• Kevin Kelly: Your Most Improbable Life.

Your life’s goal should be to become the most improbable person you can be. Your path, your character, your life, should be the most unlikely, the most unexpected, the least predictable version you can make. Improbable lives have fewer competitors, more unique rewards, and are harder to replace with AIs, since AIs run on the predictable. This is true whether you favor traditional humanist directions or work on a frontier.

This is a nice preamble to a bit of personal news I can finally share: I will soon be going back [Note: It is a qualified “back”, as I have never actually practiced medicine full time, being either in training, doing clinical research as my main job, or being out of clinic altogether save for a few hours a week doing charity work. ] to the practice of clinical medicine. This week is in fact the last in my current position, which had been a magnificent experience but was going, as the careful reader of this blog would have already noted, in a direction not entirely suited to my preferred lifestyle and more importantly — let’s not sugarcoat it — values and beliefs. Onwards and upwards!

• Derek Robertson: 5 questions for Meredith Whittaker. ⊕ [Note: ᔥVoline on Mastodon ]

Whittaker, who is the president of the Signal Foundation (as in the app), had this to say about venture capital back in 2023:

Venture capital looks at valuations and growth, not necessarily at profit or revenue. So you don’t actually have to invest in technology that works, or that even makes a profit, you simply have to have a narrative that is compelling enough to float those valuations. So you see this repetitive and exhausting hype cycle as a feature in this industry. A couple of years ago, you would have been asking me about the metaverse, then last year, you would have asked me about Web3 and crypto, and for each of these inflection points there’s an Andreessen Horowitz manifesto.

It’s not simply that one piece of technology is overhyped, it’s that hype is a necessary ingredient of the current business ecosystem of the tech industry. We should examine how often the financial incentive for hype is rewarded without any real social returns, without any meaningful progress in technology, without these tools and services and worlds ever actually manifesting. That’s key to understanding the growing chasm between the narrative of techno-optimists and the reality of our tech-encumbered world.

Emphasis is mine, as it could be transposed word-for-word into the current world of drug development. Consider it a more polite rewording of prof. Taleb’s take.

• Venkatesh Rao: Commodity Intelligence.

Commodified knowledge is “general knowledge” in the sense tested by trivia/quiz contests. In grade school, we actually had a subject on the curriculum called “GK” and kids good at it (I was one of them) got put on quiz teams to represent their class or school. General intelligence of the sort we actually have today is simply AIs trained on general (ie commodified) knowledge.

But the theological motte-and-bailey move that conflates it with some totalizing-universal divine-omniscience idea of “Artificial General Intelligence” traps a great many of even the smartest people. A category error motivated by theological yearnings, validated by second-order Labatutian psychoses, sustained by epistemic bubbles, and encouraged by sketchy business roadmaps that need a story to justify trillion-dollar investments.

This is a charitable way of justifying the AI billionaire panhandlers’ selling of large language models as AGI, even putting the term in official titles. Less charitably, they all know what Yann LeCun has been saying for years: LLMs will never reach human level of intelligence (“ChatGPT, make me a sandwich”). Whether LeCun’s own pursuits are wise is a different matter.

Separately, Rao gives some good book tips and Benjamin Labatut’s When We Cease to Understand the World is now on the Pile.

• Andrew Gelman: Don’t cite sources you haven’t read, and don’t trust when people claim to be reporting something from the literature.

No quotes because, true to form, everything salient is already in the title. Natural continuation of the debate started last week (see the last link), although apparently written before the new arXiv policy for a 1-year ban for hallucinated references.

• Kieran Healy: Zero Sum Problems.

Healy wrote a book about data visualization so I feel somewhat foolish in writing this, but I do not find Apple Sports’ presentation least bit confusing: the numbers are absolute, the bars show percentage of the total. If the goal is to have more of each (assists, rebounds, steals, etc.) the bigger bar shows the opposing team’s dominance. It’s fine. Healy’s proposed solutions are all notably uglier and demote low-occurrence events like blocks and steals even though they may be crucial in a game. Shows how little both Healy and Gruber — on whose post Healy riffs — know about the game of basketball.

• Sarah Kliff, Margot Sanger-Katz, Erin Schaff and Asmaa Elkeurti for The NYT: Short Naps, Long Hours: How Autism Clinics Squeeze Medicaid Dollars Out of Preschoolers.

At Compleat Kidz, a fast-growing chain of autism clinics based in North Carolina, the policy is firm: Naps cannot be longer than seven minutes before children are awakened to resume therapy. The company says this is necessary to prevent fraud since clinics can be paid only when children are awake and getting services. But it also allows the clinic to bill insurers or Medicaid for more hours.

Yes, you have read that correctly. Waking up a child after a 7-minute nap to perform “therapy” — as if anything meaningful can be accomplished in that hypnagogic state — is both cruel and unusual. But not a punishment! It is merely a way to avoid fraud while optimizing revenue under the watchful eye of private equity:

Private equity firms have acquired at least 500 clinics over the past decade. “There’s just huge opportunities to grow these businesses and help increase access to care,” said Jon Krieger, a managing partner at Calex, a financial firm that assists with autism clinic mergers and acquisitions. He estimates the market could grow to $90 billion.

Mr. Market is a bad doctor, an even worse vet and, it seems, a most diabolical nanny.

The departure of Marty Makary is looking more and more like a Murder on the Orient Express situation: everyone wanted him out. Well, everyone except for uniQure, Capricor and ImmunityBio who were named in the original version of that Endpoints News story as some of the companies lobbying for Makary’s ouster, then asked for their mentions to be removed, as the Editor’s note now helpfully clarifies. C’mon, people. Own it.

Back in September 2023 I noted that the biggest hurdle for AI completely replacing physicians is the physicality of the job. Sure, LLMs are good at giving differential diagnoses and faking empathy once somebody’s problem has been reduced to text, but the art of medicine is in the act of seeing, feeling, smelling, etc. [Note: Although increasingly less so, as doctors and trainees are becoming experts at treating patients in the chart and not those in front of them, making themselves the perfect foils for replacement; queue photo of the old man yelling at clouds. ] If clankers have any hope of replacing humans, they’d better get some senses.

At first glance, a recent Nature Medicine paper aimed to do just that by introducing what the group of authors — all of them Google employees based in the UK and California — call “multimodal reasoning” but is in fact the chatbot being able to interpret images, ECGs and lab reports in addition to the pre-digested clinical pearl. The topline result, one that the journal itself felt obligated to headline, was that “AI had superior performance compared with physicians for almost every metric (29 of 32 axes)”. But at what?

You would think that the question would have been easy to answer, this being a peer-reviewed paper and all, but no. In fact, I am still not completely certain what interactions were performed and whether they completely match what was reported. What is certain is that a set of primary care physicians and patient-actors from Canada and India — countries different from the author’s own countries and let’s wonder conspiratorially for why that may be the case — interacted via an instant messaging-like service. This is the first oddity: even remote health visits are performed using video calls, and yes you may occasionally get a text through the EMR or if you are a VIP/boutique physician maybe your phone, but that is far from the norm.

The primary report is on what happened when the patients uploaded the skin photos, ECGs, lab results, etc. and then asked the physician or LLM on the other end questions about it. Pretty standard fare for a human-to-LLM interaction, but not exactly natural for a doctor-patient relationship which usually starts with questions being asked of the patient. This is the second way in which the setup was made to fit the computer and not the human.

But then the last section of the paper is about what happens when there is, in fact, a back-and-forth by the way of taking a history. The extended figures — “extended” here meaning not worthy enough of being included in the main paper — say it improves the performance of the LLM. They do not say how it affected the human performance, or how the patient-actors rated humans versus LLMs in history-taking. I would call that strike three.

To the journal’s credit, they did not allow Google to get away with it completely. “To evaluate the performance of our finalized system, we conducted a randomized, blinded human evaluation that emulates an objective structured clinical examination”, says the final paragraph of the introduction, only to end with:

We note, however, that our study is not a randomized clinical trial with prespecified endpoints and preregistered statistical analysis. Rather, it is an exploratory study investigating the properties of multimodal diagnostic dialogue.

Peer review is at least good for something, even if it does result in self-contradiction.

Meanwhile, in the world without motivating reasoning, more objective assessments of the usefulness of AI in medicine show that it is in fact still quite bad. This does not prevent the massively funded hordes of AI researchers from flooding the field with sloppy work, creating the impression that the rise of the machines is imminent. Comply or relegate yourself to the permanent underclass, serf MD. But of course, relegation will only be possible to the extent doctors — or any other profession, really — has already debased itself and abandoned its core professional principles in the service of electronic ease.

After dissecting the minutiae from the ongoing battle of the bozos ⊕ [Note: To save you a click: it is about the Musk-Altman trial. ] , Andrew Sharp’s weekly column ends with this paragraph:

The reality is knottier. Had the OpenAI founders not launched with a nonprofit structure in 2015, they probably never recruit the talent required to compete with Google. And had they done anything else other than exactly what they did in 2018 and 2019, all of computing would be less interesting today, and the company probably wouldn’t exist eight years later. Musk’s trial has been clarifying on that point, at least for me.

The AI side of technology is one of those rare occasions where biotech may indeed be like tech: people with knowledge, skills and ambition to make the early steps towards creating something new generally don’t do it for the money. Accolades, titles, a few more increments on their h-indices sure, but unless they are seriously delusional a lab postdoc coming in on a weekend to split the cell culture generally has no hope of getting into the top percentile in income. Up until a few years ago AI research was much like that, until it wasn’t.

Sharp writes that OpenAI had to flip the switch if it were to survive in these shark Google-infested waters once they smelled blood profit an opportunity to tell a new story to investors. Same can be said about any biotech: become successful enough, and there will come a time when the academic founders are asked to step away and let someone with different motivations run the show, lest they be lost in a sea of copycats, smoke-peddlers and competitive intelligence officers. The whole business has just become too expensive for some Jonas Salk-wannabe to dabble in.

A person of bad intent may propose that the adults coming to run the show once it becomes too expensive are the ones making it expensive in the first place to justify their existence, contributing the health care cost ouroboros on the way. But that is of course nonsense. The proof is in the pudding, what with famously efficient drug development pipelines, low health care costs and improving lifespans.

So let’s do what a genuine financial scion once proposed: invert. Instead of asking ourselves how to make drug development more efficient and cost-effective, let’s see how we could make it more expensive. Number one thing to do would making it all about the money: let’s portray people who don’t capitalize on their inventions as losers not heroes, make Nobel Prize winners notable only if they are billionaires (who won the Nobel Prize in Physiology or Medicine last year, again?), measure success of drugs in dollars earned not lives improved, extended or saved, have everyone skim a percent or five of the money swishing around in the ecosystem as their primary source of income without any penalty for ultimate failure ⊕ [Note: For more on this, do read Nassim Taleb’s Skin in the Game, which is about much more than the titular phrase which has become — much like his The Black Swan — a phrase people throw around without having any idea of the underlying concepts. ] guaranteeing that they will have every incentive possible to grow the pie, and I think you see where this is going because the system functions as designed so why should you complain? After all, there is no alternative.

Except that, of course, there is. It would be a big lift, to remove incentives of skimmers to inflate the balloon, stop various influencer platforms from inducing FOMO in everyone and anyone, recalibrate the median science journalist’s value system from Mr. Market to something more reality-based. Big, but not impossible, provided there is a will.

Therein lies the problem: that kind of thinking is somewhat at odds with the shared American culture, at least as recently described by Chris Arnade, that “you can live how you want, eat what you want, live (up to a point) how you want at a thin level, as long as you ultimately believe in making big money through hard work and playing by the rules.” Determining if the other two legs of the three-legged money/work/rules American stool are performing as intended I will leave as an exercise for the reader.

• Kristen French for Nautilus: New Fathers Are Dying, and We Don’t Know Why.

Oh but we do, at least superficially: “of 130,000 men who became new fathers between 2017 and 2022, almost 800 died during that same 5-year period, and 60 percent of those deaths were from potentially preventable causes like homicide, accidental injury, and suicide” which is about what you would expect for a group of men that skews younger. The authors of the paper make a comparison between fathers who died and those that survived but a more interesting one would have been a demographically matched of childless men. Alas, all we have is all the men in Georgia and lo, for each age range the new fathers have a lower mortality and the discussion appropriately leads with “Fatherhood appeared to be associated with reduced mortality.“ ⊕ [Note: Another reason to have more children. Though, if you are going to do it solely because of a misguided belief that you yourself would live longer, then perhaps don’t? ] Methinks French — or her headline writer — were fooled by randomness.

• Derek Lowe: What Success Can Look Like, Darn It.

Vepdegestrant for breast cancer seems to be another entry in the annals of approved drugs being considered failures by Mr. Market. Let it be noted that a chemist (Lowe) writing for a prestigious peer-reviewed journal (Science) dunks on a drug while citing millions and billions of dollars exchanged or promised to various stakeholders while barely mentioning, and wrongly at that, the actual trial results. “It did not really demonstrate any advantage versus the comparison in the trial, fulvestrant” is factually incorrect: median progression free survival was 5 versus 2.1 months, which, fine, is tiny and may have been the result of statistical shenanigans; but it may also be a true and meaningful incremental improvement and if we are going to dismiss it out of hand then what are we even doing here? The rot runs deep.

• Deena Mousa: We don’t know why Malawi is poor.

It is a genuine mystery of why a mostly agrarian functional democracy with no separatist movements, demographic catastrophes, curses of resource wealth and the other usual suspects of stalled growth should completely flatline their GDP. Mousa shows compelling data and many hypotheses, though I wonder whether there is something that isn’t and can’t be measured which is keeping the country where it is. And if you are thinking that oh, GDP can’t measure happiness, I bet that at least they are happy, think again: it was the 4th least happy country last year. But then the “Happiness Report” methodology takes GDP into account (!?) so it is almost impossible for a GDP-poor country to break through in the rankings.

• Dynomight: What’s with all the slide decks?

This is about slides shared via email, never meant to be presented, but rather serving as a landscape-oriented picture book for adults. I don’t know what is behind communication-by-slide, and as a seminar-attending Tufte acolyte I abhor it. Management consultants spreading them around like a viral respiratory disease — which is the thesis of the blog post — certainly has something to do with it, but the syndrome is now bottom-up as well. My third-grader asked me just this morning why they were forced to watch and make (!?) slides at school.

The good: How an ‘Impossible’ Idea Led to a Pancreatic Cancer Breakthrough by Gina Kolata and Rebecca Robbins for The New York Times. The breakthrough discussed is the real deal, and they manage to do it in a measured tone which correctly identifies daraxonrasib as a stepping stone and not a miracle cure. It has this important note up top and not buried down at the end:

The pills, three taken daily, are not a cure — eventually, daraxonrasib stops working. Many patients do not respond. And it has side effects that can be harsh, including rash, diarrhea, fatigue, nausea and raw, split fingertips.

How refreshing — I hope Derek Thompson takes note.

The bad: The Human Body’s Hidden Pathways by Dr. Avraham Z. Cooper, who is a pulmonary/critical care physician at the Ohio State University, for The New York Times Magazine. For the life of me I can not figure out the point of this post-modern journalistic exercise.

Nominally it is about a peer-reviewed research article which came out in 2021 under the title “Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans”. The NYT Magazine staff did not deem it worthy of being linked to, but here it is in its entirety. In it, the authors showed small fragments of tattoo pigment migrating into tissues — skin and colon — deeper than they expected. We are not talking about ink being injected into a bicep and showing up in someone’s rectum here, but rather a series of biopsies of tattooed skin or the lining of the colon where there is a lot of pigment up top, and much less and in smaller pieces down at the bottom of the slide, deeper in the tissue.

Let me pull out my rarely used master’s degree in histology and note that this is hardly surprising. Connections between cells are not exactly air-tight — other than maybe in the brain and the testes — so of course there is some gel-like fluid circulating in the space. Or did the original article’s authors not realize why people tend to rub their feet when they get swollen?

But that is only the introduction. The meat of the article is Dr. Cooper’s theoretizing that this has something to do with — drumroll, please — acupuncture. With no evidence, mind you, but a tingling sensation in the back of his neck or somesuch. By the time the 30th single-sentence screen scrolls by we are firmly in bullshit territory, in the formal sense of the word. Caveat lector.

The ugly: Longevity Medicine - An evidence based guide by Dr. Vinay Prasad who is out of the FDA and back making YouTube videos. And oh my, the contrast between the most recent thumbnail and the one posted just before he joined the FDA is striking. Has it only been a year? No wonder that his first topic back as an influencer is about longevity.

A sidenote here which I will put at the end: the increased interest of Silicon Valley types with longevity, and I am not thinking only about Bryan Johnson’s delusions here, reminds me of the recently quoted speech Charlie Chaplin gave at the end of The Great Dictator, the relevant quote being that “so long as men die, liberty will never perish.” Good for us that snake oil salesmen are still the longevity field’s most prevalent phenotype.

What possessed me to type x.com into the address bar I can tell you not, but there I was, staring for the first time in weeks at the “For you” tab. And there it was, in all capital letters: “THIS IS HOW WE CURE PANCREATIC CANCER”, staring back.

That was the X-crement of one Derek Thompson, writer for The Atlantic, podcaster, abundance enthusiast. It was promoting his most recent blog post which, being on Substack rather than X, had a more subdued name: “How AI Could Help Cure Pancreatic Cancer”. It is, supposedly, an interview with a co-author of a paper with an ever-less-so boastful name: “Next-generation AI for visually occult pancreatic cancer detection in a low-prevalence setting with longitudinal stability and multi-institutional generalisability”. Most of the interview, however, is behind a paywall which I shall not climb.

Above the fold is Thompson’s exuberant, hyperoptimistic speculation. He approaches the problem from the perspective of the three recent developments — one from above, the other two previously discussed — but presents the areas which they are “solving”, targeting KRAS mutations, pancreatic cancer’s immune evasiveness, difficulties with early detection, as the sole reasons why the disease is so difficult to treat.

But that is disingenuous. There are so many more reasons why it is hard: the uniquely hostile, acidic, high-pressure environment of the tumor that makes drug delivery to it nigh-impossible. It’s propensity to metastasize — spread to distant organs — no matter what size the original tumor is. A biochemical storm it stirs up in the body leading to rapid weight loss, blood clots and horrendous pain which are distinct even among other cancers. Why not highlight those three as the “3 broad reasons why pancreatic cancer is so hard to treat”, to use Thompson’s terminology? Well, no recent high-profile studies for those, are there?

I understand that he has some personal reasons to be interested in pancreatic cancer, and I am sure it is coming from the best of intentions, but please.

• 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.

Last week I wrote about the scammy way in which a large hospital system, Johns Hopkins, tried to bully us into paying them money we didn’t owe. The responses to it on Mastodon after a boost from Corey Doctorow were unlike anything I have received before, at least in the English language. [Note: There was a period of about a year or two, early 2020 to late 2021, when a thing I tweeted in Serbian ended up in a tabloid. Around the same time a Serbian TV station lifted an annotated covid graph I had been updating, without attribution of course. Crazy times, may they never return. ] Who knew that American “health” “care” “system” could arouse such strong feelings.

An unexpected turn in the conversation was towards veterinary medicine and how it too is undergoing general enshittification under pressure from private equity and no regulatory barriers. Which got me thinking: could veterinary medicine serve as a proxy for what would happen to human medicine if it were to become deregulated? What would a wholly free-market medicine, a libertarian’s wet dream, look like? Now clearly I have neither the time nor the will to sink hours into this kind of research, but do you know who does?

Yes, I asked Gemini to formulate a research plan, then passed on the plan with the Deep Research toggle on to create a report titled “A Comparative Analysis of Veterinary and Human Medicine: Evaluating Deregulation Proxies in the United States Healthcare System”. The goal was to test whether veterinary medicine could serve as a proxy for deregulated human healthcare and personally I don’t think it achieved that objective — this could be just my anti-AI bias — but it did provide a few juicy quotes, such as:

Theoretical free-market economics suggests that corporate consolidation should benefit the consumer by driving down costs through supply-chain efficiencies, centralized administrative services, and immense economies of scale. The empirical data from the veterinary sector directly contradicts this theory. Instead of utilizing their massive scale to lower consumer costs, corporate consolidators have leveraged their localized monopolies to exercise extreme, unchecked pricing power.

And two paragraphs down:

Furthermore, corporate management fundamentally alters the clinical culture at the ground level. Veterinarians operating within these corporate structures report worsening working conditions, including intense pressure from non-medical corporate managers to “do more and see more patients,” meet specific monthly revenue quotas, and upsell clients on expensive and potentially unnecessary diagnostics to satisfy debt obligations. (21) To protect their market share and ensure high practitioner retention despite these conditions, these corporations frequently deploy aggressive non-compete and non-solicitation agreements, legally preventing veterinarians from opening independent practices nearby and artificially suppressing labor mobility. (21) This data definitively indicates that in a deregulated medical market, institutional capital prioritizes relentless profit extraction and margin expansion over consumer cost-savings or provider well-being.

Reference 21, to save you a click, is a letter from Elizabeth Warren to CEO and President of Mars Inc — which in addition to hocking teeth-numbing treats is also apparently a veterinary behemoth — outlining her concerns about the industry consolidation with ever more references. An actual report would have to dig down into them and find primary sources for Gemini’s claims, but even this is publishable.

And here is the conclusion:

Ultimately, the hypothesis that veterinary medicine serves as a highly accurate proxy for human medical deregulation is remarkably robust. The comprehensive data confirms that stripping away third-party mandates, emergency care obligations, and unlimited tort liabilities yields a highly efficient, point-of-care transaction model that eliminates administrative bloat, enforces total price transparency, and accelerates clinical innovation. Yet, it simultaneously exposes the harsh, unyielding realities of a pure free-market health economy. The veterinary paradigm proves definitively that while deregulation optimizes the speed of scientific advancement and the profitability of specialty providers, it structurally abandons the foundational concept of healthcare as a universal human right, replacing it entirely with a ruthless, capital-gated commodity market.

Woah there, Gemini. With such strong language I do feel obligated to declare that the original prompt was as neutral as possible. I wonder what ChatGPT, Claude or Grok would have to say on the topic, and if Grok in particular would have a different view.

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.