At Los Alamos in the early 1950s, Enrico Fermi, John Pasta and Stanislaw Ulam - with Mary Tsingou coding it on the MANIAC - modeled a simple chain of masses and springs with a touch of nonlinearity. Statistical mechanics said that energy poured into one mode of vibration would spread out and equilibrate across all the others. Thermalization was the obvious answer. Instead, the energy unpredictably sloshed into a handful of modes and then astonishingly came flooding back, reconstituting the original state almost perfectly. Then it did it again. This is the Fermi–Pasta–Ulam–Tsingou recurrence. It was the first computational demonstration of unpredictable chaos and non-linear dynamics (before Edward Lorenz's more famous one later), and it upended a lot of intuition about how nonlinear systems reach equilibrium. It helped launch soliton theory and the modern study of nonlinear dynamics. Mary Tsingou wrote the program that produced the result. Her name went missing from the story for nearly fifty years. I built an interactive version with Claude Code so you can watch it happen: pick a force law - linear, quadratic, cubic, quintic or inverse - and see the energy wander and return, as a live 2D plot or a colorful 3D surface (especially mesmerizing at low speeds). Overlay a linear "ghost" and watch the nonlinear chain peel away from the boring standing wave. Enjoy! Play with it here: ajogalekar.github.io/fput #physics #nonlineardynamics #computation #appliedmathematics

And Opus 5.5 won’t tell me the lengths of amino acid sequences I designed with *Claude* I have the sequences already! Do you think not telling me the lengths will prevent human extinction?!??!????????

People are asking how AI companies will discover the next breakthrough drug. I think they're asking the wrong question. Generating molecules is a commodity. The limiting factor is no longer the ability to create hypotheses. It's the ability to test them in the real world.

Born #OTD 1866: Thomas Hunt Morgan, the American biologist whose work with fruit flies helped establish that genes are carried on chromosomes. Morgan and his students connected inherited traits to particular chromosomes, discovered genetic linkage and recombination, and showed that genes occupy ordered positions. This gave heredity a physical map and helped make genetics an experimental science. He received the 1933 Nobel Prize in Physiology or Medicine. Morgan began as a skeptic of Mendelian genetics and the chromosome theory. After two unproductive years breeding Drosophila, he called the effort “two years’ work wasted.” Then a white-eyed male appeared among the usual red-eyed flies. Following that result led him to sex-linked inheritance and helped overturn his own skepticism.

Indeed. This is something that chemists and physicists like us take for granted right from the beginning as if it were the most obvious thing, and yet it's amazing if we think about it.

Edward Teller: "I very clearly claim that I got my Doctor's degree because I did not let Heisenberg sleep" “All right", says Heisenberg, "that is the lower state of the hydrogen molecule ion, and you say it's correct. Now calculate all the other states." That was the origin of my PhD thesis: "The energy states of the hydrogen molecular ion". I can tell you, I couldn't do it. Nobody else did. Not in the form of definite known formulae. I could do it numerically, using a computing machine. Well, you know, what am I talking about? I am talking about the year 1929. The computing machines were sizable. They had a handle which you could turn and if you turned the handle, you made a lot of noise and you got one number out of it. In the meantime, as you all know, the computers made a little progress. But there I was, you know, not liking to get up early in the morning, I got in late. Each night I was turning the handle and got more and more of the excited states of the hydrogen molecular ion. Now, all this is relevant, because Heisenberg, at that time unmarried, tried, not always effectively, not always successfully, to sleep in the room right above the one where I turned the machine. So I noticed - I did not know it at that time - but I noticed that Heisenberg would come down and started to chat with me. And those were very amusing, very interesting conversations. I remember one when I had to contradict Heisenberg. He said- Now everything is done in physics, what will I do next? I sort of said, not quite in these words- Damn it, aren't you satisfied? And he said to that, very explicitly- No. I think I'll go into music. Well, on another occasion, he came down and asked- When we will be through? I said- I think in one or two years I could finish it. Heisenberg said- I really think you have done enough. I think these are nice results. Just write them up and it will make a good thesis. Now look, I very clearly claim that I got my Doctor's degree because I did not let Heisenberg sleep.” piped.video/watch?v=hPLf1DkU…

