But they are far from the only medicine with more than one use. Aspirin, colchicine, minoxidil, and Viagra were all found to treat more conditions than expected, and about a third of drugs end up with a second approved use.

In this episode, Jacob and Saloni explore the idea of drug repurposing: taking a medicine made for one disease and finding it works against others. They trace how GLP-1 drugs emerged from an adorable Gila monster, why some drugs have multiple uses, why so many of those uses go untested, and how patents, competition, prizes, and platform trials shape whether we ever find them.

Hard Drugs is a podcast from Works in Progress about medical innovation, presented by Saloni Dattani and Jacob Trefethen.

You can watch or listen on YouTube, Spotify, or Apple Podcasts.

Transcript

Saloni Dattani: New weight loss drugs called GLP-1s, which include Ozempic and Mounjaro, have transformed treatment for two diseases: obesity and diabetes. They reduce high blood sugar levels, slow down the stomach’s emptying of food, and suppress appetite, which causes weight loss.

Jacob Trefethen: New research suggests they also help with other conditions, including heart disease, kidney disease, sleep apnea, and potentially even Alzheimer’s, and clinical trials are underway to test these too.

Saloni Dattani: But these aren’t the only drugs with multiple effects. Although aspirin has been used for more than a century, it was established in the 1980s that it could help treat cardiovascular disease as well. The same is true for colchicine, an ancient gout medicine that was recently found to help treat heart disease. There’s omalizumab, originally an asthma drug that, it turns out, helps treat food allergies.

Jacob Trefethen: In this episode, we’re going to talk about the multiple effects of GLP-1 drugs and the broader idea of repurposing: when you take a drug that’s used for one condition and find it works for other diseases too. What if many more drugs like these are hiding in plain sight? How do we get more of them?

Saloni Dattani: Welcome to Hard Drugs, a cool, awesome new podcast by Saloni Dattani, that’s me, and Jacob Trefethen.

Jacob Trefethen: I don’t know if we’re new anymore, Saloni.

Saloni Dattani: Oh, that’s true.

Jacob Trefethen: But it’s awesome still.

Saloni Dattani: It’s been our first birthday. We started our podcast a year ago.

Jacob Trefethen: That’s right. That’s right. Did you do anything to celebrate?

Saloni Dattani: No, I only realized a few days after.

Jacob Trefethen: That’s a classic anniversary right there, you know? We both missed it.

Saloni Dattani: Okay, so I want to start this episode by doing a little bit of trivia. There are a lot of drugs that have multiple effects, multiple uses, and I wonder how much you know about them.

Jacob Trefethen: Hmm. I’m ready. I think I’m going to, well, we’ll see. You hit me and then I’ll tell you how well I’ll do.

Saloni Dattani: I’m going to start with an easy one.

Jacob Trefethen: Oh gosh.

Saloni Dattani: I think you’ll get this one. I hope. Okay. In the early 1990s, researchers at Pfizer tested a new heart drug for angina. It turned out it did very little for chest pain, but male volunteers in the study were strangely reluctant to return their leftover pills. What was it? What did it eventually become used for medically?

Jacob Trefethen: I think I’m going to get this one. I think it’s Viagra.

Saloni Dattani: Ding, ding, ding! You’re right. It’s Viagra.

Jacob Trefethen: Yes. This one is a famous repurposing story that I’ve heard before. Yes. Viagra or Sildenafil, or I forget what the, what’s the name for Viagra?

Saloni Dattani: Yep. Sildenafil.

Jacob Trefethen: Sildenafil, sildenafil, yes. Some surprising side effects found in the clinical trial.

Saloni Dattani: So what’s the other condition that it’s used for?

Jacob Trefethen: You mean now or in the 90s?

Saloni Dattani: Yeah, like medically.

Jacob Trefethen: Oh, I see.

Saloni Dattani: I guess that’s also medically.

Jacob Trefethen: In my memories, it’s something to do with the heart and blood vessels, but I actually can’t remember.

Saloni Dattani: Yeah. That’s right. It’s hypertension, so pulmonary hypertension. It reduces the blood pressure.

Jacob Trefethen: Very good. Did the original thing it was tested for, is it used for that?

Saloni Dattani: I think the original use was angina as well, which is also related to blood pressure, but it basically acts on certain enzymes that are much more common in the lungs and the penis than in the heart or near the heart. So that’s how it works. Okay. You got that one. I have another, this one’s harder, maybe. I didn’t know this until recently. So have you heard of thalidomide?

Jacob Trefethen: I have heard of thalidomide.

Saloni Dattani: Thalidomide is an infamous drug because it was originally sold for morning sickness in Europe and many other countries. Later on, it turned out that it actually caused birth defects as well. It’s one of the worst medical scandals and led to the FDA changing its oversight on safety for new drugs. But it turns out that’s actually also a treatment for another disease. It’s used as a standard treatment for another disease today. Do you know which one?

Jacob Trefethen: This rings a bell... Oh, gosh. What is it used for? Um. Oh, God, I’m embarrassed. I can’t remember. I remember it is used, and I can’t remember what’s for.

Saloni Dattani: Maybe take a random guess.

Jacob Trefethen: Okay, random guess. Thalidomide might be used for... hair loss.

Saloni Dattani: That’s a good guess. It’s not hair loss though. It’s multiple myeloma, which is a blood cancer.

Jacob Trefethen: A little bit more serious than hair loss. The reason I should have done better test-taking skills there is the fact that thalidomide can have quite severe side effects related to the fact it’s only used for a severe disease.

Saloni Dattani: Yeah.

Jacob Trefethen: That was what we would say pretty bad guessing from a trivia participant.

Saloni Dattani: It’s also used in some cases to treat leprosy.

Jacob Trefethen: Oh, okay.

Saloni Dattani: Which I didn’t know either. But the way that it works is it tags a cancer-causing protein for destruction. That tagging and causing destruction thing is also what happens in limb development in babies. That’s how it causes birth defects as well.

All right. Third one. This one is not a single answer, but you can give as many answers as you can. It’s about Botox. Botox paralyzes muscles and it was originally discovered as a toxin, but in small and precise quantities, it can be used medically or cosmetically, for example, in reducing frown lines and wrinkles. It’s actually approved for around a dozen medical conditions in the US, and over 30 worldwide. How many of those medical conditions that Botox is used for, can you name?

Jacob Trefethen: Okay. Over a dozen?

Saloni Dattani: Around a dozen.

Jacob Trefethen: Over 30 worldwide. Okay. I think it’s frown lines between the eyebrows, number one. Frown lines on the side of your eyes, number two. I think little sort of cheeks sometimes we’ll be going for. We’re already at three. Oh, there’s left side of the face, right side of the face. We’re actually at six.

Saloni Dattani: Oh, yeah.

Jacob Trefethen: The remaining six approvals, I’m not sure. Do you want to give me some?

Saloni Dattani: Frown lines on your arms, frown lines behind your ears. Okay, no, let me name them. I think you had the right idea-

Jacob Trefethen: That’s VERY generous.

Saloni Dattani: -that it was kind of about muscular paralysis. But it’s not about frown lines. It’s used to treat crossed eyes, strabismus, and eyelid spasm, neck muscle spasm, also for preventing chronic migraine and severe underarm sweating.

Jacob Trefethen: Oh, I know that one. Yeah, I know someone.

Saloni Dattani: You knew that one? Then to treat overactive bladders and urine leakage that’s caused by neurological conditions, then also spasticity of the legs and arms. It kind of makes sense, they’re just different reasons that you would want to paralyze muscles.

Jacob Trefethen: Right. Luckily for us, we...

Saloni Dattani: You don’t have any wrinkles yet?

Jacob Trefethen: Thank you. I was waiting. My armpits so far are, doing just fine.

Saloni Dattani: Not sweating that much.

Jacob Trefethen: Well, how do you rate that? I do think that men sweat more.

Saloni Dattani: There’s probably a way to, I don’t know, collect the sweat and see how much volume of sweat.

Jacob Trefethen: Good point. Good point. Yeah. I think the thing that matters is, is it enough sweat that someone can see it on my shirt? So that’s actually, it’s a binary.

Saloni Dattani: Right. Right. That makes sense.

Jacob Trefethen: And as soon as that happens... We’re going into general anesthetic.

Saloni Dattani: I don’t actually know if people use anesthetic to- before they use Botox. I thought it was just still injection or something. I have no idea, obviously.

Jacob Trefethen: Obviously. You’re making so many YouTube watchers jealous right now.

Saloni Dattani: You’re welcome.

Jacob Trefethen: They’re like zooming in on our faces. They’re like, oh shit.

Saloni Dattani: ‘Wow, they really don’t have wrinkles.’ Last question. Out of all the small molecule drugs that the FDA has approved, roughly what proportion of them have an approval for a second medical use? How many, what proportion have been repurposed?

Jacob Trefethen: That’s a really fun question, although I think those are two different questions because you don’t need an approval for a second use. A doctor can prescribe off-label if they think it might help you even without approval. So let’s just break down the question.

Saloni Dattani: I just mean the ones that are approved for a second use.

Jacob Trefethen: Totally. I’m breaking it down in my own head. So there’s small molecules. There’s different types of drugs and therapeutics. Small molecules are, in my head, more likely to go all around the body and have effects in places you might not expect.

Saloni Dattani: Right. These aren’t hormones or peptides. They’re not vaccines or antibodies. They’re small chemicals.

Jacob Trefethen: Yeah. That’s going to increase the number here. I would say the off-label use of small molecules is probably quite a large percentage, I would guess, have doctors who at least have once prescribed it off what it was approved for.

Then in terms of how many approved for a second condition or disease, I bet that it’s going to be less than 50%, would be my guess. Because to get that approval, you often have to generate an evidence package and, are you really going to have an effect size large enough on a new condition? I bet it’ll be less than 50. Then will it be more than 10%? Yeah, I bet it will be, because these drugs go everywhere. But I bet it’s going to be between 10 and 50, so I’m going to say 20%.

Saloni Dattani: I think that was a great reasoning process. You’re pretty close. It’s about a third.

Jacob Trefethen: Wow. That’s cool.

Saloni Dattani: Yeah. Which is quite a lot.

Jacob Trefethen: Yeah.

Saloni Dattani: This is out of drugs approved between 1997 and 2020.

Jacob Trefethen: Okay.

Saloni Dattani: Yeah. About 32% have a new use approved.

Jacob Trefethen: Okay. Wow. If we run the clock for another couple decades, some of the ones in that batch will get more uses approved probably.

Saloni Dattani: Probably, yeah. Isn’t that cool?

Jacob Trefethen: That is cool.

Saloni Dattani: It’s not that uncommon for drugs to have multiple uses.

Jacob Trefethen: I think I did pretty poorly in that trivia.

Saloni Dattani: How many did you get? You got the Viagra one.

Jacob Trefethen: I got the Viagra one.

Saloni Dattani: You sort of got what it was used for.

Jacob Trefethen: Yeah, I got the gist. The thalidomide one, I recalled that it was used for something and didn’t even get close. Then the Botox one I got, I pretty much nailed that one. Okay, so maybe one for four. That’s about the same amount as drugs get repurposed.

Saloni Dattani: Very good. All right. So the most famous current drug that is being repurposed or actually has already been repurposed, I think, are GLP-1s, and so these are weight loss drugs that act on a receptor called the GLP-1 receptor. They include Ozempic and Mounjaro and a bunch of other ones that are kind of in the pipeline right now.

They’re used currently for treating both diabetes and overweight or obesity. But it seems like they might work for other conditions as well. They already have benefits for kidney disease, heart disease, sleep apnea - among people who have diabetes or obesity. But it’s possible that they also have benefits for people without diabetes or obesity. So I wonder if you can guess how that’s possible.

Jacob Trefethen: Yeah, how it’s possible there’s multiple effects, basically? Yeah, I think in general, if you’re creating a drug that intervenes in some way in a process that happens in multiple parts of the body or a process that is pretty general purpose, then you might find that you’re having effects down the line that aren’t the primary thing you were aiming at. I think that’s probably the core of the answer here. Is that fair?

Saloni Dattani: I think that’s right. There are a lot of drugs that are called ‘promiscuous’. They can act on multiple different receptors in the body, especially if they’re small molecule drugs, because they’re so small, they can get to lots of places that bigger drugs can’t. Yeah, they have lots of effects.

But also sometimes, different diseases share the same pathway, like lots of viral infections use similar viral enzymes, or lots of allergies have kind of some similar pathway. So drugs that work for some of them could work for multiple.

Then there’s also this idea that the benefit is sort of downstream. You’re treating obesity and because you’re treating obesity, it also has benefits for, let’s say, heart disease or something else. Then I think there’s a last example with a lot of mood disorders or mental health conditions where the conditions are often treated in similar ways. Antidepressants, many of them are also approved to be used for treating anxiety, for example, that might be because somehow biologically they’re related. So yeah, there are lots of different ways that you can do that. With GLP-1s, they’re not a small molecule drug. They’re peptides.

