I have been using OmniFocus since 2016 and from the very beginning have kept a running list of blog post ideas which I almost never use. ⊕ “Write about Taleb’s VC quote” says an entry from October 11, 2024. More than a year later I did write about it, but not because I saw it on the list and have in fact only just now realized that it was on the list in the first place. The oldest active entry is from August 15, 2021: “Write about theoretical biology”. The second-oldest is from four days later: “Write about Waddington’s epigenetics”. This was a few months before I had read any of his books, so maybe it was just mine discovering what Waddington did? In any case, consider this post as a way to cross both of these tasks off the list.

And yet again, the writing is not prompted by any list, but rather by this question on X — what are the major breakthroughs in biology that were idea-driven arguments based on existing data — which duly reminded me of CH Waddington (or, as iOS 26 autocorrect misspelled it just before I had hit return, “CH Washington”). Waddington, a proponent of theoretical biology as a parallel to theoretical physics, organized symposia in the late 1960s on the topic. Alas, it never took off. He died in 1975, age 69, just in time to see research funding for experimental biology skyrocket making everyone an experimental biologist. The theoretical part is now mostly mathematics: see, for example, the Mathematical Oncology newsletter, but what Waddington proposed was not really maths. Interestingly enough the man behind the newsletter, Jeffrey West, has co-authored a paper with Taleb that was very Waddingtonian, with a recent follow-up and a whole book (which I am yet to read).

For an example of what Waddington wrote about see his most well-known work: the epigenetic landscape, proposed before we even knew what genes were. To me these were incredibly useful when thinking about differentiation of complex cells and how it can go sideways. It is also incredibly annoying that the term epigenetic has been hijacked by molecular biologists to mean solely chemical changes to DNA and adjacent proteins which are more likely than not merely a sideshow to what really controls gene expression (3d structure, mRNA, other genes, i.e. everything that goes into a gene regulatory network). Ask a doctor what epigenetics means and the first thing they say will be acetylation and methylation, and if they are oncologists they will talk about “epigenetic drugs” whose job is to inhibit methylation (“hypomethilators”), or what not. I would wager that GLP1 inhibitors like Ozempic are more epigenetic than the most active hypomethilator, but I may as well go after windmills.

Now, the person who asked the question that kickstarted this thinking is the founding editor of Assimov Press which is a charming publication about science and scientific progress. I hope his asking questions will lead to more writing about what happened to theoretical biology and that I’ll learn more about people who carried the flame (or, more likely, rediscovered the concept after everyone forgot about poor old Waddington).

Update: Dr. West has pointed me to the work pf Sui Huang from the Institute for Systems Biology who has tried to bring to terms the two different meanings of epigeneticts with explicit tie in to GRNs. I am sure that very paper is where I got the notion from, but have of course completely forgotten about it. Thank you, Jeff!

📚 Finished reading: Breakfast of Champions by Kurt Vonnegut, which I had first read 20-some years ago and found merely amusing. Well, Vonnegut was in his late 40s and I turn 42 next month, and I found the entire thing more than just amusing this time around. Listen:

And here, according to Trout, was the reason human beings could not reject ideas because they were bad: “Ideas on Earth were badges of friendship or enmity. Their content did not matter. Friends agreed with friends, in order to express friendliness. Enemies disagreed with enemies, in order to express enmity. “The ideas Earthlings held didn’t matter for hundreds of thousands of years, since they couldn’t do much about them anyway. Ideas might as well be badges as anything. “They even had a saying about the futility of ideas: ‘If wishes were horses, beggars would ride.’ “And then Earthlings discovered tools. Suddenly agreeing with friends could be a form of suicide or worse. But agreements went on, not for the sake of common sense or decency or self-preservation, but for friendliness. “Earthlings went on being friendly, when they should have been thinking instead. And even when they built computers to do some thinking for them, they designed them not so much for wisdom as for friendliness. So they were doomed. Homicidal beggars could ride.

Ain’t that the truth…

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.

