Did Your Cancer Treatment Just Get Taken Away?

It starts with a little bump on your neck. You notice it when your hand brushes against it while you’re washing your hair, but at first you don’t pay it much attention. Then your spouse looks at your neck and asks you “What’s that?” It’s a little brown bump, maybe a mole. You think that maybe you should get it checked out by a dermatologist, but you forget to make an appointment, because work has just been so busy lately.

Then a few weeks later you look at the bump again, and it looks noticeably bigger. This time you call the dermatologist, but the soonest they can get you in is three weeks from now. By the time you’re in the doctor’s office, the bump is at least double the size it was when you noticed it. The doctor is tense and concerned, and he does a biopsy. Five days later you get the result over the phone: Melanoma.

“That’s cancer, right?” you ask, just to confirm, feeling something fall away in the pit of your stomach. “Yes,” the doctor’s assistant confirms. “That’s cancer.”

Cancer. The word is like the fall of an axe, cutting off the future you had imagined for yourself. Now instead, the days ahead are filled with surgeries, chemotherapy, radiation, CT scans, MRIs. You will never again entirely be free of the eternal gnawing fear of discovering that the cancer has spread. Your hair is going to fall out, you’re going to go under the knife, you’re going to be weak and sick. You’re going to to read everything there is to read about cancer, and it still won’t help. It may go into remission, or you may die, but your life will never read the same.

This story reflects the sad reality of life for millions of Americans. Cancer is the second most common cause of death, just barely behind heart disease, killing over 600,000 every year. And every year, almost 2 million Americans are diagnosed with new cases of cancer. Some kinds, like prostate cancer, are usually manageable; others, like pancreatic cancer and glioblastoma, are practically death sentences.

Now, there’s a common myth that cancer is an intractable disease that will never succumb to modern medicine. In 1971, President Richard Nixon launched the so-called “War on Cancer”; for many years, it was fashionable to say that cancer had won the war. But in fact, since around 1990, humanity has been making steady gains. Thanks to advances in early detection, screening, and various treatments, as well as the drop in smoking and a vaccine against a virus that causes cervical cancer, death rates have fallen at every age for almost every type of cancer. For a while this was masked by an increase in lung cancer from the smoking boom, but now that’s over too:

The problem is that since the population is growing steadily older, overall death rates are still higher than they were in Nixon’s day:

We’re delaying death from cancer, but not eliminating it.

In recent years, however, an explosion of new therapies has promised to accelerate our progress in treating the disease, changing the very nature of what it means to have cancer. The most promising of these are immunotherapies — medical techniques that use the body’s own immune system to attack cancer cells. And of those therapies, one of the most promising is mRNA vaccines.

Yes, mRNA vaccines — the same kind of technology that we used to vaccinate Americans against Covid during the pandemic. But it works a little differently. These mRNA cancer vaccines aren’t something that everyone takes in advance, to prevent themselves from getting cancer — instead, they’re a type of therapy that you take after you get diagnosed with the disease. Often, the vaccines are personalized, meaning that they develop a specific vaccine for your particular cancer.

mRNA vaccines, in combination with other therapies, promise to contain many cancers, turning them from a death sentence into a manageable, non-fatal disease. These vaccines are currently in development to fight all of the biggest killers: lung cancer, colon cancer, pancreatic cancer, breast cancer, and melanoma. They’re even being used against glioblastoma, the most aggressive and common type of brain cancer. There are even some tantalizing results suggesting that mRNA could soon be used to create a universal cancer therapy.

Imagine how the story I told at the top of this post would go in an age of highly effective mRNA therapies. Instead of being sentenced to years of gut-wrenching fear, possibly followed by an agonizing death, someone diagnosed with cancer would simply sigh and realize that they would have to spend a bunch of money on treatments for the foreseeable future. That is the world toward which science is taking us.

And yet now all of this is in danger. The MAGA movement, which now holds near-absolute political power in America, has gone to war against mRNA technology. RFK Jr., Trump’s Secretary of Health and Human Services and a prominent vaccine skeptics, just canceled a large amount of federal funding:

The Department of Health and Human Services (HHS) announced this week it is beginning a "coordinated wind-down" of federally funded mRNA vaccine development.

This includes terminating awards and contracts with pharmaceutical companies and universities and canceling 22 investment projects worth nearly $500 million. While some final-stage contracts will be allowed to be completed, no new mRNA-based projects will be initiated, the HHS said.

Officially, all of the cancelled funding is supposedly for mRNA vaccines for upper respiratory illness — basically, Covid and anything that looks remotely like Covid. So officially, cancer research isn’t being cancelled — yet. But cancer researchers are terrified that this move will derail their whole field, and with good reason. The chilling effect of this funding cancellation will cause a general loss of enthusiasm for the technology.

If you’re a researcher developing an mRNA treatment for lung cancer, how would you rate your chances of RFK Jr. approving your therapy for mass use when it has “mRNA” in the name? If you’re a private funding organization, do you really want to fund a technology that the government — and a large chunk of the American electorate — has an irrational vendetta against? What lab is going to want to allocate resources toward a field that’s marked for destruction? And what aspiring researcher is going to want to dedicate their career to it? (...)

So it’s very possible that thanks to RFK Jr., the Trump administration, and the MAGA movement writ large, cancer vaccines will not be available nearly as soon as it looked like they would just a few months ago. Eventually, the technology will be developed, with some combination of funding from Europe, China, private companies, and so on. But in the meantime, many people — including many Americans — will experience the nightmare of a traditional cancer diagnosis, like what I described at the top of this post.

Why is this happening? Why is the U.S. government attacking the technology that offers us the greatest chance to defeat one of humanity’s oldest and most terrible scourges?

It’s pretty easy to trace the reasons historically. During the pandemic, the antivax movement took over the American right — possibly because of fear of needles, possibly as a macho way to express bravery against the virus itself, possibly because of instinctive dread of modern technology or expert consensus or government recommendations. But whatever the reason, Trump — despite having authorized the project that created mRNA vaccines, and despite wanting to take some deserved credit for defeating Covid — was forced to accede to the wave of antivax sentiment, and to ally with it in order to win reelection in 2024. Part of that meant hiring RFK Jr. and putting him in charge of HHS — a political marriage of convenience.

But fundamentally, it’s hard to fathom just how America arrived at this juncture. We’ve certainly seen both sides of the U.S. political divide embrace blatant lies in order to express solidarity. For the right, the biggest lie was always that climate change isn’t happening, or isn’t caused by humans. Climate denial might seem like a lie without consequences — after all, the worst harms from climate change are going to arrive decades in the future. But because green energy technologies also happened to become cheap, the right-wing dogma that anything “green” is bad is causing the MAGA movement to oppose the cheapest and most reliable energy sources available:

Not having cheap energy is certainly bad. But dying of cancer? You’d think that would be a bridge too far, even for Trump’s followers. But recall how during the Covid pandemic, right-wing types died in droves because they refused to take the life-saving vaccine: 

by Noah Smith, Noahpinion |  Read more:

Image: OurWorldInData

Of Mice, Mechanisms, and Dementia

“The scientific paper is a ‘fraud’ that creates “a totally misleading narrative of the processes of thought that go into the making of scientific discoveries.”

This critique comes not from a conspiracist on the margins of science, but from Nobel laureate Sir Peter Medawar. A brilliant experimentalist whose work on immune tolerance laid the foundation for modern organ transplantation, Sir Peter understood both the power and the limitations of scientific communication.

Consider the familiar structure of a scientific paper: Introduction (background and hypothesis), Methods, Results, Discussion, Conclusion. This format implies that the work followed a clean, sequential progression: scientists identified a gap in knowledge, formulated a causal explanation, designed definitive experiments to fill the gap, evaluated compelling results, and most of the time, confirmed their hypothesis.

