Where are all the trillion dollar biotechs? asked Lada Nuzhna in her rarely updated blog. I will paste only the conclusion but the entire post is thoughtful and well-documented:

Drug development, like any other industry, is greedy - it addresses the most tractable diseases with the biggest outcomes first. Genetic targets, clear biomarkers, and one-pathway wins gave rise to the biotech boom of the 70 and 90s, when recombinant insulin, monoclonal antibodies, and early gene therapies created a sense of an endless frontier. Unlike with other industries, reinvesting capital from those early wins back into the ecosystem didn’t accelerate industry’s progress – we’ve been on a reverse trend for a while now. Today, remaining problems resist the very playbook this industry was built on.

Most industries have eras when progress stalls before a new paradigm unlocks scale again. Electricity needed transmission grids, computers needed operating systems, and aviation needed jet engines. For biotech, whether the shift will come from new modalities, new regulatory frameworks, or entirely new ways to validate efficacy in humans is not yet clear, but we can, perhaps, outline the boundaries within that future will exist: manufacturing and trials should get cheaper with each run, regulations should become more adaptive, approval frameworks should increase and not decrease in variance, and new therapeutic modalities should focus on unlocking new biology, not just producing slightly better iterations on problems we already know how to solve. Until those new paradigms take hold, building a trillion-dollar biotech will remain caught in Lewis Carroll’s logic: running as fast as we can just to stay in place, and twice as fast to make any real progress.

Note that “trillion-dollar biotech” is (hopefully) just shorthand for a company that produces truly world-changing drugs, and is rewarded accordingly by the all-knowing all-seeing Mr Market to reach a trillion-plus valuation. But if you put dollars first and benefit to humanity second, would that not perhaps contribute to these Alice in Wonderland dynamics? Maybe it’s the gold-digging approach to this decades-long gold rush that caused the shovels to become so expensive, maybe even more valuable than hitting gold. More than that: hitting gold — i.e., developing an effective drug — in this topsy-turvy world can even get you punished.

As Kyla Scanlon stated so succinctly, it is a casino economy now. In biotech it isn’t just now but from its very inception, as I have recently learned, and surely there are downstream effects in this approach to drug development. Again, Nuzhna’s blog post is exceptionally well-written and researched but maybe just maybe the problem deserves to be reframed?

• June 25, 2024: Inside the controversy over FDA’s recent gene therapy approval
• July 18, 2025: Analysts demand transparency after Sarepta’s roundabout disclosure of 3rd patient death
• July 18, 2025: FDA Requests Sarepta Therapeutics Suspend Distribution of Elevidys and Places Clinical Trials on Hold for Multiple Gene Therapy Products Following 3 Deaths
• July 30, 2025: Prasad Resigns From Top FDA Post Amid Fallout Over Sarepta Dispute.
• August 7, 2025: The Sarepta Scandal: Laura Loomer, Vinay Prasad, and the history of pharma’s latest attempt to reassert control at Trump’s FDA
• November 3, 2025: Sarepta’s Duchenne confirmatory trial fails, but biotech will ask FDA for full approval anyway

All this for drugs that cost millions of dollars per dose from a company with $2B in revenue. Neutral people in the know have their opinions too. Know me by my enemies indeed.

• Rusty Guinn: Conjuring Consent. Is ignorance, malice or cynicism behind ICE’s attempts to co-opt Lord of the Rings into their anti-immigration narrative? I would say it’s their propensity to bullshit, which matches Guinn’s cynicism take. See also: Guinn on the “woke right”.
• Neil Armstrong for the BBC: Slow Horses: The anti-James Bond that gets to the heart of Britishness. Written last year just after Season 4 started, but seeing as Season 5 was even better it is truer than ever.
• Tanner Garity: Kurt Vonnegut’s Advice for Making the Most of Your Day. Read this only for the exceptionally relevant story from Vonnegut’s 1995 interview with Inc., which isn’t the primary link because it lies behind a paywall. A Vonnegut quote from that interview: “The information superhighway will be two lanes loaded with tollgates, and it’s going to tell you what to look for.”
• Oliver Burkeman: You have to do the living yourself. In which Burkeman answers the question of “Isn’t there something I could do, some rule I could follow, such that if I obediently followed the rule, I wouldn’t have to show up for life, in all its uncertainty and riskiness and intensity, in quite such a full-on way? So I could sort of hang back, hide out, and take things a bit easier instead?” and of course the answer is no.

It wasn’t my imagination: the MacOS 26 Tahoe slowdown I noted immediately after upgrading was due to an Electron bug. Shamelectron (↬ATP) is a website that helpfully lists all Electron apps that are yet to fix it. The last holdout on my Mac has been Logitech’s Logi Options, which is now deleted and everything is — knock on wood — flying like before. Whew.

🎃 At a friend’s recommendation, our trio of children dressed up as Greg, Wirt and the frog from Over the Garden Wall, a family favorite for over a decade now. To our surprise and delight, they kept being recognized. A group of millennials handing out candy even broke out into song (To Adelaide, then Potatoes and Molasses). “Greg” had some candy in her pockets to throw out each time people guessed, but soon ran out and had to recycle the hard-earned treats from her bag. So, I’d call this Halloween a great success.

Rejoice: our national nightmare is over, at least until March.

The Billion-Dollar Molecule tells the story of the late 1980s and early ’90s world of biotech. The only change since then has been that ⊕ Well, there is one more difference. One billion United States dollars in September 1989 is 2.5 billion of 2025’s USD. one no longer faxes a manuscript and sends supplemental materials by snail mail when submitting to the journal; the personalities, incentives, tradeoffs and challenges are all the same.

Also typical of biotech, and sobering, is that 95% of industry-led research Werth described in the book did not matter: for all the lofty ideals of rational drug design espoused at road shows in investor slide decks, Vertex would chase one fad after another hoping for a hit. Once it got one, a truly life-changing set of drugs for cystic fibrosis, it had burned through so much money and became so profit-driven that it actively blocked low and medium-income countries from developing generic versions. Score for big pharma, which has no qualms about giving away drugs where they are needed.

The story was engrossing enough for me to tolerate Werth’s pulpy writing style, full of adjectives for tortured scientists and smoke-filled rooms. One could easily imagine it serialized on Netflix with distinct chapters, and it had indeed been shopped around, apparently without success. That last link ends with a side note that a movie about Theranos was also planned, and the juxtaposition is apt: more than once Werth notes the dramatic discrepancy between what Vertex management tells investors and the ground truth in the labs. There is certainly a difference between the sociopathy of Elizabeth Holmes and the goings on at your typical fly-by-the-seat-of-your-pants private startup, just not as large as you may think. This is, after all, why most of them go bust.

📺 Six episodes in, Season 5 of Only Murders In the Building — the only show we were excited about on Hulu — has been a thorough disappointment, and now Disney+ hits us with a whooping 100% increase in the annual subscription for its package deal. Granted, we were grandfathered into the $80/year plan and the new one is still better than the current price of standalone Disney+ Premium, but still — how much is it worth to pay for something you will never use?

By the way, the link above is to the Disney+ pricing website, and it is confusopoly on steroids, a roadmap to the world Philip K. Dick so brilliantly described in Ubik. I regret every bit of schadenfreude I had canceling cable.