From First Principles

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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Which quantum computer will actually scale?
In Part 2 of our quantum computing deep dive, Lester Nare and Krishna Choudhary move from theory to hardware—comparing superconducting qubits, trapped ions, neutral atoms, and silicon spin qubits before going inside the new Nature cover paper Krishna co-authored with the HRL Quantum Team and collaborators.
The episode begins with a simple question: what makes a good quantum computer? We evaluate each architecture using three criteria: qubit quality, qubit control, and scalability and economics.
Superconducting qubits offer extremely fast operations, but scaling them introduces challenges involving microwave control, frequency crowding, cryogenic wiring, physical size, and cooling. Trapped ions preserve quantum information for extraordinary lengths of time, but their slower gates and increasingly complex optical systems introduce a different set of tradeoffs. Neutral atoms can be arranged in dense, reconfigurable arrays using optical tweezers and entangled through Rydberg interactions, while raising questions involving atom loss, correlated noise, readout, and execution time.
Then we get to silicon.
Beginning with the Loss–DiVincenzo proposal, Krishna explains how individual electron spins can be confined inside semiconductor quantum dots, manipulated through exchange interactions, and measured using single-electron transistors. We then explore exchange-only qubits, where three electron spins encode a single qubit and quantum gates can be performed using electrical control.
That leads to the Nature cover paper, A digitally controlled silicon quantum processing unit. The HRL system integrates 18 encoded qubits built from 54 quantum dots with cryogenic control electronics, a superconducting interconnect, automated calibration, and an engineered silicon-germanium heterostructure.
Krishna also explains his own work using machine learning to automate quantum-device tuning—an essential problem if spin-qubit systems are ever going to grow from dozens of components to millions.
The larger thesis is about manufacturing. The semiconductor industry has spent decades learning how to fabricate silicon devices at enormous scale. If quantum processors can inherit that infrastructure, the architecture that ultimately wins may not be the one that reaches the finish line first—but the one humanity already knows how to manufacture.
Nature paper:A digitally controlled silicon quantum processing unitDOI: 10.1038/s41586-026-10754-7https://www.nature.com/articles/s41586-026-10754-7
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Quantum computers do not simply “try every answer at once.” So what do they actually do—and why have governments and technology companies spent billions trying to build them?
In Part 1 of our two-part quantum computing deep dive, Lester Nare and Krishna Choudhary build the field from first principles.
The series was prompted by a new Nature cover paper, A digitally controlled silicon quantum processing unit, co-authored by Krishna and members of the HRL Quantum Team and collaborators. Before getting into that hardware in Part 2, we first need to understand why anyone wanted to build a quantum computer in the first place.
We begin with Bell’s theorem and the failure of local hidden-variable explanations of quantum mechanics. From there, we follow the realization that information is fundamentally physical through Rolf Landauer, reversible computation, Charles Bennett, Tommaso Toffoli, Paul Benioff, and the origins of quantum information science.
Then Richard Feynman changes the question. Straightforward classical simulation of an interacting quantum system requires tracking a state space that grows exponentially with the number of particles. If nature itself is quantum mechanical, Feynman asks, why not build a computer that is quantum mechanical too?
David Deutsch formalizes the universal quantum computer and introduces the first quantum algorithm. Using the Deutsch–Jozsa problem, the double-slit experiment, and Feynman’s path-integral intuition, we explain what a quantum algorithm is actually exploiting: carefully engineered constructive and destructive interference.
Finally, we reach the discoveries that turned quantum computing from an academic curiosity into a strategic technology. Daniel Simon develops an early exponential quantum speedup. Peter Shor recognizes how the underlying mathematics can be used to attack problems central to public-key cryptography. Lov Grover follows with a quantum search algorithm—and suddenly governments have a very different reason to care about quantum machines.
We also explore quantum money, quantum cryptography, the many-worlds interpretation, Google Willow and parallel-universe headlines, post-quantum security, and what useful quantum computers may ultimately be good for.

Part 2: How do you actually build one?

Nature paper:A digitally controlled silicon quantum processing unitDOI: 10.1038/s41586-026-10754-7
Link: https://www.nature.com/articles/s41586-026-10754-7

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Claude did not solve the Riemann Hypothesis. But what it actually did may be one of the clearest examples yet of how rapidly AI systems are changing the way difficult mathematics can be attacked.
In Episode 53, Lester Nare and Krishna Choudhary go from first principles on arguably the most famous unsolved problem in mathematics.
We begin with Euler and the Basel problem, build the Riemann zeta function from the ground up, explain its deep connection to prime numbers, move into the complex plane and analytic continuation, unpack the famous 1 + 2 + 3 + 4 + … = -1/12 result, and finally arrive at the Riemann Hypothesis itself: the claim that every non-trivial zero of the zeta function lies on the critical line.
Then we get into Claude.
An unreleased Anthropic model was prompted to take a serious run at the problem. It orchestrated roughly 60 autonomous sub-agents, tested hundreds of mathematical approaches, executed code, searched academic literature, challenged its own strategies, created adversarial referees to attack its work, and ultimately produced a result pushing a related mathematical bound well beyond the previous state of the art.
The human behind the prompt was not a mathematician. One of his instructions was essentially: believe in yourself.
We explain what Claude actually accomplished, what it absolutely did not accomplish, why moving a bound toward two-thirds does not mean the Riemann Hypothesis is “two-thirds solved,” and what the process tells us about agentic AI, mathematical research, scientific discovery, and AI safety.
Then it’s transfer season.
For the first FFP Summer Transfer Window for Scientists, we look at prominent researchers leaving American institutions for universities and research centers abroad. Using the language of football transfers, we examine major moves in chemistry, battery research, gravitational-wave astrophysics, and neuroscience—and what they reveal about research funding, immigration, scientific infrastructure, and the global competition for talent.

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In this anniversary episode, Lester Nare and Krishna Choudhary look back at how two longtime friends turned their regular conversations about science into a show now shared by millions of people around the world, and what they hope to build with FFP Nation in Year Two.
Then we turn to a new Nature paper challenging the idea that the precolonial Amazon was sparsely populated. Airborne LiDAR revealed hundreds of geometric earthworks hidden beneath the rainforest canopy. Combining the new survey with earlier archaeological evidence, the researchers estimate that the region could contain more than 20,000 earthworks and may have supported 1.25–3 million people around AD 100–300.
Lester and Krishna explain how LiDAR sees through dense vegetation, why early European accounts of crowded Amazonian settlements were dismissed, how disease and forest regrowth could erase the visible traces of large societies, and what the findings mean for our understanding of the Amazon’s human and environmental history.
The conversation then becomes a thought experiment: if our civilization disappeared, what would future archaeologists—or extraterrestrial visitors—recognize as our pyramids? Apollo landing sites, CERN, LIGO, and the James Webb Space Telescope become candidates for the enduring signatures of a curiosity-driven civilization.
Finally, we christen the From First Principles library. Krishna shares the mathematics, physics, biology, history, and philosophy books that shaped how he thinks, including Baby Rudin, Landau–Lifshitz, Fermi, Jackson, Sakurai, Einstein, Schrödinger, Gibbs, Newton’s Principia, Plato, the Upanishads, and Adam Becker’s What Is Real?

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Research and show notes:
Over 20,000 precolonial earthworks in the Southwest Amazonia
Nature Research Briefing
FFP episode archive and research library