Jake Miller

You should be changing your mind about AI at least every 12 months. zou-group.github.io/llm-clai…

We're already at the third point. Walmart only lets third-party agents connect to its retail platform through its own agent, Sparky. This was always the path the largest retail platforms would take. They won't let independent agents intermeditate their relationships with consumers, and they need to retain their advertising revenue. Both Sparky and Alexa for Shopping expose ads in their agents. (Third-party) agentic commerce is a mirage.

Epigenetic aging of kids and adults was accelerated during the Covid pandemic From a prospective longitudinal study pnas.org/doi/epdf/10.1073/pn…

My podcasts are way too long and way too technical. Few people have time to sit through 90 minutes of hardcore immunology! But if there's just one idea to take away from my interview with Jake Glanville at Centivax, a company developing universal flu vaccines and antivenoms, then I think it's this: First, influenza (and many other viruses or pathogens) mutate so rapidly that we keep getting infected by slightly different versions of them. And so the challenge of making a universal flu vaccine is to elicit antibodies that recognize many different strains, including ones that don't yet exist. The normal approach to this problem is just to mix together antigens from many different strains and inject them into humans all together. But your immune system then generates separate antibodies against each antigen, without necessarily producing antibodies that recognize ALL of them. (Imagine a vaccine with 20 different versions of influenza's hemagglutinin protein. Your immune system might make antibodies against version A, others against B, and others against C. But what happens when influenza mutates again, producing version 21? Your body has no antibodies.) What we really want are antibodies that recognize regions of the virus that rarely change! These so-called "conserved epitopes" are more likely to be shared across past, present, and future strains of ther pathogen. So Jake, noticing this problem, invented a thing called conservation–concentration coupling. The gist is that, instead of injecting ALL of the antigens into a human at high doses, you deliberately lower the concentration of each one. There's only a tiny bit of each antigen in the vaccine, in other words; too little to elicit an immune response on its own. (If a B cell comes along and recognizes only antigen A, that B-cell won't become strongly activated!) If, however, a B cell comes along that recognizes some converved region across MANY of the antigens, and it can bind to all of them, then it WILL become activated. Even though each individual antigen is present at a very low concentration, the B cell effectively encounters 20 times as much antigen, or 20x the normal dose. It is stimulated enough to proliferate, while the B cells recognizing only individual strains get "outcompeted." In other words, you're using antigen concentration to bias the immune system toward making broadly reactive antibodies. This is the key idea behind Centivax, and they've gotten really compelling data that this actually works in mice and humans (~180 patients in their phase I, which is now finished.)

If they dared, biohacking bros who seek to defy aging could try a simple, time-tested method: castration. Removing the testicles extends male life span across many mammalian species, including humans. But a research team exploring this effect has now found the surgical procedure doesn’t have to be performed early in life to boost longevity, as scientists had assumed. In a new preprint, the group reports that neutering older male mice lengthens their lives by more than 30%, upending prevailing ideas of how the testes influence aging. Learn more: scim.ag/4eMYMV1

Cancer therapy has genotoxicity, as reflected by mutational signatures. We need to know more about the "genomic afterlife" of people treated with cancer. "For long-term cancer survivors, the biological consequences of treatment do not end after the original cancer is cured." @jclinicalinvest jci.org/articles/view/213544

I've redesigned my personal website You can now play with my face Please don't pull too much. It hurts.

