A brief update to yesterday’s post notes that there are still people who care about the true meaning of epigenetics, and even call themselves theoretical biologists. Note that the Institute for Systems Biology is not some drive-by operation, and indeed is the home of this year’s winner of the Nobel prize in medicine. There may be hope yet. (ᔥJeffrey West, on X)
I did it: I have found my coffee preciousness threshold. Our local coffee shop changed suppliers and only had the beans depicted below to offer. The very helpful barista even offered to pack me a bag of their own in-house coffee beans, which I declined but should have taken as the warning it was.
Because the beans were… fine. For a light roast, and particularly for the price. Perhaps even on par with Bird Rock, though I will need to make more than one pot for a real test. But everything about this coffee was over-designed, from the embossed packaging to the transparent plastic bag holding the beans to the “tasting notes” insert tucked into the outside pocket. And just look at that website (and the price)!
I am in fact embarrassed for buying it. Who is this for, and do they also own a Juicero? I choose beer over wine because I am repelled by the (usually faux) sophistication of the wine connoisseurs. I’d better reign in my coffee enthusiasm or else switch to tea.
Joseph Heath: Populism Fast and Slow. An aside from this article did more to dissuade me from spanking (sorry, “whacking”) as a teaching method than anything Gelman cited. Its main point is also important, and I will quote it here:
People are not rebelling against economic elites, but rather against cognitive elites. Narrowly construed, it is a rebellion against executive function. More generally, it is a rebellion against modern society, which requires the ceaseless exercise of cognitive inhibition and control, in order to evade exploitation, marginalization, addiction, and stigma. Elites have basically rigged all of society so that, increasingly, one must deploy the cognitive skills possessed by elites to successfully navigate the social world.
As a card-carrying member of the cognitive elite, I fully support the rebellion.
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!
Last year, Nassim Taleb was on a podcast with Joe Walker. It became “controversial” in some circles because of some things he said about negative probabilities and quantum mechanics — ha ha, look at Taleb, barging into the wrong lane again — but the highlight for me was what he said about the world of startups and venture capital:
TALEB: No, no, the mechanism. They don’t make their money, venture capitalists, they don’t make money by waiting for the company to really become successful. They make their money by hyping up an idea, by getting new investors and then cashing in as they’re bringing in new investors. I mean, it’s plain: look at how many extremely wealthy technology entrepreneurs are floating around while not having ever made a penny in net income. You see? So the income for venture capital comes from a greater fool approach.
WALKER: Okay, so a Ponzi kind of dynamic?
TALEB: Not necessarily Ponzi, because you’re selling hope, you package an idea, it looks good, so you sell it to someone, and then they have a second round, a third round. They keep [doing] rounds so you can progressively cash in.
WALKER: Got it.
TALEB: It’s not based on your real sales. Or your real cash flow. Particularly in an environment of low interest rates, where there was no penalty for playing that game.
WALKER: Do you think there’s any skill in VC?
TALEB: They have skills, but most of their skills are in packaging. Not in …
WALKER: Not for the things people think.
TALEB: Exactly. Packaging, because they’re trying to sell it to another person. It’s a beauty contest.
Of course, these dynamics continue to be in play beyond the private equity stage, reigned in somewhat by financial market rules or what is left of them. Assuming what Taleb said was correct — and if you disagree you may as well skip reading (or better yet, drop a comment below because I would love to see the arguments against Taleb’s thesis) — the VC-backed startup model is uniquely ill-suited to funding drup development, and I would wager that many of the issues lamented over substack articles and policy papers can be traced back directly to its rise.
Of course, this blog being what it is you will not get graphs showing the parallel increase in sheer number of biotech startups, the cost of clinical trials, and the millions of dollars spent per sucsessful drug (by whatever definition you chose), with a few thousand words on why this particular correlation does imply causation. If you have enough time to make such a graph, please share. Instead, here are three reasons I came about by the way of armchair research for why biotech is not tech:
Larger freedom to bullshit (than tech)
Harder to test against reality (than tech)
Less end-user price sensitivity (than in tech)
The first two apply to many non-tech fields: social sciences, philosophy, interpretive dance, etc, and in those two ways it is tech, by which I mean both software and engineering (though software is somewhat more malleable) that is unique. What sets anything related to medicine apart is that sick people and their families are willing to spend unlimited amounts of money to get their health back, or even to just squeeze out a few more good months out of a dire prognosis. This is as true for America’s hyper-capitalist health care “system” as it is for any “socialized medicine” country whose citizens still find ways to collect money via online fundraiser or SMS services to send their loved ones abroad for life saving therapies and stem cell scams alike.