Jacob Trefethen: Well, that’s pretty close to small molecules as far as I’m-. They’re pretty small and they’re a molecule.

Saloni Dattani: Yeah, right. They’re a big molecule.

Jacob Trefethen: They’re not that-

Saloni Dattani: They’re a medium molecule.

Jacob Trefethen: Yeah, medium. I’ll take medium. I’ll take medium. But the reason I’m harping on this is because presumably the fact that they’re a peptide, not a big antibody or something like that, means that they distribute to more tissues around the body. Is that true?

Saloni Dattani: I think that’s true. Also their receptors are found all around the body. There are GLP-1 receptors in the pancreas, which release insulin and reduce glucose. Then there are GLP-1 receptors in the brain in the hypothalamus, which suppress appetite. Then there are GLP-1 receptors in the stomach, which slow down how quickly the stomach empties food into the intestines. And there’s also GLP-1 receptors in the heart and blood vessels, and probably in a bunch of other organs as well. So lots of different effects that you can have with this one type of peptide.

Yeah I think what’s interesting about GLP-1s is that a lot of people now have heard of them as weight loss drugs, but they were first used for diabetes, and they still are used for diabetes. That is pretty long, like the first GLP-1 drug, that was approved in 2005, which is pretty long ago. We have a lot of data on this and we know that it can be used for these two conditions and it’s pretty effective for them and safe.

Jacob Trefethen: I actually think the first GLP-1 drug was approved thousands of years ago. I’ve been using that stuff naturally. It just created in my body. You got any of that?

Saloni Dattani: That is true. I have that too. We all naturally have GLP-1 as a hormone in the body to reduce our appetite and reduce blood sugar levels. But the versions that are used in drugs are much longer lasting. This is what is really interesting because the GLP-1s that are used in drugs were originally discovered in a type of lizard called a Gila monster. It’s spelt G-I-L-A, but it’s pronounced ‘Heela’. There’s no G sound.

Jacob Trefethen: No G sound? Wow.

Saloni Dattani: There’s no G sound.

Jacob Trefethen: Gila monster.

Saloni Dattani: I have been pronouncing this wrong for the last two years.

Jacob Trefethen: It’s better than saying GAILA monster.

Saloni Dattani: That’s true.

Jacob Trefethen: Actually, two wrongs make a right. Maybe GAILA monster is better.

Saloni Dattani: I guess there’s no G sound because it’s Spanish. It’s found in the southwestern parts of the U.S.

Jacob Trefethen: So do you call them Hee-L-Ps?

Saloni Dattani: No.

Jacob Trefethen: You’re taking your latest HeeLP-1 agonist.

Saloni Dattani: Have you ever seen this lizard before? This Gila monster?

Jacob Trefethen: I think I have seen one picture from maybe a scientific article, but I have not met one in real life, yes.

Saloni Dattani: Me neither, which is kind of a shame because it’s really cute.

Jacob Trefethen: Is it time for a Hard Drugs expedition?

Saloni Dattani: What, to Mexico?

Jacob Trefethen: Yes, we have to meet one.

Saloni Dattani: I want to meet one. It’s quite deadly though.

Jacob Trefethen: Oh.

Saloni Dattani: We’ll come to that soon.

Jacob Trefethen: Oh.. kay. Deadly to diabetes too?

Saloni Dattani: Yes.

Jacob Trefethen: Good. That’s the goal.

Jacob Trefethen: Just remind me, so the way that this was discovered is that a patient with diabetes got bitten by a Gila monster and there were surprising effects!

Saloni Dattani: No, but that would have been a great story. Yes, but they’re found in the southwest parts of the U.S. and North Mexico, and they’re about two feet long, or one to two feet long. Pretty big for a lizard. Actually, one of the largest lizards in North America, apparently, or maybe the largest.

Jacob Trefethen: It goes with the name monster, fair enough.

Saloni Dattani: That’s true. They really do look really cute. Like if you’re listening, I would highly recommend googling them and looking at these cute lizard pictures.

Jacob Trefethen: Okay. But didn’t you just tell me they’re deadly?

Saloni Dattani: Yes. Just forget about that part.

Jacob Trefethen: Got it. Okay, great.

Saloni Dattani: I have a few more trivia questions for you. They’re more just like, fun facts, but some of them are fake. You have to guess which facts are true.

Jacob Trefethen: I’ll try and redeem myself. Hit me.

Saloni Dattani: All right. Number one, Gila monsters can detach and regrow their tail when threatened by a predator.

Jacob Trefethen: When a predator is threatening... their tail? Why would that help them? They could run faster?

Saloni Dattani: Yeah, yeah. They could run away.

Jacob Trefethen: Hmm. Let me think. I mean, that’s random. I don’t know that it would speed you up that much when they start losing balance or something. I feel like that’s so random that has to be true. I’m going to say true.

Saloni Dattani: Well, it’s actually false.

Jacob Trefethen: No!

Saloni Dattani: That’s true of some other lizards, but not Gila monsters. They actually do that. They’re just like, you’re trying to bite my tail. Well, guess what? I’ve just dropped it.

Jacob Trefethen: Honestly, the predator probably likes that too. Tasty tail.

Saloni Dattani: That makes sense. But I think they’re probably quite disappointed. Wait, what? Your tail just dropped off!

Jacob Trefethen: It is kind of like an ultimate gag. It’s like Arrested Development with the guy with the arm that is trying to teach them a lesson.

Saloni Dattani: I watched this so long ago that I don’t remember.

Jacob Trefethen: George Sr. hires his friend who has a detachable arm to teach his children lessons because the arm comes off.

Saloni Dattani: Wow. I would love that.

Jacob Trefethen: Yeah.

Saloni Dattani: Okay. Here’s the second fact. I think I gave this away a little bit. Okay.

Jacob Trefethen: Finally one I’ll get right.

Saloni Dattani: The Gila monster is sluggish in nature so it is not generally dangerous and very rarely poses a real threat to humans.

Jacob Trefethen: Okay. I think this might be a little of column A, a little of column B. I think it is dangerous to humans because of maybe venom would be my guess. But maybe that is compatible with it being sluggish. I sort of do think of it as sluggish. I think maybe... Yeah, I’m going to go with sluggish, but deadly.

Saloni Dattani: You just have a stereotype in your mind that it’s like, oh my God, it’s so slow.

Jacob Trefethen: Yeah, basically. I definitely think of it as lounging. Do you know what I mean? It’s not like one of those geckos. We’re talking a monster. It’s lounging. It’s baking in the sun. That’s the kind of energy.

Saloni Dattani: You are exactly right.

Jacob Trefethen: Oh, finally.

Saloni Dattani: It is a very slow lizard. Its top speed is about one and a half miles per hour.

Jacob Trefethen: You’re kidding. That can’t be-

Saloni Dattani: Can you imagine being that slow?

Jacob Trefethen: That is really embarrassing for the Gila monster. Wow, I kind of feel... I really changed my perspective on the Gila. That’s also... Who measured that?

Saloni Dattani: They were in a little race. They were like, oh, wow.

Jacob Trefethen: I guess you would put some prey in front of it that it wants and then see how fast it could go after.

Saloni Dattani: Maybe they’ve just been videotaping it for a really long time and seeing how fast it usually goes. But you were right, so its venom is very poisonous, its bite is excruciating. But they just don’t encounter humans that much, so they’re not very...

Jacob Trefethen: Who are they mainly biting then?

Saloni Dattani: I guess its food, usually it eats small animals like mice.

Jacob Trefethen: Right.

Saloni Dattani: And little birds, I guess.

Jacob Trefethen: It’s kind of interesting because I feel like it’s kind of like Tom and Jerry, but if Tom couldn’t run. It’s surprising, but anyway, okay.

Saloni Dattani: Okay. Next one. The Gila monster has very muscular jaws that produce a firm, tenacious bite with the venom dripping into the wound as the lizard chews.

Jacob Trefethen: Oh my God. And so is that true or false, basically?

Saloni Dattani: Yeah.

Jacob Trefethen: Okay. I think that’s true.

Saloni Dattani: That is true. Pretty terrifying.

Jacob Trefethen: Oh God.

Saloni Dattani: That is the exact description that I found in a paper.

Jacob Trefethen: Okay. Delightful.

Saloni Dattani: Sounds quite horrible. Okay, last one. Gila monsters spend most of their life underground and can survive eating only a few meals per year. True or false?

Jacob Trefethen: That is going to be true because that and that’s really going to be related to, I think that’s going to be related to Hee-LP.

Saloni Dattani: Yes, it is. It is true. They stay underground most of the year. They come up overground only during the spring, usually. And they can survive eating only a few meals per year. They’re really good at fasting. I was wondering if you could only eat three meals per year, what would those three meals be?

Jacob Trefethen: I have a sort of tradition I’ve lapsed that I, a few years ago, very much valued, which was having pancakes the night before Thanksgiving. I’d probably keep that one then. Okay. I’ve got two left. You have to really be eating the most calorie dense thing... No, I guess I’m taking that too seriously. We’re going to die in this example.

Saloni Dattani: Oh no!

Jacob Trefethen: No, no, no. Two more. Maybe, well, I have always been a sucker for cornbread. I would have a meal that was very cornbread forward. Right.

Saloni Dattani: Pancakes, cornbread.

Jacob Trefethen: Yeah. Everything’s yellow. That’s the theme.

Saloni Dattani: Potato?

Jacob Trefethen: No, the third would be a delicious salad, actually, Saloni. Oh. You got a problem with that?

Saloni Dattani: I find this hard to believe.

Jacob Trefethen: What’s your answer then?

Saloni Dattani: Potatoes. Potatoes and potatoes.

Jacob Trefethen: All three? Oh, no. I didn’t know that about you.

Saloni Dattani: I heard that potatoes contain all the nutrients that you need.

Jacob Trefethen: That’s right. That’s why I make sure to avoid other foods.

Saloni Dattani: What’s interesting about the Gila monster is that they also, they eat very large meals. They eat just like entire quail eggs at once and stuff, and they store fat in their tails.

Jacob Trefethen: Oh, their non-detachable tails.

Saloni Dattani: Yes. If they were detachable, they actually would be yum for predators to eat.

Jacob Trefethen: Okay.

Saloni Dattani: Separately, I wonder if you’ve ever wondered how venoms work. It’s not that common for lizards to be venomous and Gila monsters are venomous. I hadn’t really thought about what makes venom actually deadly to people.

Jacob Trefethen: Yes, I, um... I have looked into this a bit in my previous day job, and there’s a multitude of ways they can, is what I remember. But messing with your blood is a classic sort of vector of destruction. But is there a more... Do you have a list of destruction methods?

Saloni Dattani: What makes venom venomous? The answer is you can either use your venom to destroy red blood cells, or wreck clotting mechanisms so you cause lots of internal bleeding. The one that I had thought about was like being a nerve agent, disrupting nerve signaling, causing paralysis.

Jacob Trefethen: Yeah, yeah, yeah, definitely.

Saloni Dattani: Then some venoms digest cell membranes and connective tissue, and that spreads the rest of the venom even further.

Jacob Trefethen: Wonderful... So if anyone wants to lose weight, then...

Saloni Dattani: Let’s talk about medicines instead.

Jacob Trefethen: GLP-1s, how does this relate to GLP-1s, Saloni?

Saloni Dattani: Yeah, how does this relate to GLP-1s? What are GLP-1s? They are a type of gut hormone that is released when you eat, naturally. They’re a type of gut hormone called an incretin, and those hormones tell the pancreas to release insulin. In the 1980s, people found a natural incretin, which they called GLP-1.

But what’s sad about natural GLP-1 is that it has a really short half-life. It only lasts about two minutes in the body. That’s not very useful medically. The reason for that is that it just gets destroyed by enzymes and removed by the kidneys. So scientists were looking at this two minute long hormone and they thought maybe there’s a better version of this that we could make that we could use as a treatment for diabetes. If you can stimulate insulin production, you can treat diabetes.

There were a bunch of scientists who were trying to study that, but also trying to study this Gila monster, the lizard, for other reasons. The story here, I feel like, is kind of different from what I had heard about this. I feel like I had heard several times that GLP-1s were discovered accidentally. People were studying this lizard and then somehow it produced this hormone that was really helpful and was a source of GLP-1 drugs. But when I looked into it, it turned out that it wasn’t very accidental at all.

Jacob Trefethen: Oh, as in the Gila monsters were planning this the whole time?

Saloni Dattani: Yes, that’s exactly what I meant.

Jacob Trefethen: I knew it!

Saloni Dattani: The Gila monsters were actually- the scientists took off their masks and it turned out...

Jacob Trefethen: That is, it actually does all make sense now. The scientists were- The way they found out was they were walking at 1.5 miles an hour. Oh, sorry, sprinting.

Saloni Dattani: The other scientists were like, why are they so slow? There must be something special about them.

Jacob Trefethen: If it’s not accidental discovery, so what happened?