If you liked Ted Gioia’s reminiscence of David Foster Wallace that I linked to yesterday, you will love Gioia’s follow-up post with recommendations on where to start if you would like to read DFW’s work. To this I would add a plug for The End of the Tour (2015) which is now on my to-watch pile.

There is much to learn from Alan Jacobs’s brief post about the pleasures of reading, if you don’t take it too seriously. Who apologizes for re-reading? Where is the line between keeping count of books read and surveying what you have read in a year? And of course, if after a long day at the office and sharing some evening time with the family the only way to get to a book is to crack it open at 10pm while lying in bed and at least try to read, who is Jacobs (and who am I) to judge? We can’t all be humanities professors.

The Occasional Human Sacrifice puts faces, personalities, anxieties and neuroses to the names of people who acted as whistleblowers to some of the biggest ethical failures in clinical trials. Some are textbook, like Tuskegee or the Willowbrook hepatitis studies, but many were either new to me, or just barely registered when they were briefly covered.

Elliott was himself a whistleblower in the case of Dan Markingson so he is hardly impartial to their cause — caveat lector — but the cases presented seem truly egregious. And not all of them are ancient history: Paolo Machiarrini experimented on humans without oversight as recently as 2014.

The picture you get is bleak and does not fill one with confidence about clinical research anywhere in the world. Physician-scientists are careless at best, selfish profiteers at worst, people who sit on ethics committees are a bunch of box-checkers, institutions are insular and protective of their own. Of course, there is major selection bias going on: yes, institutions protect their own but then there are many of their members who are accused daily of misconduct by conspiracy theorists, biopharma lobbyists, and the occasional psychopath. Some IRBs are indeed approval mills, but then there are those which truly protect research subjects, though alas what they do doesn’t make it into a book. How to tell where the equilibrium should lie?

In fairness to the book, it does not pretend to be a grand unifying theory of what is wrong with medical research. It is a collection of vignettes, no more and no less, and as such is an important source of “real-world” information to the research community. It is also a big honking red flag to any person thinking to blow the whistle on wrongdoings medical or not: it is a difficult path to take, with no vindication at the end.

• Breakneck: China’s Quest to Engineer the Future, an intro to this book that will make its way onto the pile as soon as it comes out
• Inclusivity In Healthcare Should Not Be Valued Above Our Paramount Mandate: First, Do No Harm (controversial?)
• New capitalism III: Capital from Branko Milanović, who should be on the short list for the “Nobel” in economics for this series of posts alone
• Things: The Surprising Power of Stuff That Exists is a brilliant description of every book Malcolm Gladwell and his lookalikes ever published

Note: While these link posts are usually untitled, this one is in reference to recent troubles at the Marginal Revolution blog. Isn’t HTML great?

📚 Finished reading: In the Beginning… Was the Command Line by Neal Stephenson, almost thirty years old and more relevant than ever. Download it for free here, and if you think you don’t have time for all 65 pages Chapter 12 about the Hole Hawg should motivate you to read the entire essay.

📚 In response to Nassim Taleb’s list, here are 10 writers whose books I’ve read five or more of:

1. Agatha Christie
2. CS Lewis
3. JRR Tolkien
4. M. John Harrison
5. Kurt Vonnegut
6. Neil Gaiman
7. JK Rowling
8. Charles Dickens
9. Arthur Conan Doyle
10. Taleb himself (who is, I now realize, the odd one out here)

📚 Finished reading: Babel by R. F. Kuang. It has a simple world-building conceit, an ending that announces itself from the very title, and fully Hamiltonified (or is it Bridgertonified?) characters. And yet I couldn’t put the 500-plus pages away, because in an alternate but extremely adjacent universe I went off to study languages instead of medicine as I still eat up anything etymology-related.

Of course, had I known a month ago what I know now I would have taken up Jonathan Strange & Mr Norrell for a re-read instead: it is a deeper, more thoughtful, and infinitely more interesting take on magic in 19th century England. No powerful messages on colonizers and colonized there, sadly, but those I regularly get elsewhere.