When I wrote that opening up science and increasing trust in it are mutually opposed goals, I didn’t imagine the perfect example would come up so soon in both the thing that happened and the commentary about the thing. It is helpful, when interpreting what follows, to keep in mind CS Lewis’s lecture on The Inner Ring with the following two adjustments: there are in fact many rings, concentric, with people ordered in them according to some gradient; and although academia has the secret rings Lewis talks about there are also many public ones with members known, where the innermost ring to a high degree overlaps with Harvard.

The first thing that happened was a segment on 60 Minutes, America’s premier newstainment show, about the current administration’s defunding of Harvard and the implications for science. A few scientists gave interviews, including a bench researcher whose lab studied “different aspects of cancer biology, including tumor heterogeneity, cell-cell interactions, tumor microenvironment, cancer metabolism, drug resistance, and cell signaling.” So, very much a “cancer researcher”, though as far removed from the practical aspects of cancer management as you can imagine. Still, from applying for grants to writing up research results for peer-reviewed journals, scientists have been conditioned to tie whatever they are doing to real-life, practical applications: in the interview Dr Brugge said what she and her post-docs must have written hundreds of times before, that her work has the potential to prevent breast cancer.

There is a legitimate discussion to be had about overblown claims to practicality. The debate has in fact been ongoing for decades now in the editorial pages of various scientific journals. But then someone formerly of Harvard, then Duke, then out of academia completely after a legal dispute, wrote about the issue in light of the segment. This is the second thing that happened.

The article for the most part lists personal observations about the two scientists interviewed for the segment (the second was David Liu, about whom the authors had kinder words). It very much had the sound of someone expelled from the circle grinding an ax with the inner ring. This led to even its salient observations being framed somewhat maliciously. For example:

Universities and their faculty have learned that success in today’s system depends not as much on actually doing science but on marketing the perception of science — framing even routine findings as lifesaving advances. “Cancer” has become a brand, a universal justification for more funding and prestige. The public sees heroism; insiders see dollar signs. One of the strangest features of this ecosystem is how many researchers who do pure basic science — work with no foreseeable medical application — nevertheless frame their research as “curing cancer.”

Which goes from pure speculation to undisputable fact. The need to frame everything as “curing cancer” stems from all the money being allocated to cancer research. It is all about the incentives: Willie Sutton robbed banks because “that’s where the money was” and scientists are no different.

But did I just, even in this gentler framing, compare scientists to bank robbers? See, this is why the debate is best held behind closed doors, lest a politician uses the fact that most research findings are false as an excuse to cut funding. This is what most comments to [Mike

This is the open science dilemma: have the debate out in the open and risk providing ammunition to your enemies? Or do it behind closed doors and risk mistrust? A few decades ago the point was moot as the “enemies” were first powerless hippies, then only slightly more empowered religious zealots. As we all know, the anti-science front has since strengthen. Why that is, well, that is yet another debate. Since one of the reasons is that many scientists openly picked sides, whether out of conviction or out of fear from being ostracized, this is also a debate best held behind closed doors.

Until that happens, we will continue to have dialogues such as this one, ⊕ The link is to what I think is the final post in the back-and-forth, which I think is the only guaranteed way to show the entire thread, but X truly wasn’t built for sharing these kinds of interactions and is not the best medium for having them. all in support of the beef-industrial complex. Other fields have already wised up: the Internet is dying on the outside but growing on the inside, with important conversations moving to private forums. Which, as I argued, they should.

After citing Niko McCarty’s list of 30 biomedical essays yesterday, I had an urge to find each and have a separate post linking to them. Well, good thing I procrastinated because he just came out with an ever longer list (130 and counting) that does have the links. Still no Mansions of straw…, but I’ve just asked asked him to consider adding it so let’s see how the list evolves.

• Niko McCarty: Here are 30 great essays about biology. They are indeed great, and it even includes one where I gave a modest and unattributed contribution (you will be able to guess which one). To this I would add William Kaelin’s Publish houses of brick, not mansions of straw, cited many times on this blog (most recently just last month).
• Jason Locasale: My latest article in The National Review on what 60 Minutes got wrong about Harvard and the biomedical research industrial complex, and why the deeper issues in science can’t be fixed by throwing more money at broken institutions. Here is the article, which I agreed with directionally but had so many “I know this person and let me tell you what they are truly like” moments that I thought there had to be a backstory to this insider-ish scoop. And indeed there was, as noted in responses to Michael Eisen’s tweet. So much drama, and all it does is make it easier for people to shrug their shoulders, say that it’s complicated, and defer to higher authorities (i.e., Harvard).
• Nassim Taleb: I believe this paper addresses, even solves, the most relevant statistical problem of the century, including the replication crisis & the fake results in publication. No false modesty here. Papers like this make me think that frequentist statistics are fine for the lab where you can truly do the same experiment over and over, but when it comes to clinical trials you can never cross the same river twice and we should all be Bayesians.
• Christopher Hooks: I sincerely believe that anyone pushing this should be shot. I agree in spirit. Whoever made this AI abomination should study Hayao Miyazaki and his work.

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 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!

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.

• David Li: lots of discourse on here recently on how to get FIH clinical data in US cheaper, faster, and more competitively with China. “One thing I have not seen folks talk about, which to me is the most obvious, is - wait for it - the intense competition that breeds insane levels of hard work in China.” From a clinical trial perspective, let’s not forget how receptive the audience is to clinical trials, and how deferential to the doctor/investigator’s opinion. (ᔥRuxandra Teslo)
• John Collison: Dave Ricks has been at @EliLillyandCo for 20% of its 150-year history. He came to the pub, poured his own Guinness, and gave us a 2-hour state of the pharma union. Fear not, there is also a YouTube video of the conversation.
• 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.

• Ruxandra Teslo: What will it take for AI to change drug discovery?. Producing boatloads of hypotheses won’t be enough, and would even set the field back. Good stuff. Again, China is eating America’s lunch here so something better change, and soon, but it is unlikely LLMs will be of immediate help.
• Chris Arnade: Asian style materialism. And if you think, well, maybe it is time for one civilization to sunset so that another one will rise, observations like Arnade’s should make you pause. The culture there seems rather bleak. And I consider him a rather impartial observer.
• Sarah Kliff for the NYT: The ‘Worst Test in Medicine’ is Driving America’s High C-Section Rate. It is about fetal HR monitoring, a particularly salient topic right now. It seems to be the Swan-Ganz catheter of obstetrics, thankfully much less invasive.
• Anish Koka on X: In the wake of the hubbub on novel promising gene therapy approval for Huntington’s disease, this video on the Sarepta debacle is a must watch. Can’t be… I am sure that everything was on the up-and-up.

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.