Saloni Dattani: There were two scientists studying these lizards for different reasons. One scientist was an endocrinologist who was interested in the venom and the fact that if people were bitten by this venomous lizard, the Gila monster, they often developed this extreme pancreatic reaction to it. It somehow stimulated the pancreas so maybe it’s involved in doing something to pancreatic hormones.

Then there was another scientist called John Eng who was studying peptide hormones in animals. He had already studied a beaded lizard’s venom and found a hormone that resembled human GLP-1. Then he turned to study the venom of another lizard, Gila monster, to find out whether it had a hormone like that too. That’s why they were studying the venom of this lizard, the Gila monster.

Jacob Trefethen: So are you telling me the venom is circulating through its veins and keeping it skinny?

Saloni Dattani: Yeah, that’s a good point. I don’t know why this hormone is in its venom. That part is surprising.

Jacob Trefethen: Yeah.

Saloni Dattani: Okay. Maybe venom is just a mix of random stuff.

Jacob Trefethen: Yeah. Yeah. Maybe. Okay. Interesting. Were they collaborating or were they working at cross purposes?

Saloni Dattani: Yeah. They were working together. Okay, so they were interested in this lizard for these two different reasons and decided to look at what was in the Gila monster’s venom and they found a bunch of peptides, and one of them turned out to be really similar to GLP-1, the natural gut hormone. It was called Exendin-4. Sounds like a villain from a cartoon I would have watched when I was five years old.

Jacob Trefethen: Did they get to name it that villain or was it already named?

Saloni Dattani: I think they named it.

Jacob Trefethen: Maybe they were watching the same cartoons as you.

Saloni Dattani: Probably. They found this other hormone that was similar to GLP-1 in the Gila monster’s venom. It also switched on the same GLP-1 receptor, so this was all in 1992. But what was even more cool about this version of the hormone in the Gila monster was that unlike natural GLP-1s in humans, which only last a few minutes, this hormone lasts hours. That makes it much more useful as a drug. The reason for that is just it contains a slightly different amino acid at the place where the enzyme was breaking down natural GLP-1, so it doesn’t get degraded as much.

Jacob Trefethen: But overall, they look pretty similar?

Saloni Dattani: Yeah.

Jacob Trefethen: Yeah. Okay.

Saloni Dattani: I guess what also I found kind of interesting was how long it took between when they discovered this Exendin-4, this Gila monster GLP-1, and how long it took from that to developing it into a drug. It was first approved for diabetes in 2005, which is really like 13 years later, which seemed pretty long to me. Apparently John Eng, who discovered it, patented it pretty quickly and presented his findings to a bunch of pharma companies but some people just thought the idea was too weird and they just didn’t see like a commercial use for it.

Jacob Trefethen: People.

Saloni Dattani: ‘What do you mean it’s too weird? It’s just a lizard!’

Jacob Trefethen: He’s walking around with his vial like, ‘There’s nothing weird about this!’

Saloni Dattani: Yeah, but that changed in San Francisco, which is where you are, at the 1996 American Diabetes Association conference, where scientists from a biotech company called Amylin Pharmaceuticals-

Jacob Trefethen: Yes, Amylin!

Saloni Dattani: were interested in this and they decided to license his patent. Then they turned it into a drug. The drug is called Exenatide. It’s a synthetic version. They’re not actually extracting it from the lizard each time. That was the first GLP-1 drug that was approved.

Jacob Trefethen: That’s great. I’m glad we got our first one. But exenatide is not what we all talk about now, so...

Saloni Dattani: Maybe we should be talking about it.

Jacob Trefethen: Maybe we should be talking about it. Exenatide in the armpits. That sounds like it was a great beginning, but how does it relate to other GLP-1s? What’s the story?

Saloni Dattani: Yeah, the other GLP-1 drugs are basically modifications of that first one. After Exenatide, the first GLP-1 drug was developed, scientists at Novo Nordisk tried to tweak it and they turned it into a longer lasting drug called liraglutide.

The way that is tweaked is basically it has like a fatty acid chain attached to the molecule, to the peptide, and that means that it can bind to albumin in the blood. Albumin is a protein in the blood that just carries around lots of different things. It’s basically like a little bus that’s going around your body and it’s like, hey, get on the bus and then the little hormones get on the bus and then eventually they get off the bus. Liraglutide can last a day versus exenatide, which could last hours. This was another advance.

Then after that, there was semaglutide, which was modified even more to last about a week. It just had a stronger fatty acid chain that grips onto the albumin more tightly.

Jacob Trefethen: We basically have this original insight starting in 1992 from the Gila monsters. Then that insight is built on to its first pharmacological point in ‘96 and onwards, and then we’re iterating, iterating, iterating off of this idea.

Saloni Dattani: Yes, exactly. You’ve probably heard of tirzepatide and retatrutide as well.

Jacob Trefethen: I have. Yes, retatrutide, yes.

Saloni Dattani: Retatrutide. What’s so interesting about these is that now it’s not just that they act on the GLP-1 receptor, they actually act on multiple receptors. Tirzepatide, which is by Eli Lilly, or it’s called Mounjaro, that acts on both GLP-1 receptors and GIP receptors. Then there’s retatrutide, which acts on GLP-1s, GIP and glucagon.

Jacob Trefethen: Boom, boom, boom, triple!

Saloni Dattani: The way that it does that is all of these receptors are evolutionarily related to each other and they look kind of similar. So you can design, you can just slightly tweak a drug so that it fits into multiple receptors and not just one.

Jacob Trefethen: It’s sort of fascinating to think about that because this is one molecule doing three things. It’s kind of like, why, why, why not have three molecules? If you ask a drug developer, a medicinal chemist, I think the answer you’ll get is, well, you can control better the dosing. You kind of want one. But it’s all over your body and randomly interacting with all sorts of things all over it. You’re making this statistical bet of how much you will interact with the three different things.

Saloni Dattani: Yeah, I think there’s like another layer of that though, because even GLP-1 receptors, on their own, they’re present in multiple parts of the body. Sometimes it helps to have a really specific drug that only attaches to one thing. Sometimes it’s better if they act on multiple things - then they could have multiple benefits.

Jacob Trefethen: Now, I live in San Francisco and I was recently at a conference where a British person was, I was talking to a British person who was visiting about science and he immediately, well, he from context got that despite the fact I grew up in England, I now live in San Francisco. So he said, oh, probably you have to leave soon so you can go buy your peptides on a street corner.

I thought, that’s a bit rude. He’s telling me that I have to go buy peptides on a street corner. Then I thought, this man, he’s stereotyping San Franciscans. Then I sort of ran through my head and I thought, well, I do have a lot of friends who have bought peptides if not on a street corner, then from an apartment.

The most common one that I have seen is retatrutide. This is not approved yet, but it’s going through the process of the FDA. But the data looks so strong that to the San Franciscan mind, you want to be getting illegal imported versions of it as soon as you possibly can, stirring them up in your fridge and then jamming yourself. Yeah, around here it’s actually called Rita. People don’t even say retatrutide.

Saloni Dattani: Rita like Rita Hayworth.

Jacob Trefethen: Yes, exactly.

Saloni Dattani: Just like her.

Jacob Trefethen: Just like her.

Saloni Dattani: I find it also, yeah, I find it interesting, the new GLP-1 drugs, they’re more effective partly through working on multiple receptors. They act on more receptors than the previous ones did, and they’re more effective probably because of that.

Jacob Trefethen: What fourth and fifth receptor would you add?

Saloni Dattani: Oh, I don’t- I think I would stop there. Honestly, that’s enough.

Jacob Trefethen: At some point, it gets so effective. It’s like, the serious point is that all of these things come with trade-offs. If you’re hitting more things, that might dial up your efficacy depending on what you’re trying to measure. But also it adds risk. You’re hitting things you might not want to or that have some function that is beneficial or keeping your body normal. Most things in the body happen for a reason. There is a genuine trade-off. You might not want to add a fifth or a sixth. I do find it funny that we now kind of have GLP-1 and then it feels like GLP-2, GLP-3. It feels like GLP-3. We’ve got to get to 5.5.

Saloni Dattani: I think I remember reading that one of the most common reasons that people dropped out of the clinical trial for it was that they lost too much weight.

Jacob Trefethen: Totally. Yeah.

Saloni Dattani: Yeah. It’s pretty high. Retatrutide in its phase three trial caused a 28% reduction in body weight. It’s huge.

Jacob Trefethen: It’s absolutely crazy. That is crazy. And that happened over the course of one day.

Saloni Dattani: What? No, it didn’t. It’s more like a year and a half.

Jacob Trefethen: I don’t even think I tricked you with that one, I think.

Saloni Dattani: I’m very used to this because when I was growing up, my brother used to just make up things and he’d say things that sounded plausible. It wouldn’t be like in the context of like, oh, do you believe or whatever. You would just say things that were false. He’d be like, ha, you believed that!

Jacob Trefethen: It’s a trick with no upside.

Saloni Dattani: That’s why I’ve turned into a really skeptical person now. I just don’t believe anyone at all.

Jacob Trefethen: Aww. No, that’s not true. You believe.

Saloni Dattani: That’s true. I thought you were right about the tapeworm being called a tapeworm because it was sticky underneath.

Jacob Trefethen: I now have to read to the audience, totally unrelatedly, the most Saloni text I’ve ever read.

Saloni Dattani: Oh, what was it?

Jacob Trefethen: About what you can believe and what you can’t believe. Let me pull it up. Someone on the internet posted a chart and we’re in a group chat together with some people who read charts and look at charts. Someone asked, “any takes on this?” Basically on this chart, how would you evaluate it?

Saloni responded, “I find it so odd for someone to tweet out something like that without even looking up the data quality notes.” I don’t know that anyone else would find that odd. “I just can’t imagine someone tweeting something without reading the appendix first!”

Saloni Dattani: I realized just after posting that, I was like, wait a second, I’m probably the only person who does that.

Jacob Trefethen: “I just find it so odd.”

Saloni Dattani: It’s very annoying when people do that.

Jacob Trefethen: No, I am with you. Anyway, so-

Saloni Dattani: Thank you. GLP-1s. We know that they’re useful for weight loss. Retatrutide, the latest one, causes a 28% reduction. That compares to semaglutide, the first one, which was about 15% weight loss. Tirzepatide, which was about 21% at the top dose. These are getting a lot more. This is crazy. I do think that it’s non-linear and that eventually we won’t be able to just keep increasing how much weight loss you can achieve with new drugs.

Jacob Trefethen: I hope so. Some of the weight is your organs, some of the weight is your nose, your teeth. Yeah. It’s worth saying this is... It’s not like, once you go off the drugs, you, most people start gaining weight again. It’s not like a permanent in your body forever kind of thing. But yeah, these graphs are really quite, quite something. It’s only 18 months. It’s not very long time.

Saloni Dattani: It’s much larger than I, I think that what’s interesting to me is that I remember in maybe 2021 or so, I was trying to find someone to write an article for us at Works in Progress about weight loss drugs. I remembered learning in my undergrad that there were a lot of failures in the 1970s, 80s, 90s, people trying to develop obesity medications and a lot of them were really toxic. Or they just caused weight loss in a really unpleasant way.

I was interested in like, what’s the state of that research now? Are there new drugs that are in the pipeline today? I asked this nutrition researcher called Stephan Guyenet to write an article about that for us. He wrote one on the future of weight loss, basically these GLP-1 drugs that hadn’t been, that hadn’t reached the finish line at that point, but it was so interesting even then to just see like how much happened in the meantime.

There was this period of maybe two decades where it seemed like a lot of pharma companies were pretty afraid to touch obesity as a potential area. Now it’s the biggest or one of the biggest areas for new pharmaceutical drugs.

Jacob Trefethen: Yeah. How much can change.

Saloni Dattani: So much can change. I also, I think that. Yeah. People often don’t know that these are also treatments for diabetes. I wonder if you know how they work at doing that.

Jacob Trefethen: I think of them originally for diabetes, or at least type 2. I believe they lower your blood sugar levels. But more specifically, let’s see...

Saloni Dattani: Yeah. I think you’ve kind of got it, but there’s an additional piece of evidence there that they don’t just reduce blood sugar level on the whole, but they reduce blood sugar level when the blood sugar levels are high.

Jacob Trefethen: Yeah, yeah, yes. Right. Right.

Saloni Dattani: It’s like a glucose dependent effect. What’s good about that is that a lot of previous diabetes drugs just generally reduced blood sugar levels. If you are on a high dose, then you could suffer from hypoglycemia, you could have really low blood sugar levels and that would be bad. But this doesn’t happen with GLP-1 drugs. They only reduce blood sugar levels when they’re high.

Jacob Trefethen: Although you have to watch out for it, right? But it’s not a big problem, it seems.

Saloni Dattani: Right. Also, unlike some other diabetes drugs, they cause weight loss instead of weight gain. There were a bunch of other diabetes drugs that did that, which is probably not great because a lot of people with diabetes are also overweight or obese. This is helpful because it tackles both things. I wonder if you know how- they’ve also been used to prevent the development of diabetes, so in people who have pre-diabetes but don’t have actual full-blown diabetes yet, how much it reduces that progression?