In an interview, Freeman Dyson characteristically offered one of the clearest analyses I have read of whether dropping the bombs on Hiroshima and Nagasaki caused the Japanese to surrender, and whether Truman did the right or wrong thing. As he notes, the two questions are very different and often conflated: "It is clear that the Japanese surrender was caused primarily by the Russian invasion and not the bombs - ninety percent to ten percent, perhaps." Dyson: "There are two totally different questions here, which are often confused in the public mind. It is very important to separate them. The first is: what actually happened in Japan? Why did the Japanese surrender? Did it have anything to do with the nuclear bombs? That’s one question. It’s a very important question, but it should be kept separate from the second: what did it look like to Truman? How much information did Truman actually have about what was going on in Japan? When he made the decision to drop the bombs, was that justifiable or not? That’s a totally separate question, because Truman actually had very little information. His decision wasn’t governed by what was really happening in Japan—it was governed by what he knew, which is a very different thing. From the Japanese point of view, their whole strategy in the late stages of the war was to secure a reasonably advantageous peace. By 1945, they knew they could not win; they were never going to conquer the United States. But they hoped to reach a peace treaty that would leave them with some possessions and a politically acceptable outcome. Their strategy depended heavily on Russia. As historian Tsuyoshi Hasegawa shows in Racing the Enemy, Japanese discussions made it clear: the plan was to end the war on advantageous terms with Russian help. It was vital that Russia remained neutral, since Russia had influence with the United States and was still in alliance with them while the war in Europe continued. The Japanese strategy was therefore to use the Russians to negotiate peace with America, while in the meantime fighting a defensive war for as long as possible. The Army was committed to defense to the last man, as in Okinawa, and everyone assumed they would continue fighting that way. This whole strategy collapsed when the Russians declared war on Japan. That happened three days after Hiroshima, followed by the attack on Nagasaki the same afternoon. The sequence was: Hiroshima, then the Russian declaration of war, then Nagasaki. When Hiroshima was bombed, the Japanese Supreme Council—which included about ten people, mostly military and the Emperor—did not even convene a meeting; they did not take Hiroshima seriously. The evidence is clear that Hiroshima had little effect. But three days later, after the Russians declared war, the Supreme Council met within six hours. Everyone recognized that the strategy had collapsed. They could no longer rely on Russia for peace negotiations and now faced the danger of a Russian invasion from the north while fighting Americans in the south. The entire strategy fell apart that morning, and that was the day they decided to surrender. It is clear that the Japanese surrender was caused primarily by the Russian invasion and not the bombs—ninety percent to ten percent, perhaps. Nagasaki occurred the same day but came too late to influence the decision. Now, the other question: Truman’s point of view. Truman knew that part of the Japanese government wanted peace, but he also knew that the Army was determined never to surrender. For the Army, surrender was totally dishonorable. That was a serious consideration for Truman, because it meant the Japanese were likely to fight on no matter what. If the U.S. had to invade Japan and fight street by street in Tokyo, the cost would have been enormous. Okinawa had shown how tough the Japanese were, and they would likely be even tougher defending their homeland. Estimates suggested as many as a million American soldiers might die. Truman saw the choice as either dropping the bombs, in hopes of shocking Japan into surrender, or invading and suffering massive losses. Given that framing, dropping the bombs seemed the sensible option. Japanese attempts at peace were not very clear. A faction in the Foreign Office wanted to negotiate, but the Army was uninterested. Truman was justified in what he did, and in fact, it is questionable whether he could have decided otherwise. Bureaucratic inertia also played a role: the bombing campaign had already been underway for months with massive destruction of Japanese cities. Stopping suddenly and refusing to use a new weapon would have been politically very difficult. Truman might even have been impeached had he refused to use the bombs. The power of a president depends on the consent of the military and political establishment, and if most had opposed him, he might not have been able to resist. So, the answers to the two questions seem contradictory. On the one hand, the bombs did not in fact cause Japan’s surrender. On the other hand, Truman believed they would, so he was justified in dropping them. It’s an ironic conclusion, but probably correct."

Amazing. For all the noise about American greed and obsession with making money, we are also the world's biggest philanthropists: an underappreciated fact. nytimes.com/2026/09/23/us/bi…

PSA: Protein design is often about designing distributions, not structures.

This is encouraging. I was the chemistry lead at Strateos, and much of the struggle was in two areas: getting into the hardware and operating it, and having enough throughout, especially on non-standard or complex chemistry, to make the process competitive with CROs. AI is going to make headway into the first problem, especially with innovations like MHP from Anthropic. The second is still a bottleneck that we need to address.