Real lab work rarely follows such a clear path. Biological research is filled with what Medawar describes lovingly as “messing about”: false starts, starting in the middle, unexpected results, reformulated hypotheses, and intriguing accidental findings. The published paper ignores the mess in favour of the illusion of structure and discipline. It offers an ideal version of what might have happened rather than a confession of what did.

The polish serves a purpose. It makes complex work accessible (at least if you work in the same or a similar field!). It allows researchers to build upon new findings.

But the contrived omissions can also play upon even the most well-regarded scientist’s susceptibility to the seduction of story. As Christophe Bernard, Director of Research at the Institute of Systems Neuroscience (Marseilles, Fr.) recently explained,

“when we are reading a paper, we tend to follow the reasoning and logic of the authors, and if the argumentation is nicely laid out, it is difficult to pause, take a step back, and try to get an overall picture.”

Our minds travel the narrative path laid out for us, making it harder to spot potential flaws in logic or alternative interpretations of the data, and making conclusions feel far more definitive than they often are.

Medawar’s framing is my compass when I do deep dives into major discoveries in translational neuroscience. I approach papers with a dual vision. First, what is actually presented? But second, and often more importantly, what is not shown? How was the work likely done in reality? What alternatives were tried but not reported? What assumptions guided the experimental design? What other interpretations might fit the data if the results are not as convincing or cohesive as argued?

And what are the consequences for scientific progress?

In the case of Alzheimer’s research, they appear to be stark: thirty years of prioritizing an incomplete model of the disease’s causes; billions of corporate, government, and foundation dollars spent pursuing a narrow path to drug development; the relative exclusion of alternative hypotheses from funding opportunities and attention; and little progress toward disease-modifying treatments or a cure.

The incomplete Alzheimer’s model I’m referring to is the amyloid cascade hypothesis, which proposes that Alzheimer’s is the outcome of protein processing gone awry in the brain, leading to the production of plaques that trigger a cascade of other pathological changes, ultimately causing the cognitive decline we recognize as the disease. Amyloid work continues to dominate the research and drug development landscape, giving the hypothesis the aura of settled fact.

However, cracks are showing in this façade. In 2021, the FDA granted accelerated approval to aducanumab (Aduhelm), an anti-amyloid drug developed by Biogen, despite scant evidence that it meaningfully altered the course of cognitive decline. The decision to approve, made over near-unanimous opposition from the agency’s advisory panel, exposed growing tensions between regulatory optimism and scientific rigor. Medicare’s subsequent decision to restrict coverage to clinical trials, and Biogen’s quiet withdrawal of the drug from broader marketing efforts in 2024, made the disconnect impossible to ignore.

Meanwhile, a deeper fissure emerged: an investigation by Science unearthed evidence of data fabrication surrounding research on Aβ*56, a purported toxic amyloid-beta oligomer once hailed as a breakthrough target for disease-modifying therapy. Research results that had been seen as a promising pivot in the evolution of the amyloid cascade hypothesis, a new hope for rescuing the theory after repeated clinical failures, now appears to have been largely a sham. Treating Alzheimer’s by targeting amyloid plaques may have been a null path from the start.

When the cracks run that deep, it’s worth going back to the origin story—a landmark 1995 paper by Games et al., featured on the cover of Nature under the headline “A mouse model for Alzheimer’s.” It announced what was hailed as a breakthrough: the first genetically engineered mouse designed to mimic key features of the disease.

In what follows, I argue that the seeds of today’s failures were visible from the beginning if one looks carefully. I approach this review not as an Alzheimer’s researcher with a rival theory, but as a molecular neuroscientist interested in how fields sometimes converge around alluring but unstable ideas. Foundational papers deserve special scrutiny because they become the bedrock for decades of research. When that bedrock slips beneath us, it tells a cautionary story: about the power of narrative, the comfort of consensus, and the dangers of devotion without durable evidence. It also reminds us that while science is ultimately self-correcting, correction can be glacial when careers and reputations are staked on fragile ground.

The Rise of the Amyloid Hypothesis

In the early 1990s, a new idea began to dominate Alzheimer’s research: the amyloid cascade hypothesis.

First proposed by Hardy and Higgins in a 1992 Science perspective, the hypothesis suggested a clear sequence of disease-precipitating events: protein processing goes awry in the brain → beta-amyloid (Aβ) accumulates → plaques form → plaques trigger a cascade of downstream events, including neurofibrillary tangles, inflammation, synaptic loss, neuronal death, resulting in observable cognitive decline.

The hypothesis was compelling for several reasons. First, the discovery of the enzymatic steps by which amyloid precursor protein (APP) is processed into Aβ offered multiple potential intervention points—ideal for pharmaceutical drug development.

Second, the hypothesis was backed by powerful genetic evidence. Mutations in the APP gene on chromosome 21 were associated with early-onset Alzheimer’s. The case grew stronger with the observation that more than 50% of individuals with Down syndrome, who carry an extra copy of chromosome 21 (and thus extra APP), develop Alzheimer’s-like pathology by age 40.

Thus, like any robust causal theory, the amyloid cascade hypothesis offered explicit, testable predictions. As Hardy and Higgins outlined, if amyloid truly initiates the Alzheimer’s cascade, then genetically engineering mice to produce human amyloid should trigger the full sequence of events: plaques first, then tangles, synapse loss, and neuronal death, then cognitive decline. And the sequentiality matters: amyloid accumulation should precede other pathological features. At the time, this was a thrilling possibility.

Pharmaceutical companies were especially eager: if the hypothesis proved correct, stopping amyloid should stop the disease. The field awaited the first transgenic mouse studies with enormous anticipation.

How—with Unlimited Time and Money and a Little Scientific Despair—to Make a Transgenic Mouse

“Mouse Model Made” was the boastful headline to the independent, introductory commentary Nature solicited to accompany the 1995 Games paper’s unveiling of the first transgenic mouse set to “answer the needs” of Alzheimer’s research. The scientific argument over whether amyloid caused Alzheimer’s had been “settle[d]” by the Games paper, “perhaps for good.”

In some ways, the commentary’s bravado seemed warranted. Why? Because in the mid-’90s, creating a transgenic mouse was a multi-stage, treacherous gauntlet of molecular biology. Every step carried an uncomfortably high chance of failure. If this mouse, developed by Athena Neurosciences (a small Bay Area pharmaceutical company) was valid, it was an extraordinary technical achievement portending a revolution in Alzheimer’s care.

First Rule of Making a Transgenic Mouse: Don’t Talk About How You Made a Transgenic Mouse

How did Athena pull it off? Hard to say! What's most remarkable about the Games paper is what's not there. Scan through the methods section and you'll find virtually none of the painstaking effort required to build the Alzheimer’s mouse. Back in the ‘90s, creating a transgenic mouse took years of work, countless failed attempts, and extraordinary technical skill. In the Games paper, this effort is compressed into a few sparse sentences describing which gene and promoter (nearby gene instruction code) the research team used to make the mouse. The actual details are relegated to scientific meta-narrative—knowledge that exists only in lab notebooks, daily conversations between scientists, and the muscle memory of researchers who perform these techniques thousands of times.

The thin description wasn’t atypical for a publication from this era. Difficult experimental methods were often encapsulated in the single phrase "steps were carried out according to standard procedures," with citations to entire books on sub-cloning techniques or reference to the venerable Manipulating the Mouse Embryo: A Laboratory Manual (We all have this on our bookshelf, yes?) The idea that there were reliable "standard procedures" that could ensure success was farcical—an understatement that other scientists understand as code for "we spent years getting this to work; good luck figuring it out ;)."

So, as an appreciation of what it takes to make progress on the frontiers of science, here is approximately what’s involved.