Freedom to bullshit is particularly large in cutting-edge fields, which are exactly the places where we wound now go to startups instead of established players to sow the seeds. The data is more likely to be confidential, not yet peer-reviewed or even presented at a conference. Uncertainty is always higher here, and this is why the professional sociopathic bullshitters will have an edge: earnestness may get you a miss congeniality prize but you will never get the crown.
Testing biotech against reality can only be done — for now — in clinical trials, and those are notoriously slow, expensive, and easy to explain away in case of negative results (see the case of Sarepta). A failed rocket launch is a failed launch: we will have learned more for the next one but can’t pretend we’ve reached orbit. It is also severely supply-constrained: there are only so many clinical trialists around, running clinical trials is not their day job, and those who find clinical research interesting are likely to jump ship and transition to industry further limiting supply. This is the area with most room for improvement and kudos to Ruxandra Teslo and Willy Chertman for making the case for clinical trial abundance, but there is a major headwind to their efforts:
Good health has no price or a variant thereof exists as a phrase in many, maybe most, world languages. Let’s not go into why that is (economist Robin Hanson has some interesting ideas), because my interest is in the outcome: the health care ouroboros.
Not to be confused with the ouroboreos What is that, you ask? It is the curious phenomenon of economists explaining that Americans pay more for health care than anyone else in the world because they subsidize the world’s drug development, while at the same time pointing to high costs of health care as a reason for why clinical trials in America cost so much! Truthfully, this would not be a problem if it didn’t directly contribute to item number 2, leading to an unsustainable positive feedback loop when it comes to price, and a negative one when it comes to actual working drugs making their way to patients.
So let’s review the proposed interaction between the three factors that has led to our current drug development quagmire. Bullshitters are attracted to the American medical honey pot. If there was money to be made in interpretive dance they would have chosen that, but alas it is health care that both has large amounts of money sloshing around and gives them enough freedom to perform their hijinks. The particularly outworldly bullshitters in other fields can only do this up to a point — Elizabeth Holmes hit a well when it came time to produce actual lab results — but in drug development reality is slow to come by and can be explained away, as noted above. If Liz had chosen therapy instead of diagnostics she could have avoided the anklet!
But so what? How does this prevent working drugs from coming to market? Well, it is more than anything a beauty contest: the better story wins, unrestrained by reality which is difficulty to know anyway because clinical trials are what they are. So, an otherwise sucessful drug is out-competed for clinical trials sites which can only run a certain number of trials at a time, until it is eventually dropped in the absence of a bullshitting champion. Who knows how many good drugs now languish in order for the likes of Sarepta to prosper? And this not because of any failure of structure-based drug design compared to screening, but because its rise as a drug development method came about at the same time as the field became more and more financialized.
I would like to highlight the last paragraph as an indication of me changing my mind about something, which is a rare occurrence. Two years ago almost to the day I wrote that no one was hiding miracle cures, mostly as defence of the FDA requiring clinical trials instead of “real-world data” for commercial approval of drugs. I still hide behind the final sentiment, but not behind the statement that there are no drugs that exist now which may be truly world-changing whose development is being held back by clinical trial regulation. I worry now that this indeed may be the case. The next step in bringing them to patients should not, however, be to loosen the criteria for market approval, but for getting them into trials as quickly as possible. And good luck doing that without breaking the vicious cycle of health care-trial-health care costs.
