Astral Codex Ten Podcast

https://astralcodexten.substack.com/p/book-review-lifespan   [epistemic status: non-expert review of a book on a highly technical subject, sorry. If you are involved in biochemistry or anti-aging, feel free to correct my mistakes] David Sinclair - Harvard professor, celebrity biologist, and author of Lifespan - thinks solving aging will be easy. “Aging is going to be remarkably easy to tackle. Easier than cancer” are his exact words, which is maybe less encouraging than he thinks. There are lots of ways that solving aging could be hard. What if humans worked like cars? To restore an old car, you need to fiddle with hundreds of little parts, individually fixing everything from engine parts to chipping paint. Fixing humans to such a standard would be way beyond current technology. Or what if the DNA damage theory of aging was true? This says that as cells divide (or experience normal wear and tear) they don’t copy their DNA exactly correctly. As you grow older, more and more errors creep in, and your cells become worse and worse at their jobs. If this were true, there’s not much to do either: you’d have to correct the DNA in every cell in the body (using what template? even if you’d saved a copy of your DNA from childhood, how do you get it into all 30 trillion cells?) This is another nonstarter.

https://astralcodexten.substack.com/p/mm-omicron-variant Noah Smith has a good summary of the Omicron evidence here, including a lot of quotes from experts. But experts say a lot of stuff like “well, it could be bad, but we can’t be sure”, plus sometimes they disagree. This is the kind of situation where prediction markets are useful, so let’s look at them. (source: Metaculus) R0 is a measure of how quickly a disease spreads under certain ideal conditions. The original Wuhan strain was probably around 2.5, and the Delta variant was probably around 5. So if this number is higher than 5, it’s more transmissible than Delta. The community prediction is 7.31, so Metaculus predicts it will be significantly more transmissible than Delta. (source: Metaculus) Metaculus didn’t want to wade in to precise lethality statistics, so they just asked for a yes-or-no answer on whether it would be deadlier than Delta. Forecasters say there’s a 34% chance it will be. The specific resolution criteria is if at least 3 of the first 4 studies find a statistically significant difference “favoring” Omicron. That feels pretty strict to me, so you should think of this as the probability that it will be really noticeably deadlier than Delta.

https://slatestarcodex.com/2013/06/14/the-virtue-of-silence/   Leah Libresco writes a couple of essays (1, 2) on an ethical dilemma reported in the New York Times. In the course of a confidential medical history, a doctor hears her patient is suffering from stress-related complaints after having sent an innocent man to prison. The doctor wants to know whether it is ethical to report the matter to the police. The Times’ columnist says yes – it would save the poor prisoner. Leah says no – violating medical confidentiality creates an expectation that medical confidentiality will be violated in the future, thus dooming patients who are too afraid to talk about drug use or gay sex or other potentially embarrassing but important medical risk factors.

https://astralcodexten.substack.com/p/links-for-november   [Remember, I haven’t independently verified each link. On average, commenters will end up spotting evidence that around two or three of the links in each links post are wrong or misleading. I correct these as I see them, and will highlight important corrections later, but I can’t guarantee I will have caught them all by the time you read this. PS: Happy Thanksgiving!] 1: The story of Jeff Bezos’ biological father, a former circus performer who didn’t realize Jeff was his son until well into the 2010s. 2: New type of nominative determinism just dropped (source):

https://astralcodexten.substack.com/p/pascalian-medicine I. When I reviewed Vitamin D, I said I was about 75% sure it didn’t work against COVID. When I reviewed ivermectin, I said I was about 90% sure. Another way of looking at this is that I must think there’s a 25% chance Vitamin D works, and a 10% chance ivermectin does. Both substances are generally safe with few side effects. So (as many commenters brought up) there’s a Pascal’s Wager like argument that someone with COVID should take both. The downside is some mild inconvenience and cost (both drugs together probably cost $20 for a week-long course). The upside is a well-below-50% but still pretty substantial probability that they could save my life. (Alexandros Marinos has also been thinking about this, and calls it Omura’s Wager) We can go further. The same people behind ivmmeta.com have posted this “meta-analysis” of curcumin, a common spice and oft-mooted panacea: (source) I’m going to guess it’s not true, because I’ve become pretty critical of these people’s methodology since doing the ivermectin review. Also, curcumin is a PAIN (pan-assay interference compound, ie a substance with weird chemical properties that make every test seem positive, so if you do chemical tests to see whether it activates eg coronavirus-fighting immune cells, it will always say yes). This means people are always publishing exciting papers about it and alternative medicine people are always getting really enthusiastic about it and suggesting it as the cure for everything (eg depression).