Prerequisites: Dexterity, Glassblowing, and Zen Mastery

Do you have what it takes to master transgenic mouse creation? Well, do you have the dexterity of a neurosurgeon? Because you’ll be micro-manipulating fragile embryos with the care of someone defusing a bomb—except the bomb is smaller than a grain of sand, and you need to keep it alive. Have you trained in glass-blowing? Hope so, because you’ll need to handcraft your own micropipettes so you can balance an embryo on the pipette tip. Yes, really.

And most importantly, do you sincerely believe that outcomes are irrelevant, and only the endless, repetitive journey matters? If so, congratulations! You may already be a Zen master, which will come in handy when you’re objectively failing your boss’s expectations every single day for what feels like an eternity. Success, when it finally comes, will be indistinguishable from sheer, dumb luck, but the stochastic randomness won’t stop you from searching frantically through your copious notes to see if you can pinpoint the variable that made it finally work!

Let’s go a little deeper so we can understand why the Games team's achievement was considered so monumental—and why almost everyone viewed the results in the best possible light.

by Anonymous, Astral Codex Ten |  Read more:

Image: via

Gil Scott-Heron

[ed. Ed Brady, guitar (Part II).]

GLP-1s Are Quietly Killing Your Cravings (and Maybe Your Bad Habits Too)

What happens when you can actually watch sugar cravings disappear from someone's brain? — You've probably heard people talking about 'food noise’. It’s that persistent, nagging voice in your head that keeps whispering about donuts, pizza, or cookies.

For many struggling with obesity, this chronic craving for sugar and fat feels like a voice you just can't mute.

But when people begin taking GLP-1 medications, it's as though someone finally found the volume knob and dialled it down to zero. The experience is something like an instantaneous liberation, so surreal and dramatic it almost feels like magic.

Recently, a good friend described starting tirzepatide this way:

"Bro, my food noise just vanished. Gone. Poof. I finally had the freedom to think about other things. And my shopping basket changed overnight. I actually wanted leafy greens and sweet potato. Sweet potato! Do you know how crazy that is?”

Stories like my friend's are piling up everywhere. So what's actually happening inside the brain when food noise just... stops?

When the brain says no

We've known for a while that GLP-1 meds like semaglutide dial down cravings, but now we've got visual proof of it actually happening in the brain.

A groundbreaking randomized controlled trial just published in Nature Medicine, used functional MRI (fMRI) scans to watch people's brains in real-time as they looked at images of high calorie, high sugar foods (think pizza, cakes, burgers etc) while taking tirzepatide, liraglutide, or a placebo.

Average brain activity shown on scans at the start of the study (baseline) and after three weeks of treatment (week 3). Bright colours (red and yellow) indicate higher brain activation in areas linked to cravings and reward when participants viewed images of high-fat, high-sugar foods.

Average brain activity shown on scans at the start of the study (baseline) and after three weeks of treatment (week 3). Bright colours (red and yellow) indicate higher brain activation in areas linked to cravings and reward when participants viewed images of high-fat, high-sugar foods.

After just three weeks on tirzepatide, the brain regions that light up when we see junk food went quiet. The areas responsible for cravings and reward anticipation (like the cingulate gyrus and medial frontal gyrus) showed roughly 170 % to 220 % less activation than they did on placebo, meaning these brain regions actually went into suppression. (...)

You’d think a drug like this would just crush hunger everywhere, like a sledgehammer smashing through a wall. Nope. Tirzepatide works more like an elite sniper perched on a rooftop, laser focused and zeroing in on your strongest cravings for high calorie, high sugary crap and picking them off with precision.

Amazingly, it leaves your appetite for fresh salads, crisp veggies, and sweet raspberries untouched.

Cravings for healthier foods (fruits and vegetables) remained virtually unchanged

The $1.2 Billion Question

Now, let’s zoom out for a second. What happens if millions of us suddenly lose that intense urge for soda, chips, or those wonderful chocolate chip cookies from subway (my fave)?

Agricultural economist Brian E. Roe calculated that even moderate levels of adoption of GLP-1s, say 10% among overweight people and 20% among those with obesity, would lead to a 3% drop in total calorie demand in the U.S.

That translates to around 20 billion fewer calories eaten daily and $1.2 billion less spent each week on food and drinks.

In other words, companies like Coca-Cola, Kellogg's, and Nestlé, who’ve built sprawling empires by tapping directly into the very cravings we've just seen silenced on MRI, may soon face an existential threat.

Some innovative companies, however, have already started adapting.

Smoothie King sensed the winds shifting first, cleverly rolling out high-protein, GLP-1-friendly shakes to capture the health-aware consumer.

Expect other fast-moving brands to dive headfirst into a wave of products customized specifically for people freed from the constant grip of food cravings.

The rest will need to pivot quickly or risk fading into oblivion.

GLP-1s as Impulse Dampeners

But tirzepatide might be doing something even more profound than silencing food noise. The same study suggests it's actually rewiring impulse control in the brain itself.

The researchers measured impulsiveness using the Barratt Impulsiveness Scale, a validated psychological tool that captures everyday impulsive tendencies like “acting without thinking” or “struggling to resist urges.”

After 3-6 weeks of tirzepatide treatment, participants reported feeling significantly less impulsive than those who received the placebo.

They reported feeling calmer, more in control, and far less prone to snap decisions or irresistible urges.

This is important when you consider that impulsivity is the engine behind pretty much every self-destructive habit out there. Whether you're talking binge-drinking, gambling, chain-smoking or falling into the black hole of substance abuse.

If GLP-1 meds can dial down the noisy circuits in our brains screaming 'just do it!', we might be staring down the barrel of an entirely new way of treating addiction and it’s devastating consequences.

Just imagine a world (to borrow from John Lennon) with fewer overdose headlines, calmer Friday nights in emergency rooms, shrinking gambling debts, maybe even drops in domestic violence and incarceration rates.

Researchers are taking this seriously.

Major clinical trials already underway are testing whether GLP-1 meds might quiet the destructive impulses behind addiction itself. If they're right, we're looking at something much bigger (and far more important) than just weight loss.

by Ashwin Sharma, MD, GLP-1 Digest |  Read more:

Image: GPT/GLP-1 Digest Illustration; Nature Medicine

[ed. See also: How GLP-1s Are Breaking Life Insurance; and, Why are GLP1 drugs good for everything?]

What Could Go Wrong?

Sam Altman and Jony Ive Will Force A.I. Into Your Life

Last Wednesday, OpenAI announced that it was acquiring a company called io, an artificial-intelligence-forward product-development firm co-founded, last year, by Jony Ive, the vastly influential designer known for his work with Steve Jobs at Apple. Ive led the designs of the original iMac, the iPad, and the Apple Watch, among other era-defining products. Then, in 2019, he left Apple to start his own design firm called LoveFrom. The news of his move to OpenAI felt something like learning that LeBron James was joining the Miami Heat: Ive had become synonymous with Apple’s success, perhaps second only to Jobs. Now, after a period of independence, he was choosing a new team. The announcement of the deal with OpenAI—for a reported $6.5 billion in OpenAI equity—came via a press release, featuring a rather cuddly portrait of Ive with OpenAI’s C.E.O. and co-founder, Sam Altman (shot by the British fashion photographer Craig McDean) and a faux-casual videotaped interview session between the two at San Francisco’s Cafe Zoetrope. In it, Altman describes “a family of devices that would let people use A.I. to create all sorts of wonderful things,” enabled by “magic intelligence in the cloud.” The symbolism of the partnership was clear: Altman is the new Jobs, and together he and Ive promise to create the next ur-device, a personal technology that will reshape our lives just as the iPhone did. Once it’s ready, they say, they’ll ship a hundred million devices “faster than any company” ever has.

