• Virginia Postrel for Works in Progress: Engineering the disposable diaper. I, for one, am grateful that there is no more need for “the knife method” of diaper washing — one guess as to what the knife was used for. The article doesn’t mention that the technology which made baby diapers ever so thinner and easier to transport has also helped microscopy. Knowledge begets knowledge.
• Dynomight (pseud): You’re probably taking the wrong painkiller. On the benefits of acetaminophen, the blind alley of pain medicines.
• Brennan Kenneth Brown: Video Games that Secretly Teach Mathematics. Just a few week ago my wife and I were talking about the mind-bending difference in magnitude between a googol and a googolplex, and the notations described in this article would have come in handy. More to the point, even farming games not mentioned here like Stardew Valley and Animal Crossing do wonders to teach children math.
• Ted Gioia: Socrates vs. the Venture Capitalists. Look, when FT’s Janan Ganesh praised the unexamined life I don’t think he meant going about it like an amoeba. Est modus in rebus.
• Jake Currie for Nautilus: Birds Are More Afraid of Women Than of Men. Submitted without further comment.

The essay is five years old yet I have discovered it just now because the author is also the person behind Denote, a marvelous note-taking tool for Emacs. The tone is not as dry as a scholastic text ⊕ [Note: For a Substack version of a similar message I encourage you to check out Experimental History. The most recent post, for example, is a case study of one particular aspect of scientism — zombie ideas. ] but not as entertaining as something one would find on Substack. The message is unambiguous, and rather than rehash it let me quote one paragraph out of many:

Science as a career choice rather than a disposition towards learning, and an attitude of living in accordance with the principles than (sic!) enable such learning, contributes to the distancing from philosophy and to the degradation of the moral character of those involved. The practitioner who has not been in the least exposed to the rigours of a virtuous modus vivendi is likely to prioritise superficialities that obscure their own intellectual insecurities, such as social status, a growing collection of titles and certificates that are supposed to support one’s appeal to intellectuality, or the emptiness of being celebrated as a force for so-called “progress” and “rationality” among those who are believed to be unfortunate enough not to be scientists. The latter is one of those non-scientific beliefs amplified by the oligopoly of mass media that helps the philosophically deprived science stake its claim as the tutelary figure of the contemporary world, while blithely disregarding its instrumentalisation as both the apologist and militant activist of the power apparatus that enables it.

The author, who chose to drop his surname and go just by Protesilaos thereby making me break the house rule of using last names only when referring to folks, lives in a hut he built himself ⊕ [Note: A hut which brought to mind this recent essay from Joan Westenberg about people retreating from their true calling for years in order to recharge. ] in the mountains of Cyprus. Fascinating stuff, all with a large back catalogue I will be perusing in the months to come.

The last few years have been particularly tricky to tread for people who recognize the difference between science and scientism. If the entire board of the National Science Foundation is fired in one day, is it an attack on science or an attempt to curb scientism? [Note: ¿Por qué no los dos? ] When one of the “Abundance” guys — yes, that book is still on the pile — proposes an unbaked not-even-embryonic scheme for reform, is the rebuke from a seasoned scientist legitimate or just circling the wagons? [Note: Vide supra ] So yes, a retreat to the mountains does sound appealing.

Thank you, Hacker News, for promoting — if only briefly — this marvel of an article from Physics World (or is it physicsworld?) about the more scientific aspects of the final and most important step of making coffee. Funnily enough, it focused on the two methods I’ve settled on after a couple of decades of tinkering: espresso and pour-over.

Refreshingly, it is not a “well-actually” article that would use theoretical physics and/or laboratory experiments to prove coffee experts wrong. In fact, much e-ink is spent confirming practices that baristas have settled on, including the coffee-to-water ratio, steeping time, pressure used. There were, however, two things that could make me change how I’m doing things.

For espresso, theory says that using less coffee with a coarser grind would — to me, paradoxically — result in equal extraction and coffee tasting the same despite not using as many beans. With the price of coffee rising, this could be a big deal so I will check it out. Although, to me the benefit of a proper espresso is that it allows you to get a tasty liquid out of sub-par solids, so I would never go with the most expensive beans to begin with (ahem). No, the $2/oz bag is reserved for the queen of brewing, which is the pour-over.