I wish drug discovery were like pure math where, even if the problems can be fiendishly hard, they are bounded and closed with a well-defined solution and can be solved with pen and paper or with a computer. But unfortunately drug discovery (and biology more generally) is not like math. It's not even like physics, as I wrote about many years ago. A good reminder in the age of AI. wavefunction.fieldofscience.…

How it feels to do biotech in 2026

Stan Ulam in "Adventures of a Mathematician", describing the romantic mathematical café culture in Lwów; what I would give to have been a fly on the wall. This is the culture that I am afraid we might lose if math becomes all about machine-generated proofs. And I suspect it's about more than just nostalgia; it's about the soul of doing math. "The tables had white marble tops on which one could write with a pencil, and, more important, from which notes could be easily erased. There would be brief spurts of conversation, a few lines would be written on the table, occasional laughter would come from some of the participants, followed by long periods of silence during which we just drank coffee and stared vacantly at each other. The café clients at neighboring tables must have been puzzled by these strange doings. It is such persistence and habit of concentration which somehow becomes the most important prerequisite for doing genuinely creative mathematical work."

Born #OTD 1898, Australian born British bacteriologist Howard Florey. While Alexander Fleming discovered the mold and its antibacterial properties, Florey and Ernst Chain led the Oxford team that scaled penicillin up and turned it into a practical drug. Their first patient improved rapidly, but supplies were so scarce that they recovered penicillin from his urine; it ran out and he died. However, it's worth mentioning Norman Heatley, a biochemist and member of Florey's team whose work was absolutely critical in the scale-up. As a colleague put it later, "Without Fleming, no Chain or Florey; without Florey, no Heatley; without Heatley, no penicillin." Yet while Fleming, Florey and Ernst Chain jointly received the Nobel Prize for their work in 1945, Heatley did not share it and his contribution was not fully recognized for another 45 years.

Thanks to Vertex and Gilead. Read Barry Werth's "The Antidote" for the story.

This from Murray Gell-Mann is hilarious: “I have to mention something that happened while Art Rosenfeld and I were writing the article. A man came in who said he worked for the government and showed us a badge - he was obviously from the CIA - and he said, ‘Are you Murray Gell-Mann?’ I said, ‘Yes.’ He said, ‘I'd like to talk with you - alone.’ Well, Art Rosenfeld was upset; he went down to the library to work on our article while I was interviewed by this government person who wanted to talk with me alone. And he said, ‘You were recently in Russia?’ I said, ‘Yes’. He said, and he was reading from a piece of paper but he obviously didn't understand what was on the piece of paper, he was some low-level person that didn't know what he was saying, he was just reading from this telegram that he'd got. And he said, ‘You were there and we heard that recently the…’ ...how did this work... ‘recently a prize was awarded, a Stalin prize or Lenin prize, or something of that kind, was awarded for prediction of catalysis of fusion reactions by muons and… and that the work was experimentally confirmed. Now you've visited a lot of Soviet laboratories. Will you tell us in which laboratory this confirmation was carried out?’ And I said, ‘Oh yes, I think I know what you're talking about.’ In the meantime I had wrenched the paper away from him, I wasn't supposed to look at this piece of paper, it was classified or something, but I had–since he was stumbling over it so much—I had wrenched the paper away and read it and then I understood what he was asking, because he didn't understand enough to ask the question intelligibly. I said ‘Oh, I see, you mean this award of a prize for predicting muon catalysis, and the announcement that somewhere in some laboratory this had been confirmed. Well the laboratory was not in the Soviet Union. It was confirmed at Berkeley, at the radiation lab, by the man you just threw out of the room–and his collaborators.’ He didn't see the humor.” piped.video/watch?si=_srm8--…

Every single new model from OpenAI and Anthropic (and older ones like GPT 5.5 and Opus 4.8) gave a refusal for this prompt, citing biological risk: "Create an evidence-grounded protein-engineering blueprint for a soluble human ACE2 decoy that broadly neutralizes SARS-CoV-2 variants and related sarbecoviruses while preserving developability and minimizing physiological risk." This is literally a strategy for neutralizing coronavirus. We've got to do better at discrimination.

George Dyson's "Turing's Cathedral" has one of the best openings of any book I have ever read.