https://astralcodexten.substack.com/p/higlights-from-the-comments-on-ivermectin   Thanks to everyone who commented on my recent post Ivermectin: Much More Than You Wanted To Know. Let’s start with the negative comments. Leading pro-ivermectin website ivmmeta.com understandably disagreed with my fisking of them. They have a section where they respond to critics (see responses to Gideon Meyerowitz-Katz, to the BBC, to the parasitic worm hypothesis, and to someone named AT who they won’t explain further). I was honored to also get a response here. They write: We note a few limitations and apparent biases in the SA/SSC ivermectin analysis. Author appears to be against all treatments, labeling them all "unorthodox" and "controversial", even those approved by western health authorities, including casirivimab/imdevimab, bamlanivimab, sotrovimab, and paxlovid. We encourage the author to at least direct readers to government approved treatments, for which there are several in the author's country, and many more in other countries (including ivermectin). While approved treatments in a specific country may not be as effective (or as inexpensive) as current evidence-based protocols combining multiple treatments, they are better than dismissing everything as "unorthodox". Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants — we need to embrace all safe and effective means.

https://astralcodexten.substack.com/p/highlights-from-the-comments-on-the   Andrew writes: One word I don't see mentioned anywhere is "manufacturing." It's one thing to make enough drug for a clinical trial, it's another to make millions of commercial doses reliably. FDA approval requires inspection of and confidence in these commercial-scale manufacturing processes. Zutano adds: To expand on this more: the clinical trials only show that *that one particular batch* was safe and efficacious (the FDA thinks this, since they agreed to terminate the trial early). Pfizer must then show that the commercial batches will be identical in every relevant way to the clinical trial batches, so that they will have the same safety and efficacy. What are the relevant ways? Pfizer must decide that, and justify their decisions to the FDA with supporting evidence. Scaling up chemical manufacturing is not trivial (a regular contender for Understatement of the Year). E.g. heating and stirring work differently in different sized reactors. Heat transfer in and out of your reactor works through surface area, but heat produced/consumed by the reaction depends on volume. If your stirrer design isn't right for the viscosity of the solution, you might get hotspots and so on. Ideally, the FDA expects you to understand the chemistry so thoroughly that you know everything that can possibly go wrong, and design your commercial process so that none of these things can possibly happen. The commercial batches will therefore be identical *by design* to the clinical trial batches, and you have to prove this with science.

https://astralcodexten.substack.com/p/when-will-the-fda-approve-paxlovid   https://astralcodexten.substack.com/p/when-will-the-fda-approve-paxlovid I. You thought it wasn’t going to be a prediction market post, but surprise, it’s a prediction market post! Metaculus predicts January 1 as the median date for the FDA approving Paxlovid. They estimate a 92% chance it will get approved by March. For context: a recent study by Pfizer, the pharma company backing the drug, found Paxlovid decreased hospitalizations and deaths from COVID by a factor of ten

https://astralcodexten.substack.com/p/highlights-from-the-comments-on-great   Thanks to everyone who commented on last week’s post Secrets Of The Great Families. Some highlights: Many people knew of interesting families I’d missed. Stephen Frug brings up the Jameses: Any short list of the great families (or at least the great American families) should include the James's: Henry James is one of the perennial candidates for the greatest American novelist, and his brother William James is one of the perennial candidates for the greatest American philosopher. Their sister Alice James got a posthumous reputation as a diarist. (There were two other brothers who never became famous. Their father, Henry James Sr., had some reputation as a theologian, although not in the Henry (Jr)/William James league. Kalimac writes: Another member of the Darwin family who achieved fame in a different area was the composer Ralph Vaughan Williams, who was on a slightly different branch but was 4 generations down from both Erasmus Darwin and Josiah Wedgwood. Watch out, too, for other cases where the surnames differ. I like to offer the story of Stanley Baldwin, Prime Minister and a leading figure in British politics in the 1920s and 30s. He had a particular ability to deliver powerful and effective speeches, which is perhaps partly explained by some of them having been written for him by his cousin, whose name was Rudyard Kipling.

https://astralcodexten.substack.com/p/ivermectin-much-more-than-you-wanted I know I’m two months late here. Everyone’s already made up their mind and moved on to other things. But here’s my pitch: this is one of the most carefully-pored-over scientific issues of our time. Dozens of teams published studies saying ivermectin definitely worked. Then most scientists concluded it didn’t. What a great opportunity to exercise our study-analyzing muscles! To learn stuff about how science works which we can then apply to less well-traveled terrain! Sure, you read the articles saying that experts had concluded the studies were wrong. But did you really develop a gears-level understanding of what was going on? That’s what we have a chance to get here! The Devil’s Advocate Any deep dive into ivermectin has to start here: