• 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.

• Derek Lowe: The Best Ideas Are Not Always Enough.

Drugs which look great in those cellular machinery flow charts with boxes and arrows pointing every which way, and which may even cure a few genetically monstrous and wholly artificial lab mice, tend to flop where it matters. Lowe links to 11 such examples and writes in more detail about the twelfth.

• Adam Kroetsch: Why clinical trials are inefficient. And why it matters.

An overly long article ⊕ ᔥNintil with which I don’t completely agree ⊕ For example, Kroetsch describes the role of a site investigator as resembling “that of a glorified data entry clerk - the investigator’s primary responsibility is gathering the data that the drug company needs and sending it to them”. This is incorrect: site investigators usually have clinical research coordinators and data managers to do it for them. But this deserves a post of its own. but which nevertheless provides a good overview of the many things wrong with how clinical trials are being conducted in the US, the biggest one being that they are reinventing the wheel each and every time they are done. The “lean trial” proposal at the end matches my own thinking.

• Ruxandra Teslo: A response to Dario Amodei on AI & clinical trials.

Teslo picks up on the tech bro magical thinking streak in which things you don’t sufficiently understand seem eminantly solveable using the most recent technological developments. Five years ago it was electronic medical records and blockchain, now it’s clinical trials and AI. The article gives the many reasons why things are not that simple. Now, if we all agreed on the set of LLM prompts that would provide an unbiased protocol and informed consent form review thus eliminating as many people from the loop as possible, well, then we may be on to something.

• Alex Tabarrok: If you have the right to die, you should have the right to try!

If someone qualifies for euthanasia, should they also not be eligible for every expanded acces, compassionate use, right-to-try scheme imaginable? Obviously: yes. Maybe not so obviously: there is a branch of my subspecialty aptly named desperation oncology which in the vast majority of cases leads to false hope, financial ruin and, worst of all, time misspent in doctors' offices and infusion clinics instead with your loved ones. As a doctor and a human being I am partial to life, so I see state-assisted dying programs like Canada’s MAID as monstrous, but “you’d rather be dead so here, take this drug” is only a half-step above that qualifier and leads to the bad reputation of experimental therapies.

• Rebecca Robbins and Gina Kolata for the NYT: Grail’s Cancer Detection Test Fails in Major Study. Some of my earliest tweets — now protected, so apologies for linking if you haven’t already followed me — were about Grail and why their project to screen healthy people for early signs of cancer would likely fail. Nine years and billions of dollars later…
• Peter Bonate: Drugs Explained. A layperson’s primer on drug development from a pharmacologist, available on GitHub.
• Colin Gorrie: How far back in time can you understand English?. One thousand years of the English language in one blog post.
• Joel Hawksley: How I built Timeframe, our family e-paper dashboard. It was quite the journey, interrupted by the Boulder County Marshall Fire which burned down more than a thousand buildings in late 2021. “On the night of December 31–January 1, heavy snowfall put an end to the fire.”
• ConchCat: I accidentally ate lunch with a cult. The cult in question is Twelve Tribes, accused of exploiting its followers as free labor, along with assorted abuses of women and children. But the sandwiches were good!

• Martha Lane Fox: The Price of initiative just collapsed. On the lag between invention and implementation, from printing press to AI.
• Scott Shambaugh: An AI Agent Published a Hit Piece on Me. A taste of what’s possible, with follow-up.
• Steve Blank: You Only Think They Work For You. About contracted service providers. The article is about public relations, but applies just as well to contract research organizations (CROs) and these complex dynamics are part of the reason clinical trials are so expensive.
• Andrew Gelman: The 80% power lie. A clear example of why frequentist statistics, so favored by conservative regulators, institutional review boards and scientific review committees, are more often than not based on false assumptions.
• Dr. Drang: Chinese New Year and Ramadan. The pseudonymous doctor often shifts between programming and scripting languages, from R through Python to Mathematica which coincidentally matches my own amateur programmer journey. For this post he used Emacs Lisp and I am very much interested in Emacs and Lisp right now due to recent experimentation with Linux. Saliency FTW.

I admire the fight for clinical trial abundance, I truly do, but the longer I think about it the more convinced I am that making nips and tucks to federal law and FDA guidance is the wrong way to go about it.

I have been involved in clinical trials for more than a decade and have seen it through the eyes of an investigator, sponsor and IRB member directly, and owing to a few friendships with ex-FDA employees, from the eyes of regulators as well. The common thread between all cases of delay and all frustrated attempts to speed things up were not laws and regulations but humans. The blankfaces and boxcheckers. Those IRB members who prefer the list of possible toxicities in a consent form in table form as opposed to a list, or a list as opposed to a table, and with percentages of expected occurrences instead of qualitative statements of possibility, but can you please explain what does percentages mean in qualitative terms, and is it “toxicity” or “adverse event”, and you should list only true toxicities not hypotheticals, except when we require you to add each potential adverse event — sorry, toxicity — whether it happened in this or other trials or not, and for each round of these changes there is another 3-week turn of the IRB roulette during which a different person may view the edits and give their own two cents — leave their own fingerprint.

And that is only the IRB! Their are personal imprints to be made at every level of clinical trial desing and implementation, between different departments of the Sponsor, “key opinion leaders" Or “KOLs”. The whole KOL ecosystem is worth writing about at length, just not today. sitting on advisory boards, administrators and worriers-in-chief at clinical trial sites, and even, rarely, clinical trial investigators themselves although in the US at least they are the ones least involved in clinical trials. More often than note, the way to leave your fingerprint is by citing a rule or a law or precedent from the FDA or the IRB or some other state-level regulatory agency whether or not said rule, law and/or precendent apply.

To be clear: most people in the clinical trial ecosystem are not like this. But much like airport noise complaints, in which one household accounted for almost 80% of all complaints, it only takes a handful of people to gum up the works and make it appar like the whole system has conspired against smooth trial execution.

So ho do we achieve abundance? Cutting down on the laws that govern trials is an option, and would certainly reduce the degrees of freedom at which blankfaces and boxcheckers operate. But America is a country of min-maxers and I can easily see things going sour with drive-by trials and phase 1 clinics being run out of a storage unit in South Florida. ⊕ Which operate even now, so just you wait for the walls to come down and the minmaxing trial beast to be unleashed. Chesterton’s fence and all that.

Could we not reduce the number of gummer-uppers in the chain instead? There are plenty of trials that are quick to start, quick to execute, and not even all that costly, largely due to people being reasonable. Can we inject more reasonable people into the ecosystem, if we can’t inject more reason into people who are already there?

This thought brought me to Delaware, the second smallest state of the USA that has 60% of Fortune 500 companies incorporated there owing to the convenience, flexibility and predictability of its corporate law system. To my layperson’s eyes it seems, from the example of Delaware, that its not the law itself that makes the difference but rather who implements it and how — which was on spectacular display earlier this week.

Convenience, flexibility, predictability.

Now clearly the Delaware of clinical trials can’t be Delaware — it is far too small and wouldn’t have enough trial candidates. But California, Texas, Florida and New York could all vie for the spot, each having a population similar to Australia, the phase 1/2 promised land. Texas was the first to make some waves, tiny and of an uncertain direction, but in the ballpark of what would be needed. The only changes that federal law needs are those that would allow the states to compete among themselves in being clinical trial champions.

If that last image made you think of China and its competing provinces, it is for a good reason: the Chinese have been eating everybody’s lunch for the past few years, in large part because of the vicious internal competition elaborated on elsewhere. There are other lessons there, for some other time.

• James Olds: The Hypothesis Trap.

Why no scientist should hang their hat on a single pet theory, with real-world examples. The same problem haunts the world of biotech even as its denizens claim their superiority at drug development.

• Bryan Vartabedian: AI Isn’t Ready for Your Patients.

About a recent Nature Medicine article which found that LLMs were no better than Google at helping patients diagnose and manage their self-reported maladies. The reasons are those that I suggested two and a half years ago — ChatGPT can give you the correct answer from a properly structured clinical vignette, but the art and science of medicine are transferring the reality in front of you — the patient’s haphazard story, their hodge poge of medical records, the subtle physical exam findings — into something salient. Not saying AI won’t get there at some point, but it clearly still needs work.

• Venkatesh Rao: vgr: The Twitter Years (2007-22).

Rao has collected 101 (!?) of his best Twitter threads and a few hundred single tweets into a book. A note on the title page says:

This book is LLM-friendly. Point your LLM to venkateshrao.com/twitter-book if you want it to explore it. A full interactive archive, explorable via an AI oracle, is under development.

Living up to his call to be (slightly) monstrous.

• Kriston Capps and Marie Patino for Bloomberg: Inside the Plan to Demolish and Rebuild a Swath of Trump’s Washington.

Yes, it is a person I hate making a good point, which is that the brutalist architecture of L’Enfant Plaza is out of place so close to the National Mall and should be kept where it belongs. I even prefer the proposed neoclassicist style to what Trump’s ego would want, which I imagine to be a Dubai ⊕ And even Dubai would be better than what’s in the President’s id. on the Potomac.

• Cabel Sasser: Wes Cook and The McDonald’s Mural. Sasser expands on his wonderful 2024 XOXO talk about a 10-year quest, which you should of course watch before reading.

• Luke Bouma for Cord Cutters: Babylon 5 Is Now Free to Watch On YouTube. Could it be true? Would the badly run and technologically incompetent Warner Brod Discovery really commit this act of unprovoked altruism on the official Babylon 5 Youtube channel? Of course not — as of today the uploaded pilot is set as private.

A rare day-job update: we have not one but two papers out in the journal Nature Medicine this morning. The first is clinical and the other biomarker data from the same randomized trial, both open access. The last big paper was more than two years ago, and the post-publication feeling hasn’t changed.

• Jason Kelly on X: The crisis in biotech startups is not just “biotech being cyclical” - you can see clearly that the rise in Chinese startups is not cyclical over the last 25 years - it’s spiking up in the last 10 years (see chart below from @AsimovPress). This is in response to a post from Bruce Booth arguing that the rise in Chinese biotech is not just a threat for the US but also an opportunity, and one that should be a cause for optimism. Booth responded in turn. I am close to finishing Apple in China and based on that alone I tend to side with Kelly. Riding dragons is a dangerous business, as both Apple and Tesla have found out in their respective industries. There are, of course, a few ways in which biotech is significantly different from cars and phones that requires some more thinking, but that is for a different post.
• Cory Doctorow on Mastodon: On December 28th, I delivered a speech entitled “A post-American, enshittification-resistant internet” for 39C3, the 39th Chaos Communications Congress in Hamburg, Germany. This is the transcript of that speech. Not just post-American but post-Chinese Internet as well, so this is a talk about robustness and dare I say antifragility through decentralization, not anti-imperialist rambling (although this being Doctorow there is some of that sprinkled in too). A video version is also available.
• Matthew Dowd on X: Pickle Expose: Sliced and Diced. Engrossing article in the form of a full-blown X post, with links, in-line images and half-decent typography. (ᔥJohn Gruber))
• Katyayani Shukla on X: Warren Buffett literally gave a free 1-hour masterclass on business. I saw the video and thought that Mr. Buffet was looking unusually spry for a 95-year-old! Well, the speech is from July 18, 2001 and is available in both YouTube video and transcript form, so there was no need for contextless X posts with worse quality video and audio. This particular one got 7.5 thousand likes and 2 thousand reposts in less than two days. I guess not everyone appreciates context and citation as much as I do. (ᔥJohn Mandrola, also on X)

Note: Despite three of the four links being from X, I have to admit that I am finding Mastodon more and more enjoyable and the superior of the four post-Twitter offerings, at least for me and my tastes. I am still vacillating on whether I should just use my micro.blog account to follow all non-X users, but then Ivory is too good of an app not to use. Advice appreciated.

• Ruxandra Tesslo and Asimov Press: Clinic-in-the-Loop

The case for faster bench-to-bedside-and-back type of research, with which I agree. It is remarkable, however, how each generation interested in biomedical research reinvents the wheel without checking prior art. I would also argue strongly that the (correct) thesis of the essay is not a refutation of the biotech-as-casino hypothesis but rather its confirmation, unless you enlarge “biotech” to include academia and government research but then what are we even doing. Investors have no patience for nuance and view clinical trials as dichotomous regardless of how companies try to present them, and interpreting translational research results requires even more patience and tolerance of ambiguity.

• Elizabeth Ginexi: The Quiet Power of Program Officers

Ginexi has been a program at the NIH for more than two decades, so caveat lector, but many POs are indeed mini-Moseses in their scientific domains. On one hand they perform important and valuable work, on the other the importance of a single human being to the careers of investigators young and old tend to favor those with soft skills of communication more than those of scientific and intellectual rigor. No judgements on my end because I genuinely can’t tell if the alternative would be any better.

• James L. Olds: A Grant Reviewer’s New Year Advice to Proposers: What I’d Tell My Younger Self

Some genuinely good advice on how to write grants in a way to increase the odds of them being funded, with emphasis on accepting the reviewers' comments and suggestions and approaching the grant resubmission as one would an offer to revise and resubmit a scientific manuscript, with much thanking and back-bending. Do keep that in mind when you read the next item.

• Laurel Raffington: Academia is just a job

This is true for most, as there are far too many academic right now for all of them to have soul in the game. However, academia continues to ask for more than it gives back out of too many people, while at the same time putting a negative selection pressure against people who are stubborn, single-minded and thus predisposed to a soul-in-the-game phenotype (see above). The only reason why the system survives at all is that the churn has been too low to fully reveal the tension, but it continues to creep towards the breaking point providing yet another case study of things that happen gradually and then suddenly.