Machine Learning Street Talk (MLST)

This episode is sponsored by Notion. Learn more about Notion's Developer Platform today at https://notion.com/mlstProtein folding stalled biology for fifty years. A sequence of amino acids dictates a three-dimensional shape, but reading that shape meant a year and roughly $100,000 of crystallography per structure. Then AlphaFold 2 won CASP14 so decisively the organizers called the problem essentially solved.In this documentary cut, John Jumper, who shared the 2024 Nobel Prize in Chemistry and has since left DeepMind for Anthropic, walks Tim Scarfe through what the system did and, more interestingly, what it did not. The architecture gets a proper dissection: MSAs, the Evoformer, invariant point attention, the FAPE loss, and Jumper's correction of the equivariance story, which ablations valued at roughly 2.5 of 30 GDT points rather than the whole win. He is blunt about the limits. AlphaFold predicts one experiment extraordinarily well; it is not a model of the cell, it does not capture dynamics, and on a given drug target it is "wrong nine times out of ten."From there: the AlphaFold Database of 200M+ predicted structures, AlphaFold 3 and ligands, Isomorphic Labs, and Jumper's quarrel with the bitter lesson, where finite data and human hypotheses still matter. Emmanuel Nji of BioStruct Africa closes the film on what changes when work that took years now takes months, and on training the next thousand structural biologists across Africa.---TIMESTAMPS:00:00:00 Cold open: predicting nature with a button press00:01:03 The protein folding bottleneck and CASP00:04:39 The Nobel, the database, and the move to Anthropic00:05:50 Sponsor (Notion) and framing: what AlphaFold does not claim00:07:39 Proteins as self-assembling nanomachines00:12:24 From structures to biology: drug discovery and Midnolin00:17:37 The humility of AlphaFold: a narrow predictor00:22:18 Inside the architecture: Evoformer, IPA and FAPE00:30:20 Ruthless empiricism: ablations and 100x in data00:35:20 Predict, control, understand00:40:00 Against the bitter lesson; AlphaFold 3 as diffusion00:45:07 Intelligence, representations and AGI00:49:23 Epilogue: AlphaFold in Africa00:52:16 Closing: the case for hybrid science models---REFERENCES:organization:[00:01:55] Critical Assessment of Structure Prediction (CASP)https://predictioncenter.org/[00:04:39] The Nobel Prize in Chemistry 2024https://www.nobelprize.org/prizes/chemistry/2024/summary/[00:05:18] BioStruct Africahttps://www.biostructafrica.org/[00:18:03] Isomorphic Labshttps://www.isomorphiclabs.com/paper:[00:03:09] AlphaFold Protein Structure Databasehttps://doi.org/10.1093/nar/gkab1061[00:17:25] Accurate structure prediction of biomolecular interactions with AlphaFold 3https://www.nature.com/articles/s41586-024-07487-w[00:22:18] Highly accurate protein structure prediction with AlphaFoldhttps://www.nature.com/articles/s41586-021-03819-2[00:23:10] Midnolin promotes degradation of substrates independent of ubiquitinationhttps://doi.org/10.1126/science.adh5021[00:27:00] Improved protein structure prediction using potentials from deep learninghttps://www.nature.com/articles/s41586-019-1923-7tool:[00:03:09] AlphaFold Protein Structure Database (EBI)https://alphafold.ebi.ac.uk/[00:45:55] AlphaEvolve: a coding agent for designing advanced algorithmshttps://deepmind.google/blog/alphaevolve-a-gemini-powered-coding-agent-for-designing-advanced-algorithms/other:[00:39:40] The Bitter Lessonhttp://www.incompleteideas.net/IncIdeas/BitterLesson.html---ReScript: https://app.rescript.info/share/d8cde5c221fb71e2c0f5aafe94f90dfaDisclaimer - not sponsored, editorial with us - we filmed it at GDM, London

Brad Carson was the Army's General Counsel, served two terms in Congress and was Acting Under Secretary of Defense for Personnel and Readiness. He now heads Americans for Responsible Innovation, the AI-policy advocacy group he co-founded. Keith Duggar spends roughly eighty minutes pushing back.

SPONSOR:
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Carson's whole case rests on one line: the genie is not out of the bottle. We have pulled dangerous tech back before. Asilomar halted recombinant DNA in 1975, and the West still controls the chips AI runs on. Calling it unstoppable, he says, is the most dangerous idea in the room.

Then Keith drags him somewhere darker. A Palantir heat map scores you 0.73 on whether you are a combatant, and a strike follows. The model is wrong some accepted share of the time, and when it is, nobody answers for it. You cannot court-martial a model, and not even the interpretability researchers can say why it picked you.