We don’t know what it will look like just yet, but Altman swears that it will be “​​the coolest piece of technology that the world will have ever seen.” Ming-chi Kuo, a respected analyst of Apple’s Chinese manufacturing, posted on X that the product is planned to be “as compact and elegant as an iPod Shuffle” and that it will have “cameras and microphones for environmental detection.” It might resemble other early A.I. devices announced or launched in the past year, such as Friend, another pendant-like chatbot companion; Humane, an A.I. pin with a laser projector; or Rabbit, a small handheld gadget. Yet the functionality of these nascent inventions is severely limited. “Vaporware” is a term of art from the nineteen-eighties that was popularized in the early internet era, referring to new software or technology that overpromises and underdelivers—if the product is even released in the first place. However many breathless headlines about OpenAI’s acquisition, it’s just vaporware until Altman and Ive prove otherwise. Hype, after all, is one of OpenAI’s primary achievements—despite predictions about ChatGPT changing the world, the company is losing billions of dollars a year.

What we can do, in the meantime, is imagine what an iPhone of A.I. might look like based on the A.I. technology that so far exists. Generative A.I. has already been integrated into many of our daily digital experiences, whether we want it there or not. iPhones now summarize text threads using A.I. and allow users to generate custom emojis. Google recently announced an “AI Mode” that it intends to supplant its traditional search box with, a development that threatens to slow open-web traffic down to a trickle. Meta’s “AI Glasses,” a collaboration with Ray-Ban, integrate voice chatting and live translation with the company’s A.I. assistant. And chatbots with distinct personalities, like Replika and Character.ai, are becoming increasingly popular as they get better at mimicking human connection. Perhaps Altman and Ive’s machine will mingle all of these functionalities: it might listen to and interpret the sounds around you; it might respond with predictive text, delivered to you instantaneously and in a customizable tone; and it might become your main avenue for accessing information, like a personal concierge. It will reportedly not attempt to supplant the other technologies you depend on: according to the Wall Street Journal, Altman described it as a kind of third device, meant to work within an ecosystem that includes your laptop and smartphone. But it will effectively be a self-surveillance machine that creates a technological scrim for your personal reality. The involvement of Ive invites inevitable comparisons with the iPhone, but this is not necessarily a compliment; to many of us, an iPhone of A.I. sounds less like a utopian promise than like a threat that A.I. will soon become ubiquitous and unavoidable. Smartphones have already absorbed us in our screens, creating personalized information bubbles; omnipresent A.I. will only intensify that atomization while being more automated, more inscrutable, and more inescapable.

The video claims that more information about the new product will be shared next year, which would mean that we’re currently in the Palm Pilot stage of A.I.—with the iPhone-like invention looming around the corner, poised to obliterate the competition. But there are vast logistical hurdles to achieving this optimistic timeline for ubiquitous consumer A.I. More than a billion people in the world own iPhones. Some research estimates that generating a typical e-mail using A.I. consumes a bottle’s worth of water to siphon heat away from the data centers’ servers to separate cooling towers. This means that, if we all started using our personal A.I. machines dozens of times a day, as we do our iPhones, the environmental toll of our personal technology would skyrocket—imagine something like turning every car on the road into a diesel truck. This, in turn, would warp the direction of global economies, requiring the construction of ever-larger data centers. The economic and environmental overhaul would be done in the name of outsourcing our human thoughts and memories to an omnipresent machine resting in our pockets or hanging around our necks. (...)

Speculative mockups online imagine an A.I. companion device that looks simple, like a rounded metal amulet—it would be Ive’s style to make the design approachable yet austere. Yet the sleek and frictionless object will rely on a vast infrastructure of factories and server farms; the labor of human maintenance workers and moderators; and, ultimately, the corpus of information that has been digested as training data, which is effectively the entire history of human thought. The little pendants around our necks will be a hundred million Trojan horses, smuggling A.I. into every aspect of our lives. The comforting tone of Altman and Ive’s pitch belies the enormous uncertainty of what their plan would unleash.

by Kyle Chayka, New Yorker |  Read more:

Image: Ariel Davis

[ed. See also: ‘Humanity deserves better’: iPhone designer on new partnership with OpenAI (Guardian).]

Sisters of the Valley
Images: Raquel Cunha/Reuters
[ed. Great pics.]
"Sisters of the Valley is a non-religious group founded in 2014 that has pledged to spread the gospel of the healing powers of cannabis. The Sisters argue that the fight against drugs in Latin America has been a failure, leading to widespread violence and mass incarceration"

Crashing the Car of Pax Americana

[ed. Excellent.]

My ask of you in reading this note is that we make an effort to hold several conflicting ideas in our heads at the same time. Like, for example, that the American socioeconomic system desperately needs fixing after decades of venal corruption from (mostly) Democratic but (also) Republican Administrations AND there is an underlying global system worth preserving that gives the United States enormous privilege, wealth and freedom of action in the world. Or, for example, that there’s no reason to doubt the authentic intentions of Donald Trump and his Administration to improve the position of the United States AND their economic policies can have the unintended consequence of blasting the underlying global system to smithereens, making it impossible to achieve their goals. It’s really not easy to hold all of these ideas simultaneously! Every bit of party propaganda from the left and the right, every big voice on social media, everyone wants you to give yourself over to a single idea of party purity and ignore everything else. But it’s just not true.

The truth is that the United States became as sclerotic and bloated under Joe Biden as the Soviet Union under Leonid Brezhnev, and that Joe Biden’s cognitive decline and its obscene cover-up made the United States government a global patsy and a domestic feeding trough. The truth is that our border policy was stupidly permissive. The truth is that we really do need to eliminate vast swaths of the Federal bureaucracy and the Christmas tree funding programs that always grow and never shrink. The truth is that a Department of Government Efficiency is a really good idea.

AND the truth is that the purpose of government is not efficiency for efficiency’s sake. AND the truth is that the quality of mercy is not strained and neither is due process, so that justice may be sure but never cruel. AND the truth is that spending money to curry political favor abroad through CIA USAID programs is a lot cheaper and a lot more efficient than sending in the Marines, AND is a lot more profitable than seeing the Chinese take our place in the world. AND the truth is that we have three co-equal branches of government, where the unconstitutionality of a President ‘vetoing’ Congressionally-authorized spending programs through Executive Order is well-settled law. AND the truth is that government debt isn’t like our own personal debt, so that we can’t go broke as a nation AND we’re nowhere near having a budget crisis AND we have the strongest, most vital economy in the world AND we can still grow our way to a more equitable prosperity without breaking a global system that works so formidably to our advantage.

This underlying global system has a name. It’s called Pax Americana.

• Pax Americana is the Bretton Woods monetary system and the Plaza Accords and the SWIFT banking system and the unquestioned dominance of the USD as the world’s reserve currency.

• Pax Americana is the NATO alliance and the Pacific Fleet and CENTCOM and the NSA and the unquestioned dominance of the US military as the world’s security arbiter.

• Pax Americana is the American brands, American universities, American entrepreneurialism, and most of all the American stories that have dominated the hearts and minds of everyone on Earth for the past 50 years.

• Pax Americana is the ability of the United States to set the rules for every coordination game in the world. The rules of trade, the rules of intellectual property, the rules of money, the rules of culture, the rules of war … all of those rules were made by us. Only by us! And in return we gave the rest of the world two things: global peace (pretty much) enforced by a blue-water navy with force projection capabilities anywhere in the world, and unfettered access (pretty much) to the buying power of the American consumer.

The results of Pax Americana?

• The United States has seen more than 300 million citizens lifted into the highest standard of living in the history of the world, as we have exchanged intangible things like services and the full faith and credit of the US government for tangible things like oil and semiconductors and food at an unimaginable scale.

• The world has seen more than a billion people lifted out of crushing poverty, mostly in China and India but everywhere else, too, as the capacity to make tangible things has shifted permanently (yes, permanently) from West to East.