And for the pour-over, there is but a single thing I should change: the height from which I pour, which should apparently be far higher than I’m doing now. A pretty diagram shows the reasons why 20cm is the right height from which the stream of hot — 96°C, thank you very much, so you’d better have a temperature-controlled kettle — water onto a coarsely ground pile of dreams. And there is no safe way to do it from that high up without a gooseneck kettle, so add that to your kettle requirements. Sadly, they don’t go into the quality of the filter and the differences between plain paper, Chemex and metal meshes. I am sure there is much physics involved.

Now before you start commenting that good ol’ Folgers in a hotel room drip machine will do for you, thank you very much, let me suggest a few decidedly unfussy methods of coffee making that are infinitely better than drip coffee out of a plastic tub:

• Aeropress, which used to be the main way I made coffee but abandoned as the family and the number of coffee-drinkers in the house expanded (we are currently at three; five with grandparents visiting).
• Nescafe Gold, which is probably the best instant coffee you can get and it doesn’t get any less fussy than pouring hot-ish water into a mug.
• Turkish coffee, with strong preference for Mehmet Efendi which, if not in Istanbul, you can easily get online.
• Boiling raw beans in DC tap water for about 30 minutes.

Okay, maybe not that last one.

• Cory Doctorow: The enshittification multiverse, in which Doctorow proposes a general theory of enshittification to match his initial, special theory. I enthusiastically concur.
• Anonymous on the Marginal Revolution comments section: On health care price transparency. The only non-Xified content you can find on Marginal Revolution these days is in the comments, so I am glad that Cowen highlighted this minute dissection of the madness called American medical billing. Needless to say, I concur.
• Reese Richardson: A do-or-die moment for the scientific enterprise. ⊕ [Note: ᔥAndrew Gelman, who sure loves his mile-long headlines. ] This is the author’s summary of a more detailed paper in the academic journal PNAS which points to a looming catastrophe of LLM-boosted scientific paper mills holding hands with pliant journal editors to decimate the signal-to-noise ratio of the literature. Of course I concur!
• Cory Doctorow, again: Ada Palmer’s “Inventing the Renaissance”. His review after actually reading the whole book, and yep.

Apart from looking like he has just been on the losing end of a fistfight, and having occasional bouts of nausea, Ben Sasse seems to be doing as well as someone recently diagnosed with metastatic pancreatic cancer possibly could. Both the nausea and his face peeling off are because of daraxonrasib, a new drug which targets KRAS G12 mutations which are common in many cancers but are found in most pancreatic ductal adenocarcinoma (PDAC). As a reminder, PDAC is the one that Steve Jobs did not have, the one that has the dubious distinction of being both the most common and the most lethal cancer of the pancreas.

Well, daraxonrasib seems to be doing its job and doing it well, based on a company press release. Remember, most press releases should not count as evidence for anything. This particular one, however, is worth reading because it is (1) for a randomized controlled trial with (2) a “hard” endpoint of overall survival ⊕ [Note: OK, putting my pedant hat on, the pre-specified co-primary endpoints are progression-free survival (PFS) and overall survival (OS) in the RAS G12-mutant population. What is reported in the press release is only OS in the “intent-to-treat” which is to say both G12-mutant and wild type populations, which was a secondary endpoint. A bullet point at the beginning says that all primary and key secondary endpoints were met, so why not report both? Probably because one looked better than the other, but would it not be a tad suspicious that a less targeted population did better than the more targeted one? But this is just speculation, let’s see review the actual data once they come out. ] which will (3) be presented at the ASCO annual meeting, I imagine as a plenary talk, in early June of this year. The thing to look for there will be informative censoring, in particular early censoring of frail participants — the ones more likely to die early of their disease — who were randomized to receive daraxonrasib but then withdrew due to the “manageable” toxicity of a melting face. The fact that there are no participant numbers reported at all in the release makes me suspicious, though information on the number of patients enrolled is readily available: 501. That’s a lot of patients!

The company is certainly feeling optimistic: they have already received a National Priority Voucher from the US FDA and will now submit a New Drug Application. Kudos and congrats for designing and testing a working drug without using AI, because to read both professional and lay media the past two years it is a miracle there were any drugs being discovered until Large Language Models came along.