Jacob Trefethen: Hmm. I wonder how you measure that because prediabetes is set at a debatable binary cutoff point. Do you measure it against a continuous variable?

Saloni Dattani: This is, so both of them are measured in part based on HbA1c, which is a measure of how much sugar is attached to your hemoglobin. At a certain threshold, you can be considered having pre-diabetes. Then if it’s above that level, it’s considered diabetes. The question is, if you are in this range where you have pre-diabetes, how much does it reduce your chances of eventually developing diabetes?

Jacob Trefethen: Yeah. I don’t know the number, but my impression is a lot. I think it’s a very effective way on it.

Saloni Dattani: It is very effective. There is a trial recently called the SURMOUNT-1 trial where they gave tirzepatide, that’s Mounjaro, to people with obesity and prediabetes. They had a 94% reduction in the progression to type 2 diabetes.

Jacob Trefethen: Wow. Over what period? I’m trying to make sense.

Saloni Dattani: Over three years.

Jacob Trefethen: Okay. Basically over a three-year period, if you have prediabetes, there’s some chance you’ll progress. For people on the drug, it was like basically no chance you’ll progress.

Saloni Dattani: Right. It was like 18% or so chance of progressing in the next three years if you were on a placebo.

Jacob Trefethen: Got it.

Saloni Dattani: But if you’re on tirzepatide, it’s like 2%.

Jacob Trefethen: Oh, wow. That is amazing. Wow. That’s awesome.

Saloni Dattani: We talked about how GLP-1 drugs are used for diabetes and obesity, but they’re also being studied for lots of other diseases, like kidney disease, cardiovascular disease, sleep apnea, and also diseases like Alzheimer’s and Parkinson’s. Most of those trials are being studied in people who are already diabetic or obese and the trials are looking at whether it also improves those other conditions that they have.

With the two exceptions of the two brain diseases, brain conditions. So in the Parkinson’s and Alzheimer’s trials, GLP-1s were tested in people without diabetes or obesity. But so far those trials have found null results. They haven’t been demonstrated to be effective.

I think there’s like an ongoing debate around, does it have all of these multiple benefits because it’s actually effective for those conditions? Or is it just because it’s reducing weight and improving blood sugar levels, which usually have all of these other negative consequences? So if you reduce weight, you’re going to reduce your kidney disease or heart disease as well. I think that’s still an active debate. I wonder what you think. Would you guess that if GLP-1 drugs were tested in people who are not diabetic, who are not obese, would they still have those benefits as well?

Jacob Trefethen: Ooh, depends on the benefits, depends on the people is my scapegoat answer. My guess is that there’s stuff going on that will benefit people who are not diabetic and not overweight. Yes, yes. Now, it was disappointing to see the Alzheimer’s result that came back null. I think that could still go both ways though. That trial enrolled people who already had essentially-

Saloni Dattani: Early onset.

Jacob Trefethen: Yeah. Not early onset, but early Alzheimer’s, I believe. You can tell me if I’m right. I think it was.

Saloni Dattani: No, you’re right. Early stage Alzheimer’s.

Jacob Trefethen: Early stage. Yeah.

Saloni Dattani: So it didn’t slow that down.

Jacob Trefethen: It didn’t slow that down, but that’s- the inclusion of one of the inclusion conditions to be in that trial was that you already had confirmed amyloid in the brain, or something that would signal you probably have amyloid in the brain. So I think there’s almost a separate question of, the average age of people in that trial is probably 71 or something.

If you gave people- if people were on GLP-1s preventively much earlier, before amyloid and tau had accumulated or got that far into accumulating, could you have a preventive effect? I’m actually sort of hopeful, and my read is that the jury is still out there and there may be some benefit on Alzheimer’s that’s earlier prevention. But yeah, the data... It’s pretty clear from that trial that the hope of something that as soon as you get a diagnosis, you go on that then helps, it’s not going to be as magical as that.

Saloni Dattani: Yeah, that’s a shame. I hope you’re right that it is effective for that. I feel like when I read about these for the first time, I thought, well, some types of dementias are actually caused by cardiovascular problems, like vascular dementia. I sort of thought, maybe they’ll find a benefit in this trial, if not for any other reason, for that reason. But I think people with Alzheimer’s also having vascular dementia is not that common, but also it seems like it didn’t help in that sense. Or maybe it wasn’t powered enough to find that.

Jacob Trefethen: Right, yup.

Saloni Dattani: Yeah, I think with the other conditions like kidney disease, cardiovascular disease, at least with cardiovascular disease, my guess would be probably it does help with that in part because GLP-1 receptors are also found on blood vessels and they reduce blood pressure slightly. But also I think with lots of these conditions, it’s not really like a binary of overweight or obesity or not. Right? Like it’s continuous. I’m sure that, okay, if it helps a lot for people who are obese, it probably helps as well for people who are not to a lesser extent.

Jacob Trefethen: Yep. Then, there’s, of course, as with everything in biology, you go to the other extreme and you can harm people. If you’re prone to anorexia, if you’re, if you have low body mass, there’s ways you, but these, these things can do harm too.

Saloni Dattani: Right. I was interested in this as well because I was thinking, okay, so we have now really effective drugs that help with weight loss. What about drugs that help with weight gain? Because there are some conditions where maybe someone who has chemotherapy or something and has lost a lot of weight because of that, are there any drugs in the pipeline that help them gain weight... aside from marijuana?

Jacob Trefethen: Oh, yes. Good point. Marijuana. The pathway there goes via Taco Bell, actually, at the end. No, if you are severely malnourished, then you can get prescribed Plumpy Nut or other forms of ready-to-use therapeutic food. Therapeutic food in the sense of they are treated as medicines in some sense. Yes, there at the very least is high fat, high protein food that you do get prescribed if you’re severely malnourished. Probably not the answer you’re looking for, you probably want something more biochemical than that.

Saloni Dattani: Yeah. There are apparently a bunch of drugs in the pipeline right now that are for weight gain. There’s an antibody treatment called ponsegromab, which seems to help with weight gain, but it’s in phase three trials right now. I haven’t tried it.

Jacob Trefethen: You’re making me run through the list in my head now. There’s other appetite suppressant, stimulants have often been weight loss drugs either off-label. Are there things that off-label everyone knows you gain weight if you eat? Yeah, there are a bunch of those probably.

Saloni Dattani: That’s right. Aren’t there antipsychotic drugs that make people gain weight?

Jacob Trefethen: Yep.

Saloni Dattani: Huh, interesting. Might try one. I’m kidding. But I guess the last thing to say about GLP-1 drugs is that this is not the end. There are a lot more in the pipeline. There are new drugs being developed that don’t just cause complete weight loss through both fat and muscle, but there are new drugs that are muscle-preserving, weight loss reduction drugs. There are also different types of actual dosing or different durations of these drugs. There are people developing patches like a needle patch that you put on your arm and that slowly gets released into your body.

There’s also, recently, there’s a small molecule drug version of a GLP-1 agonist. I wonder if you know, or remember, what that’s called? It has a really funny name.

Jacob Trefethen: Oh, oh, do you mean the, the oral one? Wait.

Saloni Dattani: Yeah. Yeah.

Jacob Trefethen: Okay. Gosh, yeah, what is that?

Saloni Dattani: It’s a pill. It’s a small molecule. It activates GLP-1 receptors.

Jacob Trefethen: Gosh, I can’t remember. I can’t remember. What’s it called?

Saloni Dattani: It’s called orforglipron.

Jacob Trefethen: Yeah, they really have run out of names for Pokémon these days, reaching the bottom of the barrel.

Saloni Dattani: I usually imagine a cat typing on the keyboard and that’s how these drugs are named. That’s the end of that. GLP-1 drugs have two uses already, diabetes and obesity. They’re being tested for a bunch of other uses as well.

They were originally developed by finding GLP-1 peptides in Gila monster, a type of lizard, in their venom. That hormone was much longer lasting than the natural GLP-1 that we have in our body. By tweaking that hormone, scientists made sure that it lasted longer, even longer, in the body for days or weeks. That has led us to the drugs that we have today.

Jacob Trefethen: It’s an amazing story. I wish it could have happened quicker, as is often the case with some of the stories on our episodes, but not so bad. These drugs will go on to prevent millions of people from earlier death. Even aside from the health gains that a lot of people are going to see, there’s... these are really big population-wide effects at this point. It’s kind of wild to have something that is so new that will be so impactful.

Saloni Dattani: That reminds me that with some of these drugs, they’ve also been tested for how much they reduce mortality rates overall. The first, well, the second GLP-1 drug, liraglutide, the FDA said with any new weight loss drug, it has to be tested for how safe it is for cardiovascular disease as well. They did trials to find out how effective, how safe it was. They actually found that it reduced heart attacks in that population and it reduced mortality rates on the whole by about 12% in people with obesity, which is actually quite large. Like that’s, roughly, that’s roughly the effect of, statins in reducing mortality rates as well. And that was for the earlier GLP-1 drug so I’m guessing these new ones have a slightly larger effect.

Saloni Dattani: Okay so GLP-1 drugs are a type of drug that have multiple effect. I’m going to raise a potentially controversial or surprising opinion, which is that what if there are lots of other drugs that can do things like this too?

Jacob Trefethen: Dun-dun-DUN! I don’t think it’s possible.

Saloni Dattani: You don’t think it’s possible.

Jacob Trefethen: No, I’m joking. What’s my real answer? I sort of am a bit of a conspiracy theorist on this. Often the most powerful drugs are doing something that’s quite important. Yes, I think that sometimes-

Saloni Dattani: Yes, that seems circular, though.

Jacob Trefethen: Let me rephrase it. Some of the most important functions in the body are sort of these pathways that have many different downstream effects. If you’re targeting an important node, for sure there might be repurposed things that could happen. The thing is that most people are mostly healthy most of the time. You don’t want to be messing with those important panels.

The GLP one story is so shocking because it’s like, wait, hold on, we could have just done that the whole time? Like if we’d evolved different GLP? That’s crazy. Because usually if you’re hitting a channel like that, there’s something bad happening somewhere else. This has been a big problem in Alzheimer’s, for example. The genes and proteins that are involved in the development of Alzheimer’s, there’s more and more knowledge about them every decade. A lot of the problem is happening in the brain, but those genes and proteins are doing things all over the body. So if you try and give someone a drug that is going to interfere with them, you may end up causing issues. This happened with BACE1 inhibitors. This happened with gamma secretase.

Saloni Dattani: What’s a BACE1 inhibitor?

Jacob Trefethen: B-A-C-E-1. It’s just a class of drugs that people have tried for Alzheimer’s. The off-target effects really get you. This kind of principle, if you go to something really important and it will have lots of effects is good and bad, but true.

Saloni Dattani: Right. I wonder if you remember, so we talked at the start of the episode about some examples of drugs that have multiple uses, but how many other ones can you name?

Jacob Trefethen: Oh, okay. That’s a fun prompt. Let’s see. So there’s... maybe I’ll try and get to three and then stop. Well, there are things that you would use in different contexts for different patients. I don’t know if that counts. Like low dose aspirin for different, if you are pregnant and meet certain conditions can be useful, but that’s not the main way you would think about aspirin. Or, lithium is one that we are looking into right now, actually, for Alzheimer’s, again. Is there an effect of lithium orotate on Alzheimer’s? Not on, lithium is often used for others.

Saloni Dattani: It’s usually bipolar, right?

Jacob Trefethen: Yes. Lithium carbonate is used for bipolar. Let’s see, what’s the third fun one? How about, oh, BCG. This one always blows my mind.

Saloni Dattani: Is it actually used for those yet? I think it’s still unclear.

Jacob Trefethen: For what? BCG is used for bladder cancer.

Saloni Dattani: Really? I didn’t know that.

Jacob Trefethen: Yeah, yeah, yeah. BCG is-

Saloni Dattani: The vaccine.

Jacob Trefethen: -covered in previous episodes and you should, listeners should go back and listen to every single one in case it pops up. It is a sort of wondrous vaccine from 1921 that is still used, it’s that good, against TB. It is producing some sort of non-specific immune response in that it’s not just helping with TB, it’s helping with other stuff too. One of the things that it’s now used for is bladder cancer. People have tried it out for a bunch of different stuff too, due to this kind of non-specific effect. Do you ever want to just jack up your immune system to achieve some other goal? Yeah, BCG is a fave.

Saloni Dattani: Nice. I was thinking of SGLT2 inhibitors.

Jacob Trefethen: Nerd! Loser!

Saloni Dattani: Sorry, yeah, these are kind of similar...

Jacob Trefethen: Wait, listeners, do you not think about SGLT2 inhibitors?

Saloni Dattani: I think about them every day. I think this is the original, wow, does this just work for everything? Where they were originally developed for diabetes, but it turned out later on that they also could treat heart failure and chronic kidney disease and maybe some other conditions as well. Then you mentioned aspirin, a painkiller, but also use sometimes in pregnancy and also is a heart disease drug. That was only found out, I think, in the 1980s. Have you heard of colchicine?

Jacob Trefethen: Colchicine rings a bell, but what is it?

Saloni Dattani: It’s a gout medicine. I think in the last 15 years or so, it turned out to be pretty effective against heart disease as well. Then there’s minoxidil. Have you heard of that?

Jacob Trefethen: Any man my age has heard of that, Saloni.

Saloni Dattani: That was originally an antihypertension drug, but it later turned out to be somewhat effective as a topical treatment for baldness. Why I remembered it this year was that there was a phase three trial this year with a different formulation of minoxidil, which is longer lasting and that led to hair regrowth that was much more than the previous version. I think the previous version was like, you would have to apply it every day or something. Whereas this one, it’s a pill.

Jacob Trefethen: Yep. I, you know, just talking to friends, of course, the issue with applying it every day is like, oh God, so do I do it before a shower, after a shower? It’s kind of annoying. You can’t, there’s a pill version, finasteride. But that goes all over the body and has all sorts of off-target effects. It’s much, nicer if you can just do it topically. But it’s also more of a hassle.

Saloni Dattani: Yep. Then there’s omalizumab that I mentioned at the start. That was originally developed as an asthma drug. But more recently, it’s shown to be effective for various food allergies. Peanut, milk, yeah, various food allergies. Then you brought up Viagra, Sildenafil.

Jacob Trefethen: I didn’t bring that up! You brought that up!

Saloni Dattani: Sorry. You answered that to my first question.

Jacob Trefethen: Now, Viagra, I do expect, if I had to make a prediction, we will get another usage of Viagra. People actually talk about Viagra in the context of Alzheimer’s too. There’s not, to my knowledge, been a big trial of it.

Saloni Dattani: Interesting. That seems like something, we probably have enough people taking it now that we could find out.

Jacob Trefethen: That’s a good point. Look back at that data.

Saloni Dattani: Then there’s, yeah, a lot of antidepressants are also used for other conditions like anxiety. Then sometimes there’s a kind of related phenomenon where something is tested for one thing and then it turns out to be useful for something else.

If you’ve heard of KarXT or xanomeline-trospium, that is a new schizophrenia drug that was approved, I think maybe one or two years ago. It was originally tested as a dementia drug, but in those trials, I think in the 1990s, they found that it reduced hallucinations in those patients and then thought, oh, maybe we could use this as a schizophrenia drug. But the problem was that the drug had multiple effects. One was in the brain reducing hallucinations, but the other was that it caused really severe nausea and vomiting, and that’s because it also attached to receptors in the gut. So I think researchers tweaked it and added trospium to it, which prevents it from binding to those other receptors in the gut; it’s basically tweaked to become more specific so it only reaches the brain.

Jacob Trefethen: Which is a good sort of lens to apply here as well, where repurposing is not always you have one drug used for three diseases. Sometimes you get insight from the development of a drug for one disease that leads you to keep going and keep tweaking for a different disease. From a drug developer’s point of view, maybe the more common exciting story, I’m not actually sure, but that certainly is a common thing that is a bit different. You still got to do some chemistry after you get the initial.

Saloni Dattani: Right. You might tweak, you might change the way that it’s given so that it has more effects in one organ than another, or you might attach something else to it so that it can’t get into certain places that cause side effects.

Jacob Trefethen: From the point of view of a philanthropic funder, this is often something that sounds like a detail that can be quite important because there’s the magical hope is that you could fund a trial for a drug that already exists against a new indication and then it works. Then you don’t have to go through all of the original testing again, because you already have these big safety data from the first usage! That is really amazing from a point of view of health benefit without having to spend as much money. And that can happen.

The issue is often you’re finding these insights that you actually then do want to go back a little bit to the drawing board and make some edits to the chemistry. Once you do that, you then have to sort of re-enter as if you’re a new drug to some degree. So that can get you back into more traditional pharma land and that can cost a lot more money.

Saloni Dattani: Right. I guess what’s also interesting is that we’ve talked about a bunch of different types of drugs that have these multiple effects. Small molecule drugs, which are so small and they can get everywhere, they often have effects in different places. But also some peptides, like GLP-1s, have multiple effects, and also some antibodies have unexpected effects as well. I recently saw this study a few months ago where they tested all the approved antibody drugs and found that about a third of them had an off-target effect as well. Then there are gene therapies, which I guess that’s less likely because those are so focused on a specific gene.

Jacob Trefethen: But genes do multiple things sometimes.

Saloni Dattani: That’s true. That’s true. We’ve talked about ones where there is pretty good evidence so far that they can be used for different conditions. But what about some speculative possibilities about drugs that are used today that could be used for other conditions, and we don’t really know yet? Do you have any that come to mind?

Jacob Trefethen: Yeah. Oh, well, I hate to hop on one theme of Alzheimer’s, but the shingles vaccine and Alzheimer’s.

Saloni Dattani: That is one. I’m pretty skeptical of that..

Jacob Trefethen: You’re skeptical?

Saloni Dattani: But why don’t you make your case first?

Jacob Trefethen: Okay, I’ll make my case. There have now been four, I believe, independent, quite interesting natural experiments or observational studies that point in the same direction, that show that when the shingles vaccine got rolled out to different people who are older to prevent shingles. It looks like it may have also prevented the probability you progress into develop Alzheimer’s or dementia.

The first or the most sort of striking study of these four as far as I’ve seen is in Wales, there was a introduction of the shingles vaccine, where if you were born in 1933, I believe, the cutoff date was September 2nd, if I remember. If you were born before that, you were not eligible. If you were born after that, you were eligible. You have this really clean cutoff date where you can then see what happened to the people on either side of that, what an economist would call a regression discontinuity. The answer is that in that population, the people who did get the shingles vaccine were, after seven years, had a drop in relative risk of Alzheimer’s or dementia of 20%.

That is not as high quality evidence as a randomized controlled trial, which is what you would usually do for developing a new drug that went through clinical trials. However, it’s pretty suggestive. It’s- I’ve had friends who skeptical friends trying to poke holes in it, and I’ve heard different holes trying to be poked, but you usually have a rejoinder. It’s the kind of observation I’ve been saying, like, oh, maybe there’s something here. Then the fact that this has popped up in other countries as well, in other studies, is pretty interesting.

Now, the thing that I think is not known yet, so there hasn’t been a randomized controlled trial testing this yet, and there’s various questions that are one level detailed down, but that are very important. Question number one, in the trial, in the observational setting I just mentioned in Wales, the vaccine in question was the live attenuated herpes zoster vaccine. Now, there’s another vaccine that is now used in the US, for example, called Shingrix, which is the trade name, which is a subunit vaccine with an adjuvant made by GSK.

Saloni Dattani: Right. So both of these are shingles vaccines, and the studies that showed this benefit were using the old one.

Jacob Trefethen: That’s right. Well, one of them was. There’s that one that also trying to look at, well, hold on a second, with the modern shingles vaccine that was designed to be better for preventing shingles, is it also better for preventing Alzheimer’s? Is it the same? Is there any difference?

I’ve actually heard different opinions from different scientists on that. The evidence is not strong enough to give a good answer on that. Some people actually think it is, it’s going to be worse than the original live attenuated vaccine. Because of the way your immune system responds to live attenuated vaccines differently than sub-unit vaccines. Some people think it will be better. That’s a question.

Then another question is, okay, well, what’s actually going on here? Is it about shingles? Like reducing the amount you get shingles is the channel that reduces the amount you get Alzheimer’s. It’s probably not. There’s probably something else going on about, just at that age, jacking up your immune system to clear out a bunch of stuff. That is-

Saloni Dattani: So it’s not, you’re saying it’s not shingles necessarily that’s contributing to dementia.

Jacob Trefethen: Not necessarily. People are debating this now. They’re trying to chase down what is the mechanism of if there is a real effect here, why is there a real effect here? Could you get that effect from simply an adjuvant that boosts your immune system rather than a specific vaccine.

Saloni Dattani: I guess I want to get the shingles vaccine, but if I could just prevent it with just an adjuvant, then that’s really easy.

Jacob Trefethen: If I recall from a previous episode, you have trauma related to the chickenpox vaccine.

Saloni Dattani: Oh, that’s true.

Jacob Trefethen: You weren’t allowed to get it.

Saloni Dattani: It really depresses me that in most, I think in every country or maybe most countries, you can’t get a shingles vaccine unless you’re above a certain age, and that age is like 50 or 65 or something, even though lots of people younger than that get shingles.

Jacob Trefethen: Yeah. Some countries recommend it 65 plus. The US is now recommended at 50 plus. Imagine if there is a preventive effect against Alzheimer’s and we’re just YOLO-ing it, and it’s like, what the hell? Yes, that is a fascination of mine, and I am still reading up on it. But why are you skeptical?

Saloni Dattani: Why am I skeptical? I think, so there are multiple reasons that I’m skeptical. One is that, okay, it seems like there are many vaccines that are links to a lower risk of dementia. Not just shingles, but flu and DTP and various others as well. I have to say, when I see something, when I see results like that, I’m like, what if they’re all just confounded? What if it’s healthier people tend to get these vaccines and they have a lower chance of developing dementia? That doesn’t really apply to the study that you mentioned, of course.

But I have other reasons for skepticism there. One is the specific way that these studies were done is, as you mentioned, they’re looking at a particular birth date where, after that birth date, people were offered the vaccine and people before that birth date weren’t. Even though these are somewhat large studies, when you’re doing that comparison, the thing that matters most is how much that drop is just before and after that cutoff. The number of people who are just above or below that birth date in that year, it’s not that big. So the results that I’ve seen, they seem to be kind of marginally significant. I am sort of skeptical that they’ll hold up in larger samples. I think there’s an ongoing study with a larger population of the whole of England, instead of Wales, where they didn’t find any discontinuity. So I’m thinking there’s probably something going on there.

But I think that just in general, when you look at these kind of cutoff studies, you often have to ask, what if something else changed there as well at that same time? That it was not just getting eligible for that vaccine, but also maybe that was the start of the school year and maybe grandparents with little grandchildren have a higher risk of getting shingles or something, I don’t know, whatever, something like that. There’s like little nigglings in my mind that make me think, I don’t know if this will hold up. I would say I’m pretty unconfident that it will hold up, but I would say probably about 20 to 25% chance where I think maybe it will actually prove to be true and that seems high enough to warrant more attention. But I’m pretty skeptical.

Jacob Trefethen: I would take the bet against that. I think it’s higher chance than that. I’m curious how you think about the evidence from other countries. You mentioned the England evidence that’s kind of ongoing. I should know more than I do about it. But what about the Australians? What about all these other countries?

Saloni Dattani: As far as I’ve seen, they’ve also been just marginally significant. When I look at that, it’s a bit... When you tweak certain things in your statistical analysis, you can get things that are marginally significant. There’s a really cool blogpost by a friend of mine on the Uncanny mountain of P-values. Basically, if the literature is full of results that are barely statistically significant, or just under the threshold, that’s a warning sign that the effects might not hold up.

Jacob Trefethen: Do you think that there is a real effect, but it’s so small that it won’t be detected? Or you think there’s not even a real effect?

Saloni Dattani: I guess this depends on, how small of an effect can we detect? My guess is that it’ll be too small to matter.

Jacob Trefethen: Got it. Okay.

Saloni Dattani: But I hope that I’m wrong. Anyway, shingles vaccines are just good. Shingles is terrible. It’s painful. Take it anyway!

Jacob Trefethen: Okay, so let’s just step backwards and could there be more drug repurposing than there is? Is this a panacea, Saloni? What do you think?

Saloni Dattani: What do I think? I do think with many of the examples that we’ve talked about, we only found out that they could be used for something else pretty late. With aspirin, for example, that’s been used for over a century, but people only really established that it could be used for cardiovascular disease in the 1980s. Then there’s dexamethasone during COVID - that was originally a steroid, and it took public funding to run a trial to find out that it was useful for COVID as well. There’s another one I read about recently called moxidectin.

Jacob Trefethen: Yes, moxidectin, yeah.

Saloni Dattani: Right, which was originally developed as a, I think, deworming drug for animals, is that right? It was a veterinary drug in the 1980s. People thought, oh, maybe we should try this out for worm infections in humans as well. But there was just not really a market for that because people who are most affected by that live in poverty, they’re children in poverty in Africa and south Asia, for example. So there wasn’t really interest in funding the trials for it and actually proving out that it works and getting it to market, until a nonprofit did that in the 2010s and more recently. Their trial showed that it could cure 70% of whipworm infections in kids in Tanzania.

My view is, okay, there are a bunch of examples where it took really long to figure out that these drugs that were already there were gonna be effective for something else. That suggests to me that there must be other drugs right now that are gonna take a long time to be found effective for something else. So that’s my optimist take on that.

Jacob Trefethen: Okay, let me be pessimistic then. If a drug had a really useful use, you usually spot it because people taking it will experience that side effect. Everything else is minor in comparison.