My strong, unwavering belief is that Pax Americana is a damn good deal for the United States AND the world, especially as American leadership in AI opens up an entirely new realm of intangible things that the United States can trade for tangible things. Is it a perfect deal for the United States? No. Do other countries free ride on our provision of security and an end-market of the American consumer? Absolutely. Has the system been internally captured by oligarchs and professional politicians, so that the distribution of this great wealth flowing to the United States goes less and less to ‘average’ Americans? 100%. Should we aggressively prune and reform the Pax Americana system? Should we root out its foreign free riders and domestic leeches? Yes, please!

But that’s not what this Administration believes. Neither Donald Trump nor his key advisors believe that Pax Americana is a good deal at all, much less a damn good deal like I believe. They believe the United States is being cheated and taken advantage of without end, both internationally and domestically. They don’t want to fix the Pax Americana regime of coordination through multilateral rule-setting. They want to blow up the entire deal and replace it with an America First regime of competition through bilateral engagement.

I appreciate their frustration. I share a lot of it. But I am desperately opposed to crashing the Pax Americana car, Annie Hall style, because the America First system that this Administration wants to have as a replacement is not a stable system that is possible to have as a replacement. The end result of blowing up Pax Americana and its – yes – globalist system of rules and institutions and alliances that coordinates the flow of capital, labor, goods, services and culture without ‘winning’ any head-to-head relationship will be a system that is both worse for the United States AND the world. Here’s why: 

by Ben Hunt, Epsilon Theory |  Read more:
Image: Annie Hall

[ed. From the comments:]

***

I spent almost eight years working in the Appalachian Basin. You have no idea just how bad it is and how deep the pain runs. (You also probably don’t know just how hilariously well armed the Amish are in that part of Ohio; some of those guys could put on a gun show by doing nothing more than opening their barn doors)

How can we keep Pax Americana going in a way that benefits all Americans - and by benefit I mean offers lives of dignity with meaningful work, meaningful relationships and recognition of value?

What if that’s not what a lot of those people want? Because in my experience down there this was not a universal goal, nor would it even carry the majority of the population on any given day.

When the shale boom came it brought with it billions of dollars of absolutely free money that was handed out in exchange for what the residents previously believed was damn near worthless land. Tens of billions flowed from the ground and into the pockets of landowners. All the hotels and motels were full every night for years. Every restaurant was packed day and night. Energy companies paved roads, donated to every local community organization, soccer team, bought every animal from every 4H kid at every county fair. Every county courthouse was filled with landmen who spent all day making copies of deed records, at 25¢ a page. Thousands of pages, by 15-20 guys, every day. The Recorder’s office was running a machine that spat out $5,000/d, every day, for months. Companies cut checks directly to the county for expanded hours so their people could work before and after regular closing times. They paid tens of thousands for a few extra hours a day over the course of a few months. Government revenues ballooned.

Then what happened?

Hundreds of good paying jobs were created overnight…and most went to workers from Texas, Louisiana, and Oklahoma, not Ohio or Pennsylvania. Know why? Nobody could pass a drug test. No, I’m not shitting you. I had a friend who had a wireline company and he tried to hire two locals. Both didn’t even show up for the drug test. That was the last time he bothered to even advertise his job opening in the area. He hired professionals from out of state. Less hassle.

Before a single cubic foot of gas or barrel of oil came out of the ground the local Ford dealership made news as it catapulted to the top of the list of highest volume dealers in the state. It seemed like every farm large and small had a new F-150 in the gravel driveway.

The casinos across the river had multiple record years in a row after a decade of a slow decline. Strip clubs boomed.

And nobody really built anything. The families who were rich before were simply even more rich after. One prominent local attorney—whose conduct would have gotten him disbarred in any other place—tightened his grip on the area, and after a particularly major payout bought a second home in Lake Como, Italy.

The old men dying of black lung kept on dying. The young men continued their drift into addiction, which had started to take hold years before that. Crime went up despite poverty going down.

The local wastewater treatment plants were at least smart enough to make deals with the service companies to clean the used frac water. Again, government receipts grew, but how much of that made it to the people? (Not much)

Nobody bothered to clean up the brownfields and open a new facility making drill pipe. That ended up happening an hour north instead. It took two years for the owner of a previously defunct gravel yard to open back up, despite the fact that he was sitting on a gold mine. (I know this because I tried to buy part of it from him and he not only wouldn’t sell but quite literally did not understand the magnitude of what was about to happen)

Very little changed because the people didn’t want anything to change. Many of them talked about Weirton Steel as if it was still 1981, and cursed the foreigners (ArcelorMittal) who owned what was left of it. (And in a small twist of irony the man who bought that bankrupt company off of the employees in 2002–for a hilariously low ball price—would go on to be the Secretary of Commerce under the first term of the president that they voted for in overwhelming numbers) It’s been 15 years of oil and gas money steadily flowing to the area, and nothing has changed. The complaint that “there aren’t any jobs” is old enough to drink. Some people had the good sense to leave. Everyone else was just more comfortable staying and watching everything die.

I’m not unsympathetic, but the way these folks are talked about—and talk about themselves—you’d think they had no agency of their own. They think their salvation is just around the corner, if only we’d just blew up every working institution around the globe they’d make it to the other side of this mess. It’s paternalistic horseshit that Trump is selling and they’re lining up around the block to get their wheelbarrow full of it.

Shingles Vaccine Could Help Stave Off Dementia

According to a study that followed more than 280,000 people in Wales, older adults who received a vaccine against shingles were 20 percent less likely to develop dementia in the seven years that followed vaccination than those who did not receive the vaccine.

This could be a big deal. There are very few, if any, treatments that can prevent or slow down dementia, beyond good lifestyle habits like getting enough sleep and exercise. The possibility that a known, inexpensive vaccine could offer real protection is enormously meaningful. We have good reason to be confident in the findings: While this study is perhaps the most prominent to show the protective effects of the shingles vaccine, other studies of the vaccine have come to similar conclusions.

Beyond the promise of preventive treatment, the new study adds further evidence to a growing body of research raising the possibility that we have been thinking about neurodegenerative diseases like dementia and Alzheimer’s all wrong. It’s possible these horrible conditions are caused by a virus — and if that’s the case, eliminating the virus could be enough to prevent or treat the diseases.

How the study worked

To understand why the new shingles vaccine study is such a big deal, it helps to know a little bit about how medical studies are carried out. (...)

The new study... took advantage of a quirk in Welsh health policy to do something better. Beginning on September 1, 2013, anyone in Wales who was 79 became eligible to receive a free shingles vaccine. (Those who were younger than 79 would become eligible once they turned that age.) But anyone who was 80 or older was not eligible on the grounds that the vaccine is less effective for the very old.

The result was what is known as a “natural experiment.” In effect, Wales had created two groups that were essentially the same — save for the fact that one group received the shingles vaccine and one group did not.

The researchers looked at the health records of the more than 280,000 adults who were 71 to 88 years old at the start of the vaccination program and did not have dementia. They focused on a group that was just on the dividing line: those who turned 80 just before September 1, 2013, and thus were eligible for the vaccine, and those born just after that date, who weren’t. Then, they simply looked at what happened to them.

By 2020, seven years after the vaccination program began, about one in eight older adults, who by that time were 86 and 87, had developed dementia. But the group that had received the shingles vaccine were 20 percent less likely to be diagnosed with the disease. Because the researchers could find no other confounding factors that might explain the difference — like years of education or other vaccines or health conditions like diabetes — they were confident the shingles vaccine was the difference maker.

A new paradigm in dementia research?