—
Note: after recording, we learned that Americans for Responsible Innovation is backed by EA-aligned philanthropy (not sponsored)

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TIMESTAMPS:
00:00:00 From the Pentagon to AI governance
00:04:52 Regulatory capture vs Silicon Valley networks
00:07:56 Transparency and the Claude tier changes
00:09:40 Tort liability when AI tools cause harm
00:13:40 AI is a product, not a person
00:16:01 Children, suicide, and the suicide business
00:19:59 Opaque neural nets and the law of war
00:25:54 Probabilistic targeting and the death of accountability
00:28:47 The arms race fallacy: Asilomar and restraint
00:34:02 Talking to China: track 2 talks and chip leverage
00:39:45 Air power never wins: capital for labour
00:43:29 Anthropic vs the Department of War
00:51:29 Concentration, open source, and brain drain
01:00:18 DeepSeek, Chinese culture, and AI as diplomacy
01:12:25 Upskilling Congress and why public trust matters

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REFERENCES:
organization:
[00:02:45] ICRC position on autonomous weapons
https://www.icrc.org/en/law-and-policy/autonomous-weapons
[00:05:22] Americans for Responsible Innovation (ARI)
https://ari.us
[00:07:20] Andreessen Horowitz (a16z)
https://a16z.com/
[01:16:05] Office of Technology Assessment
https://en.wikipedia.org/wiki/Office_of_Technology_Assessment
other:
[00:03:35] Beneficial AGI 2019 Conference (Future of Life Institute, Puerto Rico)
https://futureoflife.org/event/beneficial-agi-2019/
[00:18:30] Section 230 of the Communications Decency Act
https://en.wikipedia.org/wiki/Section_230
[00:19:59] Lethal Autonomous Weapons (LAWS)
https://en.wikipedia.org/wiki/Lethal_autonomous_weapon
[00:31:35] Strategic Arms Limitation Talks (SALT)
https://en.wikipedia.org/wiki/Strategic_Arms_Limitation_Talks
[00:32:28] Asilomar Conference on Recombinant DNA (1975)
https://en.wikipedia.org/wiki/Asilomar_Conference_on_Recombinant_DNA
[00:39:45] The New Iron Triangle (ARI policy byte)
https://ari.us/policy-bytes/the-new-iron-triangle/
[00:48:05] Defense Production Act
https://en.wikipedia.org/wiki/Defense_Production_Act
person:
[00:03:35] Anthony Aguirre
https://en.wikipedia.org/wiki/Anthony_Aguirre
[00:06:48] Dean Ball — Hyperdimensional
https://www.hyperdimensional.co/
[00:23:13] Neel Nanda — mechanistic interpretability
https://www.neelnanda.io/
[00:36:02] Jack Clark (Anthropic) on Conversations with Tyler
https://conversationswithtyler.com/episodes/jack-clark/
[00:39:15] Robert Trager — Centre for the Governance of AI
https://www.governance.ai/team/robert-trager
[00:41:55] Giulio Douhet
https://en.wikipedia.org/wiki/Giulio_Douhet
[01:15:05] Don Beyer (US Congress)
https://en.wikipedia.org/wiki/Don_Beyer
tool:
[00:22:19] Phalanx CIWS
https://en.wikipedia.org/wiki/Phalanx_CIWS

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ReScript:
https://app.rescript.info/public/share/9405ff35c0215b7cdae6402d41284171
https://app.rescript.info/api/public/sessions/0a6c081b8e5fe413/pdf

Michael I. Jordan, described by Science magazine as the most influential computer scientist alive, has never thought of himself as an AI researcher. In this conversation he explains why that distinction matters.

SPONSOR:
---
Cyber Fund built the Monastery to help founders ship products that were impossible a year ago. Applications for Batch 1 are now open.
Apply now: https://cyber.fund
---

Jordan trained as a statistician and cognitive scientist, and his career has been spent building machine learning systems that work in the real world: supply chains, commerce, healthcare, and large economic systems. When the field rebranded itself as AI and then AGI, he did not follow. Instead he argues that the framing is wrong. AI is better understood as a collective economic system than as a race to build a disembodied superintelligence.

We talk about why AGI is mostly a PR term, what machine learning achieved before the LLM hype cycle, and why the assistant-on-your-shoulder vision may be less compelling than it sounds. Jordan explains why explanations need to be actionable, not merely mechanistic; why AlphaFold's missing error bars matter; how prediction-powered inference changes the picture; and why drug discovery is an incentive-design problem rather than a pure pattern-matching problem.