Buckminster Fuller, who was wrong about a lot of things in a way that was usually more interesting than other people being right, noticed something in the 1930s that still holds true. He noticed that technology does not primarily get bigger. It gets thinner. The transatlantic cable got lighter per unit of message. The building got lighter per unit of enclosed volume. The engine got lighter per unit of horsepower. Each generation of a technology tends to accomplish the same function with less stuff, and then with less stuff again, until at the limit the stuff approaches zero and only the function remains. He called this ephemeralization : doing more and more with less and less until eventually you can do everything with nothing. And here were it gets interesting. What got eaten, in the first wave, was objects: my door key became a fingerprint. What's happening today is the second wave: the AI paradigm shift. It’s our thought patterns, our decisions, our generative processes, our creativity, and our communication and coordination with each other that is being ephemerized. And I think judgment abstraction has two consequences. First, the output is not checkable at a lower cost than producing it. To verify a summary you must read the document. To verify a strategic recommendation you must do the strategy. The thing that made calculators safe (verification being orders of magnitude cheaper than generation) simply does not hold for the class of work being absorbed now. Which means verification won't happen because the economics forbid it. A check that costs as much as the work is not a check. It's a second attempt. Second, the stairs are being removed as a consequence of using the lift. The way you stay able to judge a draft is by having written drafts. The capability is maintained by its own exercise and by nothing else. So the fallback and the thing it's a fallback for are the same muscle, and the system that replaces the muscle also stops the training. This is Lisanne Bainbridge's irony of automation, which she wrote down in 1983 and which the aviation industry spent the next forty years rediscovering at great expense: automate the easy 99% and you have designed a job where a human with no recent practice must handle the hardest 1% with no warm-up, at the worst possible moment, on the basis of a mental model the automation has been maintaining on their behalf. Airlines eventually responded by mandating hand-flying. No knowledge-work organization on earth currently mandates hand-thinking.

The year is 1854. Cholera is killing thousands in London. John Snow traces an outbreak to a contaminated water pump. Everyone blames bad air. Eventually cities separate sewage from drinking water. Clean water and sanitation will save more lives than almost anything medicine invents. The year is 1867. Surgery is often more dangerous than the disease it treats. Joseph Lister starts cleaning instruments and wounds with antiseptic. Other surgeons ridicule him. Infections plummet. The year is 1890. Your daughter has diphtheria. A thick membrane is forming in her throat, slowly suffocating her. The doctor injects a new antitoxin. She survives. A disease that killed tens of thousands of children will become almost unheard of in America. The year is 1922. Your 14-year-old son has diabetes. He is starving to death no matter how much he eats. The only treatment is a starvation diet. The doctor injects insulin. His blood sugar falls. Children who would have died within months will grow up and have children. The year is 1943. Your daughter has pneumonia. Before antibiotics, doctors could do little but hope. Now they give her penicillin. The fever breaks. Infections that routinely killed healthy adults become treatable. The year is 1955. Parents are terrified of polio. Swimming pools close. Children become paralyzed. Some spend their lives in iron lungs. Jonas Salk develops a vaccine, tested in more than a million children. Within decades, polio disappears from America. The year is 1960. Your wife is giving birth, and something goes wrong. A century earlier, she might have died. Now there are blood transfusions, antibiotics, safer cesarean sections, and anesthesia. Maternal mortality has fallen dramatically. Millions of women survive childbirth who otherwise wouldn’t have. The year is 1978. Your blood pressure is 180 over 110. You feel fine. The doctor prescribes a pill. Clinical trials show that treating hypertension prevents strokes, heart failure, and death. You take it every morning. Nothing happens. That’s the point. The year is 1980. The WHO declares smallpox eradicated. A disease that killed hundreds of millions in the twentieth century has disappeared from nature. Not treated. Not managed. Eliminated. The year is 1996. Your brother has HIV. A decade earlier, the diagnosis was effectively a death sentence. Now doctors combine antiretroviral drugs. People who had months to live begin living for decades. Many will have near-normal life expectancies. The year is 2014. Your father has hepatitis C. For decades, the infection has meant liver failure and cancer. Now he takes pills for twelve weeks. The virus disappears. A lifelong infection becomes curable in more than 95% of patients. The year is 2019. Your daughter has cystic fibrosis. Her lungs are slowly failing. For decades, treatment meant managing infections and delaying the inevitable. Now doctors have a drug that corrects the underlying protein defect. Her breathing improves. Hospitalizations plummet. Predicted median survival rises from roughly 40 to more than 60 years. The year is 2026. Your doctor has ten minutes and a screen. Your blood pressure is high, so the tablet is for life. Your cholesterol is high, so another tablet is for life. Your weight is high, so she offers an injection. The drugs have side effects. Not everyone needs them. But clinical trials show that appropriate treatment prevents heart attacks, strokes, kidney disease, and death. None of these treatments is perfect. None needs to be. For most of human history, parents buried their children, infections killed healthy adults, and childbirth killed young women. Today, global life expectancy has more than doubled since 1900. Child mortality has collapsed. Medicine has made terrible mistakes. We should remember them. We should also remember the hundreds of millions of people alive because somebody got it right.