As Paul Harrison, a professor of psychiatry at the University of Oxford who was not involved in the study, told the New York Times, the research indicates that the shingles vaccine appears to have “some of the strongest potential protective effects against dementia that we know of that are potentially usable in practice.”

But this is a vaccine originally designed to prevent shingles. Why does it also appear to help with dementia?

Scientists theorize it could be related to inflammation. Shingles, or herpes zoster, is caused by the same virus responsible for chickenpox, which lies dormant in nerve cells after an initial infection and can reawaken decades later, causing painful rashes.

That reactivation creates intense inflammation around nerve cells, and chronic inflammation is increasingly recognized as a major factor in cognitive deterioration. By preventing shingles, the vaccine could indirectly protect against the neural inflammation associated with dementia.

What about the amyloid and tau protein plaques that tend to be found in the brains of people suffering from Alzheimer’s, which have long been thought of as the primary cause of the disease? It’s possible that these may actually be the body’s response to an underlying infection. That could help explain why treatments that directly target those plaques have been largely ineffective — because they weren’t targeting the real causes.

by Bryan Walsh, Vox |  Read more:

Image: H. Rick Bamman/ZUMA Wire/Alamy Live News

[ed. See also: Shingles Vaccine Can Decrease Risk of Dementia, Study Finds (NYT):]

***

“If you’re reducing the risk of dementia by 20 percent, that’s quite important in a public health context, given that we don’t really have much else at the moment that slows down the onset of dementia,” said Dr. Paul Harrison, a professor of psychiatry at Oxford. (...)

Several previous studies have suggested that shingles vaccinations might reduce dementia risk, but most could not exclude the possibility that people who get vaccinated might have other dementia-protective characteristics, like healthier lifestyles, better diets or more years of education.

The new study ruled out many of those factors. (...)

They also examined medical records for possible differences between the vaccinated and unvaccinated. They evaluated whether unvaccinated people received more diagnoses of dementia simply because they visited doctors more frequently, and whether they took more medications that could increase dementia risk.

“They do a pretty good job at that,” said Dr. Jena, who wrote a commentary about the study for Nature. “They look at almost 200 medications that have been shown to be at least associated with elevated Alzheimer’s risk.”

He said, “They go through a lot of effort to figure out whether or not there might be other things that are timed with that age cutoff, any other medical policy changes, and that doesn’t seem to be it.”

The study involved an older form of shingles vaccine, Zostavax, which contains a modified version of the live virus. It has since been discontinued in the United States and some other countries because its protection against shingles wanes over time. The new vaccine, Shingrix, which contains an inactivated portion of the virus, is more effective and lasting, research shows.

A study last year by Dr. Harrison and colleagues suggested that Shingrix may be more protective against dementia than the older vaccine. Based on another “natural experiment,” the 2017 shift in the United States from Zostavax to Shingrix, it found that over six years, people who had received the new vaccine had fewer dementia diagnoses than those who got the old one. Of the people diagnosed with dementia, those who received the new vaccine had nearly six months more time before developing the condition than people who received the old vaccine.

Benefits of ADHD Medication Outweigh Health Risks, Study Finds

The benefits of taking drugs for attention deficit hyperactivity disorder outweigh the impact of increases in blood pressure and heart rate, according to a new study.

An international team of researchers led by scientists from the University of Southampton found the majority of children taking ADHD medication experienced small increases in blood pressure and pulse rates, but that the drugs had “overall small effects”. They said the study’s findings highlighted the need for “careful monitoring”.

Prof Samuele Cortese, the senior lead author of the study, from the University of Southampton, said the risks and benefits of taking any medication had to be assessed together, but for ADHD drugs the risk-benefit ratio was “reassuring”.

“We found an overall small increase in blood pressure and pulse for the majority of children taking ADHD medications,” he said. “Other studies show clear benefits in terms of reductions in mortality risk and improvement in academic functions, as well as a small increased risk of hypertension, but not other cardiovascular diseases. Overall, the risk-benefit ratio is reassuring for people taking ADHD medications.”

About 3 to 4% of adults and 5% of children in the UK are believed to have ADHD, a neurodevelopmental disorder with symptoms including impulsiveness, disorganisation and difficulty focusing, according to the National Institute for Health and Care Excellence (Nice).

Doctors can prescribe stimulants, such as methylphenidate, of which the best-known brand is Ritalin. Other stimulant medications used to treat ADHD include lisdexamfetamine and dexamfetamine. Non-stimulant drugs include atomoxetine, an sNRI (selective norepinephrine reuptake inhibitor), and guanfacine.(...)

Last year, a thinktank warned that the NHS was experiencing an “avalanche of need” over autism and ADHD, and said the system in place to cope with surging demand for assessments and treatments was “obsolete”. The number of prescriptions issued in England for ADHD medication has risen by 18% year on year since the pandemic, with the biggest rise in London.

Dr Tony Lord, a former chief executive of the ADHD Foundation, said the long-term benefits of ADHD medication were well established, and included a reduced risk of anxiety and depression, eating disorders, harm from smoking, improved educational outcomes and economic independence.

“Sadly ignorance about ADHD medications persists – a throwback to the 80s and 90s when ADHD medications were mistakenly viewed as a morality pill that made naughty, fidgety disruptive children behave – which of course it is not,” he said.

“It is simply a cognitive enhancer that improves information processing, inhibits distractions, improves focus, planning and prioritising, self monitoring and reduces impulsivity of thought and action.”

by Alexandra Topping, The Guardian |  Read more:

Image: Murdo Macleod/The Guardian
[ed. I'd love to get an Adderall prescription as a cognitive enhancer but not willing to fake ADHD, and doctors won't prescribe it for other reasons unless you're rich, influencial or have a job in finance.]

The Ozempocalypse Is Nigh

Three GLP-1 drugs are approved for weight loss in the United States:

• Semaglutide (Ozempic®, Wegovy®, Rybelsus®)

• Tirzepatide (Mounjaro®, Zepbound®)

• Liraglutide (Victoza®, Saxenda®)

…but liraglutide is noticeably worse than the others, and most people prefer either semaglutide or tirzepatide. These cost about $1000/month and are rarely covered by insurance, putting them out of reach for most Americans.

…if you buy them from the pharma companies, like a chump. For the past three years, there’s been a shortage of these drugs. FDA regulations say that during a shortage, it’s semi-legal for compounding pharmacies to provide medications without getting the patent-holders’ permission. In practice, that means they get cheap peptides from China, do some minimal safety testing in house, and sell them online.

So for the past three years, telehealth startups working with compounding pharmacies have sold these drugs for about $200/month. Over two million Americans have made use of this loophole to get weight loss drugs for cheap. But there was always a looming question - what happens when the shortage ends? Many people have to stay on GLP-1 drugs permanently, or else they risk regaining their lost weight. But many can’t afford $1000/month. What happens to them?

Now we’ll find out. At the end of last year, the FDA declared the shortage over. The compounding pharmacies appealed the decision, but the FDA recently confirmed its decision is final. As of March 19 (for tirzepatide) and April 22 (for semaglutide), compounding pharmacies can no longer sell cheap GLP-1 drugs. (...)

Some compounding pharmacies are already telling their customers to look elsewhere, but not everyone is going gently into the good night. I’m seeing telehealth companies float absolutely amazing medicolegal theories, like:

• Compounding pharmacies are allowed to provide patients with a drug if they can’t tolerate the commercially available doses and need a special compounding dose. Perhaps our patients who were previously on semaglutide 0.5 mg now need, uh, semaglutide 0.51 mg. In fact, they need exactly 0.51 mg or they’ll die! Since the pharma companies don’t make 0.51 mg doses, it has to be compounded and we can still sell it.

