• Ruxandra Teslo and Jack Scannell: To Get More Effective Drugs, We Need More Human Trials. I maintain that this will be nigh-impossible to do in the US until we break the healthcare ouroboros. AI as used now, to increase the number of drug candidates without making a dent in the speed of actually testing them, will only make things worse.
• Benjamin Mazer for The Atlantic: Yes, Some Children May Have Died From COVID Shots. Indeed, and the attempts to say otherwise can only Streisand the issue that should have been just a footnote to the long list of historical vaccine concerns.
• Simon DeDeo: Advice for Early-Career Academics, Part I: Mentorship. No-nonsense advice I wish I had 20-some years ago. I particularly like the distinction between mentors, supporters, fans, friendly elephants and noble adversaries. Left unmentioned are the many people who don’t have your best interest at heart.
• Michael Levy on YouTube: “Hurrian Hymn no. 6” (c.1400BCE) - Ancient Mesopotamian Musical Fragment. The Hurrian songs come not from Mesopotamia but from Ugarit, a city in what is now northern Syria which was one of many victims of the Late Bronze Age collapse. One would hope this would put to rest any questions on whether the humans of that age were like us, but then there are people alive now who don’t think their contemporaries are anything like them.

• Michael DePeau-Wilson for Asimov Press: Why the FDA Is Slow to Remove Drugs. And more importantly, why this is bad. You can’t accelerate drug approvals without also doing more culling on the back end. Symmetry, please.
• James L. Olds: Why Transformational Science Can’t Get Funded: The Einstein Problem. I disagree with most of it, but it is in fact the institutional point of view.
• Anonymous for the Good Science Project: A Top Scientist’s Ideas as to NIH. Did AI write this? Not great, but again, an institutional point of view masquerading as call to reform.
• Bryan Vartabedian: Physician authority and influence. An important distinction, and kudos to Dr. Vartabedian for coping that he has more influence than authority. I, on the other hand, have neither.
• Joe Boudreau: On 10 Years of Writing a Blog Nobody Reads. I have been doing it for at least 15 (13 of those in English) and it is in fact wonderful.
• Todd Vaziri: The “Mad Men” in 4K on HBO Max Debacle. The best and most concise review of this royal screwup of one of my favorite shows.

“The internet is dying on the outside but growing on the inside”, wrote Yancey Strickler last month in a follow-up to his 2019 essay The Dark Forest Theory of the Internet. To avoid misunderstanding, malicious interpretation, competitive intelligence gathering and cancelation, conversations have been moving from the public-facing “social” “media” to gated, invitation-only services (e.g., your favorite Substack author’s members-only discussion forum) and private group chats (e.g., the Let’s Bomb Yemen Signal texts).

But some parts of this Cozy Web are growing faster than others, and as if often the case doctors and scientists are ruled by inertia. Both groups have the perfect setup, in the form of professional societies, to carve off some gated space in which to have potentially controversial discussions without providing fodder to “the enemy”. ⊕ In these kinds of metaphors I always reach out to Venkatesh Rao’s The Internet of Beefs, which explains quite well why the public Internet has turned into a dark forest in the first place. And yet even the most developed online community program I know of — American Society of Clinical Oncology’s myConnection — is a stuffy, ⊕ ASCO boasts as having more than 50,000 members. The two largest “communities” on MyConnection, “New Member” and “Women in Oncology”, have more than 9,000 members each yet the last post on one was 9 days ago (with zero replies) and 7 days ago (two replies). All of November, the more active WiO group had 9 posts with median 1 reply (range 0–20). formal messaging board that can barely be considered active. Most of ASCO’s online activity is still on X, where the official account has almost 150,000 followers and the hashtag for its annual meeting is heavily promoted. Other large hematology/oncology societies like ASH (hematology) and AACR (general cancer research) don’t even have that. Their “online community” is a member directory and heavy promotion of in-person conferences, which I can only assume are the true money-makers.

So I have to wonder, do they still deserve to call themselves “societies”? It is, after all, 2025 and much of life has moved online. By not providing an avenue for true internal discussion and instead promoting public debate, are they hurting their members' cause more than helping? ⊕ Yes, it was fun to post out in public when there was a slight chance that your favorite celebrity — or the POTUS — would retweet your post, but we have since learned that this is a liability more than a benefit and there are more high-follower accounts on X now that I would rather avoid. I have argued recently that scientists may want to button up their conversations if they are to keep or regain trust. Should these societies not be providing the means to do so, and not only once per year in a stuffy conference room? ASCO’s MyConection is on the right track, but much too formal. Yes, give people the opportunity to create subgroups and even more private chats as you do now. But if you think debating on X with millions of spectators is healthy, why not give all 50,000-plus members a chance to interact by default, and do so in a format that is not an early 2000s web forum?

Concluding the most recent article, Yancey Strickler provided a toolbox for people to create their own communities which he called the Dark Forest OS, of DFOS. While laudable, this effort is to put it bluntly too artsy fartsy for me. Strickler comes from the world of “creators” whose sensibilities are much different from those of doctors and scientists. But then science and medicine already have much of DFOS in place, from a members list to paying dues. The only thing we need now is for the said societies to build their walled gardens — with an app included! — which they would promote instead of X at the annual meetings and other conferences.