Saloni Dattani: What if they don’t have the other disease though? What if they’re like quite different things and there isn’t that much overlap?

Jacob Trefethen: Hmm... You got me. The more public health benefit you want, the more it has to be a common disease. But you are, it is true, unfortunate. Wow, I didn’t manage to stay skeptical for very long, did I? It’s true that you can often, there are many diseases out there and you won’t have collected evidence for the utility against most. That’s true.

Saloni Dattani: I guess one reason that, when I first heard about this topic, I was pretty skeptical and I was like, isn’t pharma already doing this? Aren’t they already testing for whether their drugs work for multiple conditions? Because if they did, then, you know, that’s a larger market. That’s more money. Why wouldn’t this be happening?

I also, I know that pharma companies individually have hundreds of thousands of compounds in their libraries and often they will just mass screen all of them against the diseases that they’re interested in. And so, aren’t they just doing this already? How can there be more that we haven’t found?

Jacob Trefethen: What I would say to that is that presupposes we understand these diseases and we usually don’t. You can’t actually do a screen that tells you the truth because diseases are very complex and manifest in ways that are not just about cellular receptors, you know. Often you discover these things that you wouldn’t expect just in virtue of complexity of the body. So that one, yeah, I think screening can’t be the whole story.

Saloni Dattani: It also sort of made me think that often when pharma companies are testing these hundreds or thousands of drugs, they often start with a disease, or they start with a target, and they’re like, which of the many drugs we have work against that target? I think it’s less common that they have all the drug compounds and they’re like, which of the hundreds of different diseases do these work against? Because that’s like way too many combinations as well.

Jacob Trefethen: Yes, the combinatorics. Then, in addition, the amount of money that you can make off of different drugs for different diseases varies by orders of magnitude. If you’re a company that’s trying to make sure it doesn’t go bust, then you won’t be putting the same amount of energy behind leprosy as you would be behind cardiovascular disease.

Saloni Dattani: One other reason that I am a little bit skeptical, or was a little bit skeptical, was lots of attempts at repurposing drugs have failed. For example, metformin, there was a lot of hype around that.

Jacob Trefethen: There’s still hope on that!

Saloni Dattani: Oh there is? There was a lot of hope that it would be a cancer drug as well. There were a lot of academic trials on this. The same is true for, I think, vitamin D in various different conditions as a treatment. Most of, I think so far, the conclusion is that they don’t work for those.

But one of the interesting things about that was that the evidence for this before the trials were done were observational studies. Some of these observational studies were affected by various biases. One of these biases is called immortal time bias. Have you heard of that?

Jacob Trefethen: I’m pretty biased myself as a immortal demigod. Yes. But what about you?

Saloni Dattani: I had, well, I had heard about this for a long time and I was like, what does that, why is it called that? I feel like hardly anyone had given me an explanation of this that made sense. It was like really complicated and people would explain it with these diagrams that were very difficult to read.

But the basic idea is that you have, you’re looking at like, let’s say hospital data or something, and you’re comparing people who have taken a drug to people who haven’t. You look at, while they’re on the drug, what are their chances of developing the disease versus people who are not on the drug?

What a lot of these studies would often do is that they count the time that people are not on the drug, or before they start the drug, in the control group, and they take the time that they spend on the drug in the treated group. But that creates a problem. You’ve like already lived up to a certain age before you get to the treatment group, which means you’ve sort of lived longer by definition. The only way that you could be prescribed that is if you’ve lived a certain amount of time.

This affected a lot of the studies that were claiming there were benefits of metformin for cancer. That is called immortal time bias, because when you start getting on the treatment group, it’s like you’ve been immortal until that point, and that’s the only reason you’ve been included in the study. You can’t have died.

Jacob Trefethen: Right, right. Yeah, that’s a sneaky one.

Saloni Dattani: There’s also another bias that’s often called confounding by selection, which is that the people who get prescribed a certain drug are different in some systematic way from the people who don’t. So in a randomized trial, you’re randomly deciding to put some people on the placebo versus some people on the treatment. But that’s not true in the real world. People who get certain drugs might have a more advanced stage of the disease. Or with vaccines, often it’s healthier, more educated people who will get vaccines as adults. Or for certain vaccines, like the rabies vaccine, it’s often people in certain occupations, like they’re vets or something else, that get the vaccine. They’re systematically different, which might mean that they’re healthier in some way.

Jacob Trefethen: Anything observational is more stressful. It is true. I have to admit that.

Saloni Dattani: Yeah. Yeah. I think there’s just, there’s a lot of uncertainty and many or maybe most repurposing efforts will fail. I think this is why randomized controlled trials are so helpful. But I wouldn’t lose faith in the whole idea. Most clinical trials also fail, but some of them work. You shouldn’t assume that because many or most of them will fail that they’re not worth trying.

Jacob Trefethen: Let me give another pitch that there might be a goldmine out there and see what you think. One issue from a pharma company’s point of view on repurposed drugs is that if a drug has been approved for one use, then it’s sort of like an immortal time bias for drug patent length. It’s quite likely the patent has expired by the time you have suggestive evidence for second use. If I’m a company, why would I pony up $75 million to confirm an effect that then anyone legally can sell that drug? Because I don’t have a patent anymore. So what do you say to that? Doesn’t that imply there’s all of this low hanging fruit because companies aren’t paying for these trials? Why would they? We got to pay for them as taxpayers!

Saloni Dattani: I think you’re right. I think, well, the counter argument to this is that a lot of the companies still do trials before the patent expires. So maybe they’ve- if they’re taking so long to start running a trial, maybe that’s because there weren’t these other uses at all.

Jacob Trefethen: It takes a while to accumulate off-label data. I don’t know. I think, the aspirin case, it was literally decades and decades, right? I don’t know.

Saloni Dattani: No, you’re right.

Jacob Trefethen: Now, what I will say is I just have to give a shout out to one of the best trials of all time. Any guess what I’m about to... which trial that is?

Saloni Dattani: I don’t know. What are you thinking of?

Jacob Trefethen: What do you mean you don’t know, Saloni.

Saloni Dattani: RECOVERY?

Jacob Trefethen: Yes! RECOVERY! Yes! Okay, so let’s say you find yourself in 2020, which I do not recommend.

Saloni Dattani: For many reasons.

Jacob Trefethen: For many reasons. There’s an issue you face, which is an incoming global pandemic. If you want to develop a drug against COVID from scratch, it’s going to take a while because it just came out of nowhere. It’s a great time to see whether there’s a repurposed drug that could work. However, most of these drugs are off patent, because they have been around for decades. Time is of the essence. So what do you do? If you are Martin Landray and collaborators and Peter Horby, I believe, at the University of Oxford, and if you are the UKRI and MRC, the two funding agencies in the UK government, and then later, if you’re the Wellcome Trust and the Flu Lab, what you can do is fund a trial that has many arms.

You have people who are like, ‘Hydroxychloroquine is gonna prevent COVID!’ Great, chuck it in the arm. We’re gonna test. We’re gonna have some people on a control group. Okay. ‘What about, dexamethasone?’ ‘No, that’s very dangerous. You don’t want to be giving people a steroid.’ Let’s try it out. Chuck it in the arm. They had all these different arms. Then by June, 2020, which is months before vaccines, they had managed to find that hydroxychloroquine didn’t work. Some other things didn’t work. Dexamethasone did work.

And then within the day, they had, well, they had to confirm that it wasn’t spurious. They like really double checked the data before that press release went out. Then they, within the day, the NHS system in the UK absolutely flipped and said, okay, if anyone comes in, gets hospitalized with COVID. Now we know what we can give them, it’s going to reduce their chance of death. It’s a stunning result. People have tried to model out how many lives that saved. The most prominent modeling, which I haven’t gone deep to vet myself, but suggests that within 12 months that saved a million lives around the world. Oh my goodness. Just unbelievable. You could not have known ahead of time. People were saying all these different stuff. People were making all these different predictions. And they got the data. Oh my gosh.

Saloni Dattani: People have so many hypotheses and it’s hard to know which ones are actually going to work. There are probably some good reasons to believe all of them might have worked. It’s so useful to actually run the trials and figure out which ones they are. The wonder of repurposing. Save millions of lives.

Jacob Trefethen: Completely. I think that when you look at, okay, how can we repeat that for different areas? My suspicion is that you’re just not going to have many areas where you’re getting a 90% reduction from a repurposed drug. Then maybe you will have some areas where you’re getting a 20, 30% reduction. Okay, you’ve got to be kind of looking for these population-wide things. That sort of changes the catchment area a little bit. It makes you want to go cardiovascular. It makes you want to go maybe Alzheimer’s. But I’m not so sure it will be. Yeah, I guess I hold out less hope for 90% reductions.

Saloni Dattani: I think that brings me to another reason for optimism, which is that some diseases just don’t have a large enough commercial market that companies would even be willing to try to test them for them. Like they’re not interested in repurposing something for a tropical disease where there isn’t that much money in developing those drugs anyway, or diseases like addiction or something like that, where people who have them aren’t able to pay for them. That makes me think there are a bunch of diseases like this where we don’t really have the incentives for pharma companies to test them, even if they are on patent.

Jacob Trefethen: Yup.

Saloni Dattani: I think the other one, we mentioned a few vaccines, but I think this also applies to vaccines especially because once they’re universally recommended and you test them out for a different thing, you’re not going to get a larger market from doing that. You’ve already put it on the market. It’s already recommended to everyone. You’re not really going to get much more of a benefit from doing that.

Jacob Trefethen: I disagree on that one. I think GSK has a massive incentive to test Shingrix against Alzheimer’s because the Shingrix vaccine, it’s not exactly your top priority for everyone. Something like a third of people who are eligible actually get it. It’s a painful vaccine, massive adjuvant jab. A lot of people don’t go back for their second dose. If it were known that you could reduce your chance of Alzheimer’s by 20%, I think that would go to, they probably double their sales, so that’s, I think they have a big incentive personally.

Saloni Dattani: I guess, yeah, I agree with that, but I think vaccines tend to have a lower price than other drugs, and so that would make it hard for them to- and I don’t think that they would be able to raise the price that much.

Jacob Trefethen: Yeah, interesting, yeah.

Saloni Dattani: I think the last reason is that I think, even though there is this economic incentive to testing drugs for new conditions, that incentive is going to kind of run out once the patent expires and generics enter. Because like you said, if you’ve tested it for some new condition, you’ve like spent the millions or tens of millions of dollars on these clinical trials, and it turns out, okay, it’s useful for something else, well people can just get the generic version anyway, and they’re much cheaper. What’s the point of doing that?

Jacob Trefethen: Yeah.

Saloni Dattani: There’s a really interesting paper that basically looks at drugs that spend longer in clinical trials and therefore, when they finally get to market, they have a shorter patent life remaining. Those drugs tend to be repurposed less. That suggests that there are economic incentives that can run out. If you look at the kind of repurposing efforts over time, after the patent is issued or after the drug is approved for the first thing, it kind of slowly declines over time. Companies are trying, once the drug is approved, to test it out for lots of different things. Then when it reaches the end of the patent period, they’re like, ah, well, the generics are just going to undercut us.

But there is this, there’s a little bit of like a back and forth here because I think that, often when people hear about this, they’re like, well, don’t pharma companies do all these sneaky things to lengthen their patent lengths anyway? Can’t they just get around this by doing that instead? I think that’s sort of true, but there’s a limit to how true that is.

Jacob Trefethen: Only so much you can, you can finagle.

Saloni Dattani: Have you heard of some of these sneaky tactics?

Jacob Trefethen: Let me invent some. Here’s what I would do. Okay.

Saloni Dattani: What, you’re the pharma company?

Jacob Trefethen: Yes. I would, if I think, oh, hold on a second, there might be a off-target effect here that’s beneficial instead of harmful. Okay, here’s what we do. We go back and change the molecule by the minimal amount to generate a new molecule according to the US Patent Office. We generate new data on that molecule and we submit a new patent. We say, we just invented a new drug. Then we want it to have not changed that much, because the effect might disappear. Do people do that?

Saloni Dattani: That’s true. People do that, but can’t the generics just use the original version and say, hey, well.

Jacob Trefethen: Damn, wow. I’m so stupid. I’m such a bad- That was crazy. I completely missed that. Okay, let me think. Yeah, you have to then actually, well, that’s pretty cool. The system’s aligned with benefit pretty nicely because you have to then make it a better drug.

Saloni Dattani: Yeah, right.

Jacob Trefethen: I guess, yeah. Okay, here’s my new scheme. I make it so that it is demonstrably slightly better. Then the way that drugs work, you get a winner-takes-all effect where no one wants a slightly worse drug, you know? Everyone wants something that’s slightly better. That takes 100% of market share regardless of price. How does that, how’s that?

Saloni Dattani: Is that true? I feel like if I, if the brand name drug was like 5% more effective, but the generic drug is... 10 times cheaper or whatever.