ERRATA: Science magazine ranked him the most influential computer scientist, not Nature

---
TIMESTAMPS:
00:00:00 Cold open: A demoralizing message to young builders
00:02:04 CyberFund sponsor read
00:02:50 From symbolic AI to machine learning systems
00:05:42 Why AGI is mostly a PR term
00:08:48 A collectivist, economic perspective on AI
00:11:33 Why LLMs need system design, not hype
00:14:50 Predictability beats faux understanding
00:17:55 AlphaFold, bias, and prediction-powered inference
00:21:48 Stop anthropomorphizing intelligence
00:27:44 Drug discovery as an incentive problem
00:32:29 The three-layer data market
00:38:07 Social knowledge, markets, and culture
00:45:39 Creator economics beyond Spotify
00:48:30 How science-fiction AI narratives mislead young builders
00:51:45 AI should improve humans, not replace them
00:56:42 Safety is a property of the whole system
00:58:12 Silicon Valley gurus and the cream off the top
01:00:47 Game theory, mechanism design, and contracts
01:04:39 Conformal prediction, e-values, and anytime inference
01:08:11 A new liberal arts triangle for the AI era
01:11:30 The Bayesian duck and markets as uncertainty reduction

ReScript (transcript, PDF, refs etc) - https://app.rescript.info/public/share/fb68f94af29d3745c6cf6125e01328b5
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REFERENCES:
person:
[00:02:50] Michael I. Jordan (homepage)
https://people.eecs.berkeley.edu/~jordan/
paper:
[00:06:01] A Collectivist, Economic Perspective on AI
https://arxiv.org/abs/2507.06268
[00:18:09] AlphaFold
https://www.nature.com/articles/s41586-021-03819-2
[00:20:36] Prediction-Powered Inference
https://arxiv.org/abs/2301.09633
[00:33:47] On Three-Layer Data Markets
https://arxiv.org/abs/2402.09697
[01:04:39] Conformal Prediction with Conditional Guarantees
https://arxiv.org/abs/2107.07511
[01:04:51] A Tutorial on Conformal Prediction
https://www.jmlr.org/papers/v9/shafer08a.html
[01:06:00] E-Values Expand the Scope of Conformal Prediction
https://arxiv.org/abs/2503.13050
[01:08:23] Computational Thinking
https://www.cs.cmu.edu/~CompThink/papers/Wing06.pdf
other:
[00:28:20] How Should the FDA Test?
https://rdi.berkeley.edu/events/sbc-assets/pdfs/Summit%20session%20speaker%20slides%20submission%20form-s1-5%20%28File%20responses%29/Slides%20in%20PDF%20%28Please%20name%20the%20submitted%20file%20as%20_firstname_-_lastname_-slides.pdf%29.%20%28File%20responses%29/27-Michael%20Jordan-Session%20V.pdf#page=15
[00:28:40] Michael I. Jordan Session V Slides
<truncated, see ReScript link or YT VD>

Beth Barnes and David Rein on the one graph that ate the AI timelines discourse, and why the two people who built it are the most careful about how you read it.**SPONSOR**Prolific - Quality data. From real people. For faster breakthroughs.https://www.prolific.com/?utm_source=mlstInterview: https://youtu.be/cnxZZTl1tkk---Beth Barnes and David Rein from METR on the one graph that ate the AI timelines discourse, and why the people who built it are the most careful about how it gets read.Beth founded METR after leaving OpenAI alignment. David is first author on GPQA and co-author on HCAST and the METR Time Horizons paper. Together they built the measurement Daniel Kokotajlo called the single most important piece of evidence on AI timelines: the log-linear line of "how long a task a frontier model can complete at 50% reliability" vs release date.The conversation opens on reward hacking. Current models can articulate in chat why a behaviour is undesired and then execute it anyway as agents. From there: construct validity, Melanie Mitchell's four-problem taxonomy, and the ARC-AGI 1-to-2 collapse as a worked example of adversarially-selected benchmarks regressing once labs target them. Beth's counter: METR deliberately does not adversarially select. David's: models do not have to do the right thing for the right reasons.Methodology, then specification — David's compiler analogy, Beth on four-month tasks as expensive to evaluate rather than unspecifiable. Then the SWE-bench reality check, the METR finding that half of passing PRs would not be merged, and Beth's horses-versus-bank-tellers analogy for the labour market.The close: monitorability, the coin-spinning boat, two-year recursive self-improvement, and Beth's line that "overhyped now" and "big deal later" are not correlated claims.---TIMESTAMPS:00:00:00 Intro00:02:06 Sponsor break: Prolific human-feedback infrastructure00:02:33 Welcome and the scalable oversight motivation00:06:02 Construct validity, benchmark pathologies and the Chollet worry00:15:45 Time Horizons: human time, HCAST tasks and the 50% logistic00:24:50 Is human difficulty really one variable?00:33:05 Agent harness evolution and the inference-compute dividend00:40:00 Scaffolding bells, token budgets and the credit-assignment problem00:44:15 Look at the damn graph: regularisation bug and reliability nuance00:50:00 Why 50%? Reliability, reward hacking and pizza-party transcripts00:55:20 Extrapolation risk and straight lines on graphs00:59:25 Software engineering as a specification acquisition problem01:07:40 Compilers also made ugly code: vibe-coding quality and Claude on METR Slack01:15:15 Strongest defensible claim, Carlini's compiler swarm and AI 202701:23:45 SWE-bench merge rates, the bank-teller analogy and horses01:31:45 Scheming, alignment faking and the mentalistic vocabulary problem01:40:45 Reward hacking, monitorability and chain-of-thought faithfulness01:45:25 Recursive self-improvement, knowledge vs intelligence and closing
ReScript: https://app.rescript.info/public/share/de3bb40cc02ee39fdf36e2c60366eb4d
(PDF, refs, transcript etc)