The first note is on quickly estimating the 95% confidence interval of an event rate when there are no observed events: if you observe n patients, and none of these patients have the event, then a 95% confidence interval for the probability of the event goes from zero to 3/n (source, with more mathematical detail than I care for). So, if you treat 5 patients and none of them respond, the true response rate could still be as high as 60%. Note that there are many drugs on the market now approved for response rates much lower than 60%, possibly because of the flipside of this calculation (5 of 5 responders could still mean that the true response rate is “only” 40%) combined with some persistence on the part of the developers. But are some drugs dropped too quickly? Probably, which increases the urgency of making clinical trials easier and cheaper to run.
Another implications is that in your standard 3+3 dose escalation design, where you go up in dose if the first 3 study participants don’t experience a dose-limiting toxicity, the 95% confidence interval of the DLT rate at that dose level is still 0 to almost 100%. So, the trials we are running aren’t giving us good enough information. Yay!
The second note, much les philosophical, is that there exists and online tool called reference extractor which can go through a document and extract all Zotero and Mendeley references from it for export into a variety of formats. It can also select those references in your Zotero library, which is life-saving for a slob like me who keeps his references haphazardly strewn across dozens of subfolders. This way anyone who asks can get a neat export, files included.
Christopher J Ferguson, Ph.D.: No, Conscientiousness Hasn’t Collapsed Among Young People in Recent Years. A while back, when I wrote about “journalist science”, I highlighted FT’s John Burn-Murdoch as someone who’s on thin ice with regards to methodology. Well, according to this article — which I have no reason to doubt — he punched a whole straight through and is now in some icy waters. Unlimited degrees of freedom combined with an incentive towards sensationalism do not make for rigorous research. (↬Adam Mastroianni)
Erik Hoel: John von Neumann Shot Lightning From His Arse. A delightful myth-busting of some of the more out-there stories about von Neumann. These have recently been spread by, erm, “pop-hereditarianists”, which I suppose are to eugenicists what alt-right is to national socialism. I further suppose these people would also marvel at Winston Churchill’s wit, hearing all the stories about him — it takes a certain dose of credulity to buy into ideologies that have long ago been debunked.
Kyla Scanlon: 30 Days, 9 Cities, 1 Question: Where Did American Prosperity Go?. “What became clear almost immediately is that the prosperity is real, it’s just not showing up in the places people actually live. It exists in balance sheets, in stock portfolios, in data centers behind chain-link fences. But in daily life like in commutes, in childcare costs, in housing, in safety, in community, people are feeling decay.” Maybe it’s the non-economist in me but what Scanlon is describing here does not sound prosperous at all. The balance sheets and stock portfolios are a jobs report away from melting into nothing. That is not prosperity, it is a house of cards.
📚 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…
November 12, 2025
📺 The Great British Baking Show Series 16 had fewer anxiety attacks and temper tantrums, and was more enjoyable to watch than last year’s. Still, the sheen is beginning to wear off, the artifice of it is becoming more and more apparent, and am I being a horrible person just for liking that a contestant doesn’t get all teary-eyed when kicked out?
Want to introduce some drama? Have people make madelains — a desert that needs at least four hours for the batter to chill to achieve its characteristic “hump” — in 2 hours 15 minutes total and then stress about not doing it correctly. Or, come judging time, be a bit more circumspect about the clear favorite and heap praise on the also-rans so that you can hem and haw about your very difficult choice. Also, is it just my middle age performing mind tricks or are the contestants getting ever-younger? Will there be a point in a decade’s time when Junior Bakeoff and the main attraction meld?
It is still by far the best “reality TV” one would come across, and following it from beginning does make one more interested in baking. As its cultural relevance grows, however, so does the amount of pressure it puts on the bakers, to the point of unpleasantness. Luckily, the finalists this year were wise beyond their years, but how many more people are left in Britain with that kind of mental fortitude?
Michael Eisen: Needed a word, so I coined one. The word is chrysotactic — being drawn to gold, wealth, luxury, etc. — which is derived from Greek but I have to say that the Latin aurotaxis has a better ring to it. You will never guess to whom it relates.
David Weigel: How Elon Musk’s Changes to X Made Our Discourse Far Stupider. This is not on X but rather an article in Talking Points Memo and I completely agree. And yet, people worth listening to continue using it and as long as that X is the only place where they write I will continue to follow. Perhaps.