Jacob Trefethen: But consumers don’t pay. The health system pays. You might get negotiated by the NHS on that. You won’t get negotiated in the US though. I’m exaggerating. In some cases, you will.

Saloni Dattani: I was going to say that there’s this thing that generic companies can do. Let me sort of take a step back and explain how this works. Let’s say I’m the brand name drug company and I have developed drug for this thing, this one condition, diabetes, and then I’ve also tested it for weight loss. I would put both of those things on the label, but the diabetes thing came first.

A generic company, let’s say that’s you, you could decide, I’m just going to say that this is used for diabetes on the label and not also for weight loss. But doctors know that it’s the same molecule and it can be used for weight loss as well. So they can just prescribe the generic drug for weight loss.

Jacob Trefethen: But your point being that patent protection, it doesn’t really follow an indication, it follows a molecule.

Saloni Dattani: It follows an indication, but... you have to, the brand, the company that has the brand name drug has to prove that the generic company actively is trying to prescribe, get it prescribed for that second use and that’s quite hard to prove. You get undercut by the generic company.

Jacob Trefethen: Right. You’re not going to confirm that effect necessarily with a trial.

Saloni Dattani: Yeah. The patent extension or whatever is only helpful if the generics haven’t got in.

Jacob Trefethen: Got it, yes.

Saloni Dattani: There’s another thing you can do as the original brand name company, which is that you can switch patients to a different version of the drug. You can say, oh, you know what, instead of this twice-daily drug, you should take the once-daily drug instead, or once-daily version instead. If you do that, then those people can’t get the generic drug instead of your brand name drug, if they’re prescribed it. At pharmacies, they can automatically prescribe you a generic drug if it’s the same dosage and stuff, but they can’t if it’s slightly different.

Jacob Trefethen: That’s really interesting, yeah. That makes sense.

Saloni Dattani: Okay, so there are all these things, there are all these economic incentives that can affect whether generic repurposing happens. My conclusion is that there are probably a lot of repurposing efforts that aren’t happening.

That’s probably especially true for drugs that are already off-patent and that are generics. It’s probably true for things where people can already get these things very cheaply and they’ve existed for a long time, like vitamins and supplements.

Also for diseases like tropical diseases or diseases of poverty where the market and the incentive for a pharma company to run these clinical trials to try to do repurposing isn’t really there. And also for diseases where the clinical trials take a really long time, because if they take a long time, then you have a shorter time still on patent and you have less time to recoup that investment.

Finally, I think it’s probably also not happening as much as it could for vaccines. My guess is that the reason for that is that companies are trying to, generally when you’re developing vaccines and they’re used universally by children, by like 80 or 90% of children, and they’re healthy children otherwise, you kind of want to limit how many off-target effects, how many side effects there are. So you’re trying to make them as specific and precise as you can, and because of that, you’re just looking for toxicity.

Jacob Trefethen: Right. I would add in the optimism column from this episode for me is it’s just so nice that for repurposed drugs, you have an existing large safety dataset. The existing safety data is just such a boon. If you can find these now, I will give my pessimistic take from this episode is that I don’t think you’ll get many miracle drugs in the sense of I don’t think you’ll have these massive cures and reductions. I think you’re going to be improving various markers similar to the weight loss drugs by meaningful amounts, maybe you’ll be reducing your risk of heart attacks by 10 or 20% with something or reducing your risk of Alzheimer’s if we get a repurposed drug for Alzheimer’s. But I don’t think we’ll get an Alzheimer’s cure this way.

Saloni Dattani: Aww.

Jacob Trefethen: Sorry. You don’t even think the shingles vaccine works!

Saloni Dattani: Well, I don’t think the shingles vaccine works for dementia.

Jacob Trefethen: We have to come back in five years and see who is right about that.

Saloni Dattani: We definitely should.

Jacob Trefethen: Okay, so we’ve learned about repurposing drugs and I wanted to check with you right now. If I, instead of injecting Mounjaro in my thigh, injected it somewhere else, would different effects happen? If I injected it in my scalp, would it be a baldness drug? What do you think?

Saloni Dattani: Wow. This is hard. I know that-

Jacob Trefethen: I don’t think it’s hard.

Saloni Dattani: You’re trying to lose weight somewhere else?

Jacob Trefethen: No, no, no, no. I’m trying to have a different effect that I want. But because it’s a magical drug, you can have any effect depending where you inject it.

Saloni Dattani: Ooh. Hmm. You know what I would like?

Jacob Trefethen: What?

Saloni Dattani: More hands.

Jacob Trefethen: You want an increase of 50% in hands?

Saloni Dattani: Yeah. You could do so many more things with them. You know what that would make really easy? Juggling!

Jacob Trefethen: How frequently do you find yourself juggling?

Saloni Dattani: Never. I’m so bad at it.

Jacob Trefethen: You don’t have more hands.

Saloni Dattani: Exactly. It’s because I don’t have more hands.

Jacob Trefethen: Also there’s complementarities, because if you had more hands, you could inject more Mounjaro quicker. You could get the benefits of other drugs too.

Saloni Dattani: This is what I’m missing out on. What about you? What’s your answer?

Jacob Trefethen: If you had more hands, would you also want more feet?

Saloni Dattani: No. What do you do with feet? You just walk and run. They’re not that useful. You’re not picking up stuff with them.

Jacob Trefethen: I think if you had four feet... Now I’m just thinking, would I have four legs?

Saloni Dattani: I’d be a centaur.

Jacob Trefethen: Maybe if I had... Here’s what I want. Instead of two flat feet, lame, pathetic, I want two curved, kind of like...

Saloni Dattani: Oh, wow. Like a rocking...

Jacob Trefethen: Yeah, yeah. Exactly. Then walking would be kind of fun. I actually got taught how to walk once. You’re meant to land on the...

Saloni Dattani: You didn’t know- sorry, you got taught how to walk? What is the context of this?

Jacob Trefethen: Like in the sense of by a gay person, like how do you, how do you walk in a way that’s like chic?

Saloni Dattani: What?

Jacob Trefethen: You, I can’t even remember now. Wait, let me just practice. You go, yeah, yeah. You have to, you have to do the weight right at the heel and the ball of the foot, but I can’t do it without doing it live. I can’t explain it. You wouldn’t get it!

Saloni Dattani: Okay... sorry.

Jacob Trefethen: Anyway, point being, it’s a bit like a rocking horse. I think you could walk better if you had a rocking horse.

Saloni Dattani: This is a very strange choice of off-target side effect you want.

Jacob Trefethen: Okay, fine, fine, fine.

Saloni Dattani: You want to turn into a rocking horse.

Jacob Trefethen: Let’s see, what else do I want? Maybe it would be nice if... If you had the thing that would just give you massive muscles, would you do it? I guess we do have that. It’s called a steroid.

Saloni Dattani: I think, yes. Well, not massive, but bigger. No, I don’t take steroids.

Jacob Trefethen: I just entrapped you. I’m actually a police person.

Saloni Dattani: Oh, no. The other thing that made me think of was, I would love to be taller than I am. I’m very small.

Jacob Trefethen: They have that too, growth hormone.

Saloni Dattani: It’s too late for me to take that, isn’t it? I think it’s when you’re growing up.

Jacob Trefethen: It’s true. It’s true.

Saloni Dattani: I used to stretch more. When I was a teenager, I was like, maybe if I stretch more, I’ll get taller.

Jacob Trefethen: That’s so depressing. You were like, do they still have any of the torture racks that they used?

Saloni Dattani: Not that extreme. I don’t know. I just thought it was, I was like, maybe this is one of those things that’s like a ‘use it or lose it’ situation. The more you stretch, the more your body is like, oh, she needs to be taller than she is.

Jacob Trefethen: It can sense. Yeah. I guess I’m trying to think, would I want a tail? I don’t know if I need a tail.

Saloni Dattani: What about a tail that can drop off and regenerate itself?

Jacob Trefethen: Definitely better than a tail. Why not have the optionality, if you’re going to have a tail? Yeah. I think if I had a tail, I’d want it to be really long.

Saloni Dattani: To do what with?

Jacob Trefethen: Just to curl around my legs.

Saloni Dattani: Like Rapunzel.

Jacob Trefethen: You know how Italian people will gesture with their hands? I want to gesture with my tail.

Saloni Dattani: I was thinking of Rapunzel. You could let down your tail and someone could climb up.

Jacob Trefethen: I live on a first floor.

Saloni Dattani: Yeah, that’s not very useful.

Jacob Trefethen: People are always trying to climb in. Anyway.

Saloni Dattani: She uses her hair for martial arts and stuff.

Jacob Trefethen: Which presumably hurts.

Saloni Dattani: As a weapon. Yeah.

Saloni Dattani: So I guess our conclusion is there are probably a lot of repurposing efforts that aren’t happening for various reasons. According to economists, the value of that or the missing amount of innovation that’s not happening is pretty large. The estimate is around 100 to 400 billion dollars per year in social value that’s not happening because of all of these misaligned incentives. So this seems like a really important problem to solve. What’s helpful, as you mentioned, is that these are drugs that are already approved for something, so we already have lots of data on them and it wouldn’t be that hard to test them out for new conditions as well.

Jacob Trefethen: With that in mind, what are some of the- not the scientific things that can help with drug development, but some of the economic or regulatory or, related to patents policy? What are some things that we could do that would improve the system here?

Saloni Dattani: I think there’s probably a lot of things that we could do. I guess the basic idea maybe that I should re-describe is that in general, when pharma companies do more repurposing, or they’re testing their drugs for more conditions, they have a larger population of patients that the drug can be prescribed for, so there’s a larger market. There is an economic incentive to some degree to test drugs for new conditions. But that incentive is kind of time limited because once the drug goes off patent, and generics can enter the market, they can get outcompeted by those generic manufacturers and it becomes no longer worth it to run trials and expand the uses.

I think this is more of a problem for small molecule drugs, because it’s really easy for generics to develop their own version of the small molecule drug in general. It’s easier to develop small molecule drugs and cheaper, and they can get into the market pretty quickly. It’s harder for biological drugs like antibodies and vaccines. That’s for two reasons. One is that those drugs tend to have twelve years of exclusivity once the drug gets approved, rather than five. But also it’s just harder to develop those, you need a lot of technical know-how, it’s more expensive for generic manufacturers to develop them.

Based on that, how do we get more repurposing, more of the ideas? I guess the obvious one, which is probably, which I think is often pretty unpopular, is just extending the length of the patents. But right now, you don’t extend your patent length for a new use. You get more exclusivity on the market. It’s slightly different. The U.S. Patent Office gives you a standard length of 20 years after you file for a patent. A company develops a drug, maybe immediately after they develop it, they file a patent for it, they get the patent. For 20 years, they have the exclusive rights on producing that thing.

Then once it gets approved at any point during that 20 years, the FDA then gives them an additional five years where they’re the only people that can sell the drug for that condition. The idea would be either you could extend the length of the patent so it’s more than 20 years, or you could extend the exclusivity period that the FDA gives you after the first use is approved.

If you get another use approved, then you get another three years of exclusivity for that new use. But that’s only helpful if it’s before generics become available on the market. I think the downside is higher prices for longer, but the upside is there’s more of an incentive to test new uses for these drugs at all. And we find out about new uses of drugs that we wouldn’t have known about before. Does that make sense?

Jacob Trefethen: Yeah, maybe. This stuff is complicated though because you have more of an incentive for one company, that’s true, but you do incur more deadweight loss because you have a monopoly for a longer period. Yeah, I’m not sure I have a clean intuition that will point me in the right direction. My intuition could take me in either one.

Saloni Dattani: Can I give you a weird example? It’s actually, it’s not the same. It’s not what we’re talking about, but it’s kind of related.

Colchicine, the gout medicine, it’s an ancient gout remedy. I think it was probably properly developed as a medicine in the 19th century for treating gout. For drugs that are developed so long ago, before the FDA even existed, before drug regulation existed, and that were already on the market, they weren’t approved and the generics weren’t approved either. They just were there already- they’re sort of approved to be used because of that ancientness.

At some point, I think the FDA developed this pathway where they wanted to get companies to test whether these drugs were actually effective, and if they were effective for different uses as well. What they said was that, if you do test these existing grandfathered-in drugs for some other condition, then you will get exclusivity to sell them. There was this company called URL Pharma, which tested colchicine, I think for gout or maybe it was for cardiovascular disease. They found that it was effective. The trial succeeded. The FDA was like, okay, cool, now you get exclusivity. They actually cleared out and like shut down all of the unapproved competitors. This became the only one on the market and they raised the price massively and everyone got really mad. Understandably.

Jacob Trefethen: Wow. Extending patent length. That’s maybe a pretty big one, kind of blunt. Are there other options?

Saloni Dattani: What do you think?

Jacob Trefethen: There’s the classic, you know, two approaches to the economy as supply and demand, Saloni.

Saloni Dattani: Oh, really? What?

Jacob Trefethen: Yeah. When you put that in funding terms, you sometimes get into push and pull, where push funding is-

Saloni Dattani: What I’m getting really confused with, with doors.