Robert Lange, founding researcher at Sakana AI, joins Tim to discuss *Shinka Evolve* — a framework that combines LLMs with evolutionary algorithms to do open-ended program search. The core claim: systems like AlphaEvolve can optimize solutions to fixed problems, but real scientific progress requires co-evolving the problems themselves.

GTC is coming, the premier AI conference, great opportunity to learn about AI. NVIDIA and partners will showcase breakthroughs in physical AI, AI factories, agentic AI, and inference, exploring the next wave of AI innovation for developers and researchers. Register for virtual GTC for free, using my link and win NVIDIA DGX Spark (https://nvda.ws/4qQ0LMg)

• Why AlphaEvolve gets stuck — it needs a human to hand it the right problem. Shinka tries to invent new problems automatically, drawing on ideas from POET, PowerPlay, and MAP-Elites quality-diversity search.

• The *architecture* of Shinka: an archive of programs organized as islands, LLMs used as mutation operators, and a UCB bandit that adaptively selects between frontier models (GPT-5, Sonnet 4.5, Gemini) mid-run. The credit-assignment problem across models turns out to be genuinely hard.

• Concrete results — state-of-the-art circle packing with dramatically fewer evaluations, second place in an AtCoder competitive programming challenge, evolved load-balancing loss functions for mixture-of-experts models, and agent scaffolds for AIME math benchmarks.

• Are these systems actually thinking outside the box, or are they parasitic on their starting conditions? When LLMs run autonomously, "nothing interesting happens." Robert pushes back with the stepping-stone argument — evolution doesn't need to extrapolate, just recombine usefully.

• The AI Scientist question: can automated research pipelines produce real science, or just workshop-level slop that passes surface-level review? Robert is honest that the current version is more co-pilot than autonomous researcher.

• Where this lands in 5-20 years — Robert's prediction that scientific research will be fundamentally transformed, and Tim's thought experiment about alien mathematical artifacts that no human could have conceived.

Robert Lange: https://roberttlange.com/

---
TIMESTAMPS:
00:00:00 Introduction: Robert Lange, Sakana AI and Shinka Evolve
00:04:15 AlphaEvolve's Blind Spot: Co-Evolving Problems with Solutions
00:09:05 Unknown Unknowns, POET, and Auto-Curricula for AI Science
00:14:20 MAP-Elites and Quality-Diversity: Shinka's Evolutionary Architecture
00:28:00 UCB Bandits, Mutations and the Vibe Research Vision
00:40:00 Scaling Shinka: Meta-Evolution, Democratisation and the Three-Axis Model
00:47:10 Applications, ARC-AGI and the Future of Work
00:57:00 The AI Scientist and the Human Co-Pilot: Who Steers the Search?
01:06:00 AI Scientist v2, Slop Critique and the Future of Scientific Publishing

---
REFERENCES:
paper:
[00:03:30] ShinkaEvolve: Towards Open-Ended And Sample-Efficient Program Evolution
https://arxiv.org/abs/2509.19349
[00:04:15] AlphaEvolve: A Coding Agent for Scientific and Algorithmic Discovery
https://arxiv.org/abs/2506.13131
[00:06:30] Darwin Godel Machine: Open-Ended Evolution of Self-Improving Agents
https://arxiv.org/abs/2505.22954
[00:09:05] Paired Open-Ended Trailblazer (POET)
https://arxiv.org/abs/1901.01753
[00:10:00] PowerPlay: Training an Increasingly General Problem Solver by Continually Searching for the Simplest Still Unsolvable Problem
https://arxiv.org/abs/1112.5309
[00:10:40] Automated Capability Discovery via Foundation Model Self-Exploration
https://arxiv.org/abs/2502.07577
[00:15:30] Illuminating Search Spaces by Mapping Elites (MAP-Elites)
https://arxiv.org/abs/1504.04909
[00:47:10] Automated Design of Agentic Systems (ADAS)
https://arxiv.org/abs/2408.08435
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PDF : https://app.rescript.info/api/sessions/b8a9dcf60623657c/pdf/download
Transcript: https://app.rescript.info/public/share/SDOD_3oXOcli3zTqcAtR8eibT5U3gam84oo4KRtI-Vk