoring what has already been lost
    The challenge of getting drugs across the blood-brain barrier while maintaining target specificity
    How evolutionary pharmacology has previously produced medicines from adaptations found in snakes and Gila monsters
    The RETSAT Q247R variant identified in animals adapted to the hypoxic environment of the Tibetan Plateau
    How researchers engineered the high-altitude variant into mice and tested its effect on myelin
    The surprising discovery that neurons — rather than the myelin-producing cells themselves — generate the key repair signal
    How RETSAT increases ATDR, which neurons convert into ATDRA
    How ATDRA activates RXR-γ in oligodendrocyte precursor cells and promotes their differentiation
    How administration of ATDR promoted remyelination across multiple preclinical models
    Why the result is scientifically promising but still far from a proven human treatment
    Featured Paper
    A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathway
    Neuron, 2026
    DOI: 10.1016/j.neuron.2026.01.013
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