Yes, I had to invoke AI, because it is becoming exceedingly common for people to give algorithms credit where it is not due. This is what Tyler Cowen wrote yesterday about pancreatic cancer research:

AI and the pancreatic vaccine. More testing is needed, but there is a reasonable chance that we have a good treatment for pancreatic cancer, and AI was instrumental in that. It is mRNA as well, so a double burn on the haters.

The link is to a post on X by one Rotimi Adeoye, a “contributing opinion writer @nytimes” (one guest essay as of today which is one more than I have so congratulations, I guess?) who in true X fashion superimposed a screenshot from an uncredited journal abstract over someone posting a link to an NBC news article about the updated results of a phase 1 trial of an mRNA vaccine for pancreatic cancer. ⊕ [Note: For those not keeping track, you are right now reading a blog post about a blog post about a retweet of a tweet about a news article based on a press release. You’re welcome. ] These were presented yesterday at the annual meeting of the American Association for Cancer Research but were hinted at in a press release (?) from Memorial Sloan Kettering, where the vaccine — generic name autogene cevumeran which rolls right off the tongue doesn’t it? — was being tested.

Remember how a few paragraphs above I had implied that you should ignore most press releases? Well, news on academic websites should rank even lower as no one there has to answer to the SEC. The primary study was great for what it was, a first-in-human trial with laboratory endpoints meant to test whether the participants’ immune system responded at all to the vaccine. And it seems that it did, as shown in not one but two papers in Nature published two years apart. The number of original participants, all of whom had early-stage, freshly resected and otherwise untreated PDAC upon enrollment, was 19. Three of these did not make it to the vaccine as they had progression, died, or had toxicity from adjuvant chemotherapy before being dosed. Chemotherapy? Yes, in addition to the vaccine everyone also received “adjuvant” (meaning: there to “clean up” any residual cancer after surgery) chemotherapy (FOLFIRINOX, not for the faint of heart) and immunotherapy (atezolizumab which is in comparison to the chemo a walk in the park but even that has its side effects). There was no control.

Of the 16 participants, 8 were “responders” to the vaccine as measured by some highly sophisticated laboratory tests — not that the patients would care what their blood work showed — and in 7 of those the cancer hasn’t come back for 3 years as noted in the follow-up Nature paper or for 4-6 years as noted in yesterday’s update. This compares to 2 of 8 who were “non-responders” to the vaccine.

If you don’t have your calculator handy let me do the math for you: 9 of 16 patients, or 56.25%, with newly resected PDAC who received chemotherapy, immunotherapy and the vaccine were still alive more than 3 years after treatment. You may not know this, and I didn’t until I looked it up just now as it has been a while since I have treated patients with newly diagnosed early-stage pancreatic cancer, but the median OS after (modified) FOLFIRINOX alone in a recent large, randomized Phase 3 trial was 53.5 months, with 43.2% of patients still alive 5 or more years. Did the addition of atezolizumab and the vaccine change anything? I can’t tell and neither can anyone else until there is a randomized controlled trial, which isn’t to cast shade on the investigators — kudos to them as well for a successful first-in-human study — but let’s curb our enthusiasm.

So we have some updated results from a tiny trial that didn’t really move the needle one way or another, and yet Cowen et al. feel the need to push AI into the narrative. To be clear, there is absolutely no mention of LLMs, machine learning, algorithms or artificial intelligence of any kind anywhere in the autogene cevumeran literature. Granted, it is a “personalized” vaccine, meaning that every potential participant had their tumor sequenced and up to 20 vaccine targets identified among the newly mutated proteins. I am sure there was a lot of computation involved. But not every sophisticated computer analysis is AI, let alone an LLM, so I truly don’t see how they could legitimately be brought into the conversation.

And in case you were wondering, no, the screenshotted abstract did not in fact back up Adeoye’s claim. Best as I can tell this was the paper in question, a speculative review article in an obscure journal written by a Shanghai-affiliated group of authors who had nothing to do with BioNTech whose purpose was to be a never-looked-at reference for a false claim, that “AI played a critical role in advancing the vaccine”. Anything for the clicks, am I right?

Adeoye’s behavior was regrettable but Cowen’s is detestable, especially when paired with his look-at-the-sheeple attitude towards humans. ⊕ [Note: The linked to article from Cowen is particularly wrongheaded if you realize who the Luddites really were and that the label should in fact be a positive one. ] Cory Doctorow had warned about AI companies over-promising their capabilities for a short-term gain. But they don’t really need to: there are plenty of useful fools willing to promise on their behalf, giving it credit even where there is none.