• Compounding pharmacies are allowed to provide patients with special mixes of drugs if they need to take two drugs at the exact same time. Perhaps our patients who were previously on semaglutide 0.5 mg now need, uh, a mix of semaglutide and random vitamins. They need to have the random vitamins mixed in or they’ll die. Since the pharma companies don’t make semaglutide mixed with the exact random vitamins we do, it has to be compounded and we can still sell it.

• Compounding pharmacies are allowed to provide patients with drugs formulated for unusual routes of administration. All of our patients just developed severe needle phobia, sorry, so they need semaglutide gummies. Since the pharma companies don’t make semaglutide gummies, it has to be compounded and we can still sell it (thanks to Recursive Adaptation for their article on this strategy).

I am not a lawyer but this is all stupid. What are the companies thinking?

They might be hoping they can offload the stupid parts to doctors. Everyone else in healthcare is supposed to do what doctors tell them, especially if the doctors use the magic words “medically necessary”. So pharmacies and telehealth startups (big companies, easy to regulate) can tell doctors (random individuals, hard to regulate) “wink wink hint hint, maybe your patient might need exactly 0.51 mg of semaglutide, nod nod wink wink”. The doctor can write a prescription for exactly 0.51 mg semaglutide, add a note saying the unusual dose is ‘medically necessary’, and then everyone else can provide it with a “clean” “conscience”. If the pharma company sues the pharmacy or telehealth startup, they’ll say “we were only connecting patients to doctors and following their orders!” If the pharma company sues the doctors, the pharma company will probably win, but maybe telehealth companies can find risk-tolerant doctors faster than the pharma company can sue them.

The pharma company can probably still sue telehealth startups and pharmacies over the exact number of nods and winks that they do. But maybe they won’t want to take the PR hit if those pharmacies limit themselves to continuing to serve existing patients. Or maybe there are too many pharmacies to go after all of them. Or maybe DOGE will fire everyone at the FDA and the problem will solve itself. I don’t know - I don’t really expect any of this to work, but from a shareholder value perspective it beats lying down and dying.

But the compounders aren’t the only ones boxing clever. Novo Nordisk and Eli Lilly, the pharma companies behind semaglutide and tirzepatide respectively, have opened consumer-facing businesses about halfway between a traditional doctor’s appointment and the telehealth/compounder model that’s getting banned. So for example, Lilly Direct offers to “find you a doctor” (I think this means you do telehealth with an Eli Lilly stooge who always gives you the meds you want) and “get medications delivered directly to you”. The price depends on dose, but an average dose would be about $500 - so about halfway between the cheap compounding price and the usual insurance price. Not bad.

Pharma companies don’t like dose-based pricing (that is, charging twice as much for a 10 mg dose as a 5 mg dose). Part of their objection is ethical - some people have unusual genes that make them need higher doses, and it seems unfair to charge these people twice as much for genetic bad luck. But there’s also an economic objection - they want to charge the maximum amount the customer can bear, but if they charge a subset of people with genetic bad luck twice as much as they can bear, those people won’t buy their drug. So usually they sell all doses at a similar price, opening an arbitrage opportunity: if they sell both 5 mg and 10 mg for $500/month, and you need 5 mg, then buy the 10 mg dose, take half of it at a time, stretch out your monthlong supply for two months, and get an effective cost of $250/month. But here Eli Lilly is doing something devious I’ve never seen before. They’re selling their medication in single-dose vials, deliberately without preservatives, so that you need to take the whole dose immediately as soon as you open the vial - the arbitrage won’t work! So although this looks on paper like a $300 price increase ($200 to $500), the increase will be even higher for people who were previously exploiting the dose arbitrage.

The mood on the GLP-1 user subreddits is grim but defiant. 

Some people are stocking up. GLP-1 drugs keep pretty well in a fridge for at least a year. If you sign up for four GLP-1 telehealth compounding companies simultaneously and order three months from each, then you can get twelve months of medication. Maybe in twelve months the FDA will change their mind, or the pharmacies’ insane legal strategies will pay off, or Trump will invade Denmark over Greenland and seize the Novo Nordisk patents as spoils of war, or someone will finally figure out a diet that works.

Others are turning amateur chemist. You can order GLP-1 peptides from China for cheap. Once you have the peptide, all you have to do is put it in the right amount of bacteriostatic water. In theory this is no harder than any other mix-powder-with-water task. But this time if you do anything wrong, or are insufficiently clean, you can give yourself a horrible infection, or inactivate the drug, or accidentally take 100x too much of the drug and end up with negative weight and float up into the sky and be lost forever. ACX cannot in good conscience recommend this cheap, common, and awesome solution.

I think the past two years have been a fun experiment in semi-free-market medicine. I don’t mean the patent violations - it’s no surprise that you can sell drugs cheap if you violate the patent - I mean everything else. For the past three years, ~2 million people have taken complex peptides provided direct-to-consumer by a less-regulated supply chain, with barely a fig leaf of medical oversight, and it went great. 

by Scott Alexander, Astral Codex Ten |  Read more:

Image: via

[ed. See also: The cost of GLP-1s needs to come way down for benefits to be worth it, study says (Quartz).]

There Is Way Too Much Serendipity

As we all know, sugar is sweet and so are the $30B in yearly revenue from the artificial sweetener industry.

Four billion years of evolution endowed our brains with a simple, straightforward mechanism to make sure we occasionally get an energy refuel so we can continue the foraging a little longer, and of course we are completely ignoring the instructions and spend billions on fake fuel that doesn’t actually grant any energy. A classic case of the Human Alignment Problem.

If we’re going to break our conditioning anyway, where do we start? How do you even come up with a new artificial sweetener? I’ve been wondering about this, because it’s not obvious to me how you would figure out what is sweet and what is not.

Look at sucrose and aspartame side by side:

I can’t imagine someone looking at these two molecules and thinking “surely they taste the same”. Most sweeteners were discovered in the 20th century, before high-throughput screening was available. So how did they proceed?

Let’s look into these molecules’ origin stories.

Aspartame was discovered accidentally by a chemist researching a completely unrelated topic. At some point, he licked his finger to grab a piece of paper and noticed a strong sweet taste.

Cyclamate was discovered by a grad student who put his cigarette on his bench, then smoked it again and noticed the cigarette was sweet.

(I know what you’re thinking. The kind of guy who lights up cigarettes in a chemistry lab and places them in the middle of uncharacterised compounds before taking them to his mouth again, must have died young of an interesting death. I checked – he proceeded to live to the old age of 87.)

Saccharine was discovered by a researcher who ate bread without washing his hands and noticed the bread was sweet.

Acesulfame K was also discovered serendipitously by a chemist licking his fingers, although the legends don’t specify the exact circumstances behind the finger-licking.

There’s an exception: sucralose was actually the fruit of rational, deliberate design. The researchers reasoned that, if you do slight modifications to sucrose, you could find a molecule that is no longer metabolized but still activates the sweetness receptors. So they started from the formula for sucrose, then made carefully-designed chemical modifications to the structure until –

Haha, just kidding:

While researching novel uses of sucrose and its synthetic derivatives, Phadnis was told to "test" a chlorinated sugar compound. According to an anecdotal account, Phadnis thought Hough asked him to "taste" it, so he did and found the compound to be exceptionally sweet.

It is therefore a fact of the world that virtually all the popular synthetic sweeteners were discovered accidentally by chemists randomly eating their research topic.

I think this is a suspiciously high amount of serendipity. I see two options:

Super-sweet molecules like aspartame are commonplace – there are plenty of molecules hundreds of times sweeter than sucrose, but we only know the few that were ingested by accident,

Super-sweet molecules are very rare, it’s just that chemists accidentally taste a lot of chemicals. Entire chemistry departments routinely taste the entire space of possible molecules, but they don’t notice unless the molecule has a strong taste. (...)