Where a SciMeDFOS would come useful is at smaller scale, for collaborative groups and maybe even large individual labs, where members are known but there are no dues, funds, or IT workers ready to build a custom Twitter clone. If I were to make one now I would probably use Hometown, which is a fork of Mastodon that enables local-only posting, though it being a single person’s passion project makes me a bit reluctant. But then what else do we have, Discord, WhatsApp and Signal? Whatever Dave Winer comes up with in collaboration with Wordpress? Maybe Squarspace could make creating private Twitter clones be as easy as creating websites? I will be on the lookout.

• Rachael Bedard: I Went to an Anti-Vaccine Conference. Medicine Is in Trouble. Tragic considering all the good vaccines have brought us, most recently against cervical cancer. And the news from the FDA is, of course, a disaster from any perspective.
• Kurt Streeter: How to Fix a Typewriter and Your Life. A palate-cleanser for the above. And if this piques your interest, Chris Aldrich has a wonderful primer on learning typewriter maintenance and repair.
• Ross Douthat interviews Paul Kingsnorth: ‘This Is the War Against Human Nature’. Not the only interesting interview Dothat made, and they make for better reading than listening.
• Jeff Giles: How I Began to Love Reading Again. I too loved If on a winter’s night…

Enjoy!

Today I learned, thanks to a leaked email from Vinay Prasad to his staff, ⊕ I also learned that Prasad puts a double space after each period which is inexcusable in 2025 when we all use variable fonts on our electronic devices, not a fixed width-font typewriter. Whatever his high school typing teacher told him, he should drop the habit.that FDA’s CBER does actual bench research. This is pure stupidity on my part, as it is right there in the name: Center for Biologics Evaluation and Research. Silly me. They have a page dedicated to describing the work of their 65 principal investigators, and it seems to be at least on par in topics and rigor to the work done at the NIH Intramural Research Program though the latter if of course bigger.

Prasad’s email boils down to this: CBER research staff has strayed from its mission, which is primarily regulatory. We will look at work performed and planned and cut that which is not in line with the mission. He invokes sunken cost fallacy by name, so one would assume work in progress will also be cut, maybe even things completed that haven’t yet been written up — why spend hours formatting a manuscript when you could be reviewing IND Investigational New Drug applications and BLAs Biologics License Application, and let me use this sidebar to note how infuriating it is that one acronym includes the word “application” in it and the other doesn’t, forcing one to resort to clumsy phrases such as the one to the left. I supposed you could write “BLAs and IND applications” but that is listing them out of sequence. instead? And we certainly shouldn’t abuse the privilege of conducting research without having to apply for grants by just padding our CVs with insignificant work that will never be cited, which is another thing Prasad rises against.

My initial reaction was “damn right” but then I realized that regulatory review is just another price scientists-at-heart pay in order to do the work they want, similar to teaching in academia and low pay with no opportunity for outside activities at the NIH IRP. I suppose that eliminating the opportunity for self-directed research — which is what Prasad proposes instead of, let’s say, cutting it down to 10–20% of one’s time — would select for a certain type of a person (I imagine a box-checking blankface) but is that what we want? Is that what Prasad wants?

The tedious and unappreciated work of regulatory review is the price some scientists are willing to pay in order to perform research. Giving scientists the opportunity to do the work that’s meaningful to them is the price the FDA may have to pay to get good people to perform regulatory review. Any important scientific contributions that arise from this concession should be seen as an unexpected gift, not a requirement for staying employed as a reviewer.

• Tom Forsyth on Mastodon: “Recent discussion about the perils of doors in gamedev reminded me of a bug caused by a door in a game you may have heard of called Half Life 2.” Parallels in biology immediately come to mind.
• David Roberts on Blue Sky: “In an era filled with tech dipshits who never developed emotionally past the age of 13 & use their wealth to become odious monsters … listen to Steve Wozniak.” We are where we are in big part because there weren’t enough Steve Wonziaks in key industries when it mattered. Or rather, because they by definition bowed out and gave the sociopaths free space to roam.
• Ruxandra Teslo on X: “We should do smth abt this.” The “this” is the threat of clinical trial infrastructure being flooded by the biotech equivalent of AI slop. And many misguided people think that this is a good thing!
• Joe Janizek on Substack: The birth of Advanced Radiology. Or: radiology as chess. Radiology and pathology are the few areas of medicine in which AI may be produce immediate benefit.
• Nassim Taleb on Substack: Medical Mistakes with Probability, 2. Why the benefit of statins in people with barely elevated cholesterol and no other risk factors is grossly overestimated. Note that this constitutes most of the market for statins! My cynical take: Now that they are all out of patent I don’t think anyone would complain about cutting back.

• 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.

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:

1. Larger freedom to bullshit (than tech)
2. Harder to test against reality (than tech)
3. 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.

• 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?