• Monopolized by David Dayen, which Cory Doctorow recommended in response to my account from last week of the medical billing/phone scam rabbit-duck. Doctorow wrote about the book in more detail back in 2021 and yes it is now on the pile as is everything else below.
• The Credibility Crisis in Science ⊕ [Note: ↬ Joel Hamill ] by Thomas Plümper and Eric Neumayer, and if the subtitle “Tweakers, Fraudsters, and the Manipulation of Empirical Results” whets your appetite there is an excerpt available in Nautilus.
• The Art of Manliness by Brett and Kate McKay, who have had a blog of the same name for more than a decade, so it is a true mystery why an article in The Dispatch about the “gentlemanosphere” ⊕ [Note: ↬ Reader John ] chose to highlight overtestosteroned almost-douchebags such as Scott Galloway as the anti-manosphere crusaders rather than McKay. Haha, I’m joking, of course it’s not a mystery: Galloway gets more clicks, taps, swipes or rather the preferred method of interaction is nowadays. He also has a new book out, to which I shall not link.
• The Oxford Book of English Verse edited by Christopher Ricks, which someone recommended on The Honest Broker Podcast, a show that combines some of my least favorite things about this decade: Substack and using the word “podcast” to describe a video of two men talking. Still, the transcript makes for good reading and the book seems something worth keeping at the bedside, at least aspirationally.

• Bayesian Workflow, a new book from Andrew Gelman et al, coming out in June. Here is Gelman’s announcement and here is the book’s web page.
• The Alba Madonna, ⊕ [Note: ᔥ Tyler Cowen ] a painting of Raphael’s at the National Gallery of Art, which you can examine in detail on their website.
• The Classical Station, ⊕ [Note: ᔥ William Parker ] a no-nonsense, no-tracking stream of human-selected music. Here is their daily playlist.
• just the fracking QR code, ⊕ [Note: ᔥ Jahir Fiquitiva on Mastodon ] a no-nonsense, no tracking website that will give you the QR image for any text, file or hex code you desire.
• Jellyfin, a home media server which resembles Plex before it was enshittified. Note that (1) I am yet to try it out and (2) the person whom I first saw mention it does not in fact endorse it.

Per Tanner Greer, China is all-in on leading the new industrial revolution, which will of course first be a revolution in science and technology. My only insight into the tech part is that Chinese companies now make the most innovative earphones and the most electric cars, and from reading Apple in China I have a vague sense that they were contract manufacturers in those fields first, then perfected the craft and outdid their former employers.

Most relevant to the world is what they [Note: But who are “they”? CCP leadership which sets the tone, startups and conglomerates which do the actual legwork, or the provincial bosses who act as intermediaries? I won’t even pretend to know. ] have done and will do with renewable energy, batteries, quantum computing and the like. The most relevant to me is what they are doing with biomedical research, particularly in cell & gene therapy. And as the field progresses from discovery to manufacturing — both research-grade and commercial — to clinical trials and actual practice so does the extent of their involvement.

On the discovery side, Chinese authors have already overtaken their American counterparts in the number of papers in top scientific journals. A crude metric for sure — and let’s not get into the whole peer review debate — but it is a measure of general lab activity. Determining whether China overtaking the US is a direct or indirect result of American sinophobia or evidence that the sinophobia was justified I will leave as an exercise for the reader.

In manufacturing, China is in the “let us do your work for you” stage. Not a week goes by that I don’t get an email from a China-based CDMO [Note: Contract Development and Manufacturing Organization, which just to make things confusing is often shortened even further to Contract Manufacturing Organization, or CMO, which means so many different things within the same field (Chief Medical/Manufacturing/Marketing Officer, anyone?) that it has become ridiculous. ] and WuXi Biologics — headquarters in Shanghai — is among the top 5 companies of that type in the world. These companies specialize in being taught how to do things and then doing them at scale, picking up a few things about process development and optimization on the way. Why the US would not want CDMOs from China was so obvious that the bill forbidding federally funded entities from contracting with them sped through Congress, though not after being revised to not explicitly mention WuXi by name.