(There are a few other naturally-occurring low-calorie sweeteners, but they are uncommon and it’s not clear why they exist. My favourite is thaumatin, a protein involved in the immune system of a plant, who just happens to be 100,000 times more potent than sucrose. As far as I can tell, nobody knows why.)

Altogether, this illustrates the fact that it’s not common for our sweet receptors to get activated by small calorieless molecules, and chemists must have eaten a lot of weird things to find the synthetic sweeteners we currently use.

This is when things get out of control.

The big pharma tasting machinery

Hear me out: there are about 4000 clinical trials worldwide each year. Tasting is an important part of drug development – if anything, it may determine how the pill should be coated or whether to use a capsule. Therefore, several thousands of new compounds must be tasted by clinical trial participants every year.

Why didn’t we discover any new artificial sweetener this way? What are the chances that the top 5 most used synthetic sweeteners all come from chemists accidentally ingesting their works in progress, and not a single one from the cohorts of people tasting thousands of molecules all the time in controlled settings?

Let’s do a back-of-the-envelope calculation.

There are more than 19,000 FDA-approved prescription drugs on the market, 40% of which are administered orally,

About half of Phase III clinical trials fail, and this is due to a lack of efficacy 60% of the time.

So, we can estimate that the number of inactive/non-toxic oral drugs that were tasted by people in Phase III trials is upwards of 4,000.

How many were sweet? I looked at clinical trials search engines and wasn’t able to find any report of a strong sweet taste (the only hit was dextroamphetamine-saccharate, which basically contains sucrose). And of course, zero of these 4,000 chemicals ended up being commercialized as artificial sweeteners.

Meanwhile, rule-breaking chemists accidentally found the five commercial molecules mentioned above. Therefore, chemists must have tasted at least 20,000 molecules to find all five of them, and that’s only counting the ones which were actually commercialized. That’s pretty impressive.

I hear your objections

What if pharma companies are scared to use a potential medicine as a culinary additive?
The estimate above only counts drugs that were found to be ineffective, but maybe they still had some activity, at least theoretical, and that doesn’t sound safe. However, it happened in the past that a drug developed for something ended up repurposed for something else entirely. A famous case is minoxidil, which was developed to treat ulcers, but ended up being used to prevent hair loss. So that doesn’t seem to be a huge barrier.

What if people have already fully optimized sweeteners and there’s no market for new ones?
Our current sweeteners are not bad – at least we’re not using straight-up motherfucking lead like in Ancient Rome – but they are not perfect either. First, all the sweeteners I know taste bad. Second, aspartame is (lightly) suspected to cause cancer. Third, people are looking for new sweeteners: there’s no lack of studies using in-silico screening or machine learning to find them.

What if participants don’t report it when they find a drug is delicious?
Clinical trials are usually very thorough when it comes to reporting side effects – remember the guy in the Moderna vaccine trial who was struck by lightning and they had to report it as a Serious Adverse Effect? But, fine, maybe people don’t report something as benign as a sweet taste.

In that case, here is something they cannot hide: a psychedelic trip.

High probability

Like aspartame, LSD was discovered by a chemist who ingested it by accident. LSD binds to serotonin receptors, which are also the target of highly-lucrative classes of antidepressants, anti-emetics, and anti-migraine medication. So you can imagine the massive number of serotonin analogues that the pharma industry has fed to clinical trial participants. But, unless they’re hiding things from us, none of these trials resulted in participants tripping balls. From this, I conclude that LSD-level psychedelic molecules must be exceedingly rare.

Just to be sure, I checked the FDA’s side-effect database – it doesn’t have a “walls are breathing” search term, but it has “visual hallucinations”. Most of the results are boring psychiatric drugs like zolpidem or bupropion, with limited recreative potential. I mean, yes, there is a case report of a 5-years-old seeing helicopters in her room after taking antibiotics, but I don’t think this has much street value.

Meanwhile, the Psychonaut Wiki lists about a gazillion psychedelic compounds with cool names like LSM-775 (they even have one that smells like Pokémon cards – a drug taken only by the really cool kids). This is the result of extensive systematic testing by the stoner research community, most notably the Shulgin family.

Here’s the thing: among the many close analogues of LSD, most are less potent than the original LSD. Did Albert Hofmann hit the most powerful LSD variant on the first try, just by chance? More likely, chemists must also have exhausted a substantial part of all possible molecules in the configuration space around LSD. Generations of chemists must have routinely ingested all kinds of mild psychedelics, felt mildly in communion with the Universe, had a mild encounter with God, and went on with their research without telling anyone. LSD was just the only one strong enough to be noticed.

If you add the history of LSD to the history of artificial sweeteners, it follows that chemistry researchers are constantly tasting everything they touch, and I will believe that until someone gives me a better explanation.

by Malmsbury, Less Wrong |  Read more:

Image: uncredited

[ed. The Wikipedia page on Alexander Shulgin is quite interesting.]

H5N1: Much More Than You Wanted To Know

H5N1: Much More Than You Wanted To Know (ACX)
Image: Metaculus

Even if H5N1 doesn’t go pandemic in humans for a while, it is already pandemic in many birds including chickens, getting there in cows, and possibly gearing up to get there in pigs. This will have economic repercussions for farmers and meat-eaters.

The CDC and various other epidemiological groups have raised the alarm about drinking raw milk while H5N1 is epidemic in cows. There is an obvious biological pathway by which the virus could get into raw milk and be dangerous, but I haven’t seen anyone quantify the risk level. Epidemiologists hate raw milk, think there is never any reason to drink it, and will announce that risks > benefits if the risk is greater than zero. I don’t know if the risk level is at a point where people who like raw milk should avoid it. Everyone says that pasteurized milk (all normal milk; your milk is pasteurized unless you get it from special hippie stores) is safe.

There are already H5N1 vaccines for both chickens and humans; pharma companies are working hard on cows. First World governments have been stockpiling human vaccines just in case, but have so far accumulated enough for only a few percent of the population. If H5N1 goes pandemic, it will probably be because it mutated or reassorted, and current vaccines may not work against the new pandemic strain.

Some people have suggestions for how to prepare for a possible pandemic, but none of them are very surprising: stockpile medications, stockpile vaccines, stockpile protective equipment. The only one that got so much as a “huh” out of me was Institute for Progress’ suggestion to buy out mink farms. Minks are even worse than pigs in their tendency to get infected with lots of different animal and human viruses; they are exceptionally likely to be a source of new zoonotic pandemics. Mink are farmed for their fur, but there aren’t as many New York City heiresses wearing mink coats as there used to be, and the entire US mink industry only makes $80 million/year. We probably lose more than $80 million/year in expectation from mink-related pandemics, so maybe we should just shut them down, the same way we tell the Chinese to shut down wet markets in bat-infested areas. (...)

Conclusions/Predictions

All discussed earlier in the piece, but putting them here for easy reference - see above for justifications and qualifications.

• H5N1 is already pandemic in birds and cows and will likely continue to increase the price of meat and milk.

• 5% chance that H5N1 starts a sustained pandemic in humans in the next year.

• 50% chance that H5N1 starts a sustained pandemic in humans in the next twenty years, assuming no dramatic changes to the world (eg human extinction) during that time.

• If H5N1 does start a sustained pandemic in the next few years, 30% chance it’s about as bad as a normal seasonal flu, 63% chance it’s between 2 - 10x as bad (eg Asian Flu), 6% chance it’s between 10 - 100x as bad (eg Spanish flu), and <1% chance it’s >100x as bad (unprecedented). The 1% chance is Outside View based on other people’s claims, and I don’t really understand how this could happen.

Thanks to Nuño Sempere and Sentinel for help and clarification. Sentinel is an organization that forecasts and responds to global catastrophes; you can find their updates, including on H5N1, here.

by Scott Alexander, ACX |  Read more:

Image: Metaculus (prediciton market)