“They” are not taking the same approach with clinical trials: a wise decision on their part, since the only thing they could have possibly learned from American trialists was inefficiency and bloat. No, the big push is for investigator-initiated trials which can speed up approvals — they only require local oversight, not a national FDA-equivalent to give their blessing — and get cell & gene treatments to patients within weeks, provided of course that they are manufactured in China.

An eternity ago I wrote about two different types of trials, ones meant to introduce new treatments and others meant to establish guidelines and prune less effective therapies. I argued that the regulatory burden for the two should be different, since the latter — Set 2 as I called them — are clearly less risky and carry less uncertainty. We have of course already experienced the world of unregulated trials of new therapies, and it was not pretty. With its IIT push, China is speeding them up further. The risks are clear, but who benefits?

Top of mind are the patients who will get effective treatments sooner. The invisible graveyard will shrink! But of course most treatments won’t work and most patients who take part in IITs and their family members will have spent much time, some even money, to get false hope. A much larger proportion of the beneficiaries will be companies that hit a false positive, and in single-center IITs of small sample size there will be many of those. They will of course be willfully ignorant of the fact that their high response rate in a 10-patient single-arm open-label trial was spurious, but will instead get just enough conviction to pass on the asset to the greater fool. And so will the roulette wheel keep spinning, fueled by financialization that somehow ends up being the root cause of most of the world’s current ills.

I fully expect the American biotech establishment to learn the wrong lesson from Chinese IITs and instead of feeling relief that someone else is taking on the foolish risk be pressured into copying them. Here is to the steadfast box-checkers and blank faces whom I trust to put on the brakes.

• Raghuveer Parthasarathy: Space mirrors, solar panels, fools, and their money.

A few months ago I noted that the one of the main reasons biotech was not like tech was its almost unlimited freedom do bullshit. Well, people are able to raise money by BS in other areas as well, as this article shows, but an order of magnitude less because most investors are able to do back of the envelope calculations.

• Bryan Vartabedian: The Measure of Everything.

A take on Goodhart’s Law as applied to medicine, this time through the lens of instrumentalisation. If any of these articles tickle you and you haven’t yet read Zen and the Art of Motorcyle Maintenance, please do so now. Ted Gioia recently wrote about the book and its legacy. As an occasional note-taker I am in the minority club of Lila fans as well, though both of Pirsig’s books are due for a re-read.

• James Olds: The Chronology Problem.

The point is in the subtitle: “how our bias towards recency in scientific discovery hurts our understanding”. It rings true, and even reminded me of the 26 years it took for CRISPR/Cas systems to travel the path from an oddity to a gene editing platform, until I realized that those 26 years were not spent idling as this review in Cell describes in detail. So, the (lack of) developments in theoretical biology would be a much better example.

• Phil Price: Ted Williams and Me.

Ted Williams was, apparently, a base-ball player about whom John Updike had this to say: “For me, Williams is the classic ballplayer of the game on a hot August weekday, before a small crowd, when the only thing at stake is the tissue-thin difference between a thing done well and a thing done ill.” This applies to any profession you can imagine, and indeed things outside of one’s professional life. People who have the inner drive to do things well even in the absence of stakes could unkindly be called “perfectionists”, but let’s remember that they are the ones who keep the wheels of civilization in motion, in opposition to the hordes of blankfaces, lazy asses and morons.

• Aaron Cheng: On the emotional weight of a life in medicine. Thoughts of a newly-mintend hematologist which act as a good counterbalance to the popular fictional accounts. Feel free to peruse the few pre-2017 posts from the Infinite Regress archive for my own thoughts from that period.
• Fred Vogelstein: Enveda’s drugs from plants will turn pharma upside down. This is what Ruxandra Teslo warned us about a few months back.
• Joseph Howlett for Quanta Magazine: The Man Who Stole Infinity. On Georg Cantor, plagiarist. It does cause one to become more cynical, as we keep discovering that high-profile scientists built their reputiations on the backs of people with more scrupules and less need for attention. Taleb’s minority rule applied to sociopaths.
• Adam Mastroianni: The one science reform we can all agree on, but we’re too cowardly to do. It is to abolish for-profit scientific publishers, and I am all for it. But, people being people, I do not have high hopes that this prisoners’ dilemma will have a positive outcome.