Jacob Trefethen: Yes, yes. Imagine a door that could go both ways, sort of like an operating theater. No, the push means sort of grant funding investment. There’s money coming from some financial entity into some operating entity to run trials or to do something or other. Then pull funding is on the demand side. You’re saying, okay, because you’re not going to get a big payout because of all this generic entry, we have some other way of paying out.

Saloni Dattani: It’s like, if you develop the thing, we’ll pay you.

Jacob Trefethen: Exactly.

Saloni Dattani: Whereas the push funding is like, we’ll pay you to try to develop it.

Jacob Trefethen: Exactly. Yeah. I would look at both sides of this. I would say, if there’s a market failure in the sense of there’s not a private incentive for companies to generate this knowledge about whether a drug works well, number one, you can make grants. To those companies, to other entities to generate the knowledge. That’s push funding.

Number two, you could create prizes or payoffs of some form out the other end, where you say, okay, it’s not that you’re going to be able to charge a ton for this drug because there’ll be generic entry, but whoever can generate the knowledge gets a big payout. Here’s a hundred million dollar prize! Those are the two things that come to mind. What do you think?

Saloni Dattani: I really like those ideas. I think that maybe they’re useful in different situations. With a prize, you’re giving a prize for someone who can successfully test that a drug succeeds. Why would you do that? Why not just pay the company, or why don’t you just run the trial yourself? I think often the prize is more helpful when you’re not sure what the succeeding drug or vaccine or whatever will be.

You’re like, you guys try it out and you guys fund the trials. If you made the right bets, you’ll succeed and you’ll get this prize at the end. I think maybe what’s difficult about a prize is actually deciding how much the prize should be. Like, what if it is really obvious and you just didn’t know that and you might as well have just funded the trial?

Jacob Trefethen: That said, one of the nice things is you only have to pay out if it’s successful, depending on how you design the prize.

Saloni Dattani: What if the prize is too small, though?

Jacob Trefethen: That’s true. Then you have dangled something that hasn’t had any effect, but it’s better than paying for a bad outcome, which happens all the time in grantmaking.

Saloni Dattani: That’s true. I guess with the prize, the other thing is that, especially if the thing is already a generic drug, you have a prize for showing that it works, and then immediately the generic drugs can be used for a very low price. I think the other side is, maybe you have examples of this where you were pretty confident that certain things might work so why not just fund those research groups themselves, instead of having a prize or something at the end?

Jacob Trefethen: Laying my cards on the table, my biases are often in that direction. That’s because I am a grant maker though in my day job where, people say, but how are you going to pick winners? What if you don’t know? I’m like, well, how bad do you think I am? Come on.

No, I basically think that people often, economists often have an instinct of: you don’t know anything, you have to let the market decide; if there isn’t a market that works, you have to create a market. That’s a healthy instinct in some cases.

Then people like me think they know things. I’m kind of like, well, yeah, but actually I’m pretty sure we should fund this one and this one and it might actually go pretty well. So yeah, there’s a healthy tension between the two.

I think you want to be looking, the cases where the pull funding and prizes appeal more to me are when you have some reason to think that there is knowledge and data that’s dispersed throughout different firms and the economy broadly, that you’re like, oh yeah, I definitely don’t know. In some cases, I can point to those better than others. I’m sure that there is internal data on how different drugs get used that I’ve never seen that will be useful for some companies making a decision about whether to go after this prize or not in some circumstances. So there, I’m not omniscient.

Saloni Dattani: That makes sense. I guess there’s also, even with the pull funding, you have to have some people to decide that it’s worth the investment and to do the push funding. You have the prize at the end, but you need the companies, or the researchers, to decide that they think that their own candidate has good enough chances that they’ll fund the trials to get to that finish line at all.

Jacob Trefethen: Indeed, which means that the prize has to be much larger than it costs to run a trial because there’s some probability they’ll fail.

Saloni Dattani: Have you heard of CASPR?

Jacob Trefethen: I have heard of CASPR. Do you mean the addiction thing?

Saloni Dattani: The ghost.

Jacob Trefethen: I hear him right now. Ah!

Saloni Dattani: They’re the Center for Addiction Science Policy and Research, CASPR, and they’ve proposed a program that is trying to help do repurposing for off-patent drugs and supplements. Their idea is that there should be a program that is led by the NIH that funds and runs many trials for off-patent drugs, peptides and supplements, to see whether they work for other conditions. That is an exact example of one of these push funding uses, where you’re paying directly for the trials. And also the RECOVERY trial was actually-

Jacob Trefethen: Exactly. The RECOVERY trial was some of the best push funding we’ve ever seen. Genuinely, if you run the numbers there, my goodness, that costs maybe $20 million. That’s over a million lives. That’s just shocking. But you don’t get many trials that are as urgent as that, in the sense of we have no treatment for this new thing.

Saloni Dattani: I think that one was also maybe cheaper than usual because it ran through the NHS, the UK’s public health system, where people were already in hospital for COVID and it was just an extra additional one or two page form that they had to sign to be participating in this trial. They’d randomly get assigned to one of the many drugs that was in the trial. It wasn’t very much of an additional cost. It wasn’t like running a separate trial in these different academic centers or hospitals. It was already people who were already getting treated for stuff.

Jacob Trefethen: Yep. Yeah. If you were, if you as a listener happened to be in the RECOVERY trial, you are a complete fucking legend. That is so epic. Thank you for doing that. That applies to all of our listeners who’ve been in trials. I know a bunch of you have. It’s so cool. It’s like, it’s a great, it’s just a wonderful thing to do for other people. I am glad that some of our listeners are so, kind as to give to the rest of humanity.

Saloni Dattani: Right. Have you, I think maybe in a previous episode, you also mentioned EveBio, which is kind of working on this as well, from a scientific perspective.

Jacob Trefethen: That is right. Full disclosure, I am such a fan of EveBio that at the OpenAI Foundation, we just gave them some money to do more stuff.

Saloni Dattani: Oh, cool.

Jacob Trefethen: But yeah, they’re amazing.

Saloni Dattani: Tell us, tell me more about them.

Jacob Trefethen: They’re a repurposing outfit in some sense, although we actually funded them to do something a little different. But they’re taking in their original mission of all FDA-approved molecules and running that against running them all against a set of receptors on cells and seeing what happens, and generating a dataset that they then just drop into the public domain as soon as it gets created. That can give you more insights into can you repurpose any of these drugs for some effect you might not have thought.

Saloni Dattani: I found this really interesting, but I also, I think when I heard about it, I was like, aren’t pharma companies doing this already? They have these huge drug libraries, aren’t they already testing them for other effects?

What I found out was that, that’s true to some degree, but I think what pharma companies are usually doing is trying to test their drug compounds against specific off-target receptors, or whatever, that are listed as being important for safety or toxicity. They’re not testing them against all- or more receptors than that. Also, as I mentioned before, they’re often, you start with a specific disease that you’re interested in and you’re testing the drug compounds to see how they affect the receptors involved in that disease. You’re not doing like a much larger thing where you’re testing lots of drug compounds against lots of targets or lots of diseases. Whereas this is trying to create that matrix.

Jacob Trefethen: It’s really cool. You might- there’s lots of additional things you can do, lots of edits you can make, but what a cool start. That group in particular just is so into open data. You can just go on their website and you can start clicking around.

Saloni Dattani: Ooh. I read something else about them, which is that they’re a time-limited single-mission non-profit. Is that right?

Jacob Trefethen: They’re a Focused Research Organization. Yeah, they were originally founded with the idea of let’s do this in five and a half years.

Saloni Dattani: Oh, wow. And then once that happens, they were planning to shut down, but maybe they aren’t anymore.

Jacob Trefethen: We’ll see. They’re so good that they might accidentally stick around. But yeah, we’ll see. I don’t know. You’ll have to ask Elaine, the CEO. She gets to decide.

Saloni Dattani: Oh, cool. Maybe they would just shut down that project and do something else. That’s very cool.

Okay, so let’s do a quick summary of the different ideas we talked about for trying to get more repurposing. The first one we mentioned was, extending the patent term. I think probably this is pretty effective, especially for drugs where there is a large commercial market for producing new drugs for that use, but it takes a long time to run clinical trials for it that eats away the patent. Probably just, well, it doesn’t work at all for drugs where the generic is already on the market because the generic can just undercut them immediately. It probably doesn’t work very well for tropical diseases or rare diseases or diseases of poverty and addiction and things like that, where customers are too poor to pay for them.

Jacob Trefethen: What about reimbursement for off-label uses?

Saloni Dattani: What is that?

Jacob Trefethen: What I’ve heard is certainly in a US context that a lot of what happens in terms of how you make revenue as a company, a drug company, is about reimbursement codes. Does that play a role here?

Saloni Dattani: It does, yes. So helping people track what off-label uses a drug is being prescribed for as well, that could help you collect more data, which might suggest to you that this drug could be effective for something else as well. Then you might then run the trials for it. But also it can result in different pricing depending on which diseases they’re prescribed for. That would give more of an incentive, I think, for companies to test these new uses.

Jacob Trefethen: We also talked about prizes and push funding with public or philanthropic funding. With prizes, you can dangle a carrot at the end of a stick for different it’s large enough that different companies that suspect that a drug they’re working on, which could be repurposed, even if it’s off patent, end up paying for trials to confirm that. Then with push funding, you can directly pay for trials with different options, different drugs, that might be beneficial, but haven’t been confirmed or tested yet.

Saloni Dattani: You know, whenever I hear the carrot on a stick idea, I’m always like, who is actually incentivised by this? You know what I mean? Like the metaphor. Who likes carrots enough that dangling it on a stick is actually going to get something to happen?

Jacob Trefethen: Yeah. I think it is either a donkey or Bugs Bunny, I think are the two main sort of actors involved in this incentive scheme.

Saloni Dattani: Yeah. I wonder where that metaphor came from. I always...

Jacob Trefethen: I think it’s mules. Oh, it’s mules. Because it’s carrot or stick. Unfortunately, I think the stick is hitting a mule.

Saloni Dattani: I thought it was a carrot on a stick. Like a fishing rod. Like a fishing rod with a carrot on the end.

Jacob Trefethen: That’s also how I visualize it. It’s like the stick is sort of over the back of the head of this poor mule. Then it’s sort of dangling carrot. Then so it’s walking forward like, I’m going to get the carrot, I’m going to get the carrot.

Saloni Dattani: This is so sad.

Jacob Trefethen: It’s really sad. Some people don’t like to talk about.

Saloni Dattani: Wait, so the carrot doesn’t get eaten at the end. It’s just making them move forward?

Jacob Trefethen: I think they...

Saloni Dattani: That’s really depressing.

Jacob Trefethen: It’s really depressing. I believe in full emancipation for mules.

Saloni Dattani: Me too. You can just use robots or tractors for stuff, no?

Jacob Trefethen: Robots don’t even eat carrots.

Saloni Dattani: No, I mean for the things that you need the mule to do. You were just thinking of dangling a carrot in front of a tractor?

Jacob Trefethen: I’m now just thinking about the humanoid robots and yeah, you just dangle reward. All you have to dangle is a one instead of a zero.

Saloni Dattani: I mean, I do like carrots, but I wouldn’t...

Jacob Trefethen: I wouldn’t go out of my way.

Saloni Dattani: Yeah. I wouldn’t continue to follow this carrot once I realized that I wasn’t getting any closer to it.

We are now at the end of the episode. Let’s do a little summary and some takeaways that we had from all of this chat about GLP-1 drugs, all the other cool drugs that have been approved for multiple things, how it’s possible that things can be used for multiple conditions, and how we can get more of this repurposing done.

Jacob Trefethen: Let’s do it. Let’s start with GLP-1s. What did you think?

Saloni Dattani: I think GLP-1s are much more interesting than I realized. It’s not just weight loss, but they have multiple effects. They reduce blood sugar levels, which helps with diabetes. They suppress appetite and slow stomach emptying, which helps with weight loss, but also causes nausea and vomiting. They slightly reduce blood pressure as well, which might help with cardiovascular diseases. It seems like they might be effective for other diseases too. I think that research is still ongoing.

But what’s amazing about this is that there are actually many drugs like this. Around a third of all FDA-approved drugs are approved for second use. That’s much more than I would have thought. There are some other cool examples that we talked about, like SGLT2 inhibitors, and aspirin and colchicine, things like that have turned out to be effective for something quite important that we wouldn’t have predicted at the start.

The other thing that really stuck with me in this episode was Gila monsters, the lizard. They’re so cool. They’re so cute. I wouldn’t have expected them to look so cute. They’re so slow, which is so funny to me that their top speed is one and a half miles per hour. That’s hilarious. Most importantly for us, beyond the cuteness, they helped us find cool new drug compounds that we could tweak and use for various important health conditions. I think it’s kind of a shame how venomous they are but I think they’re just a very cool type of lizard that more people should know about.

When I started doing research for this episode, I had this vague idea that it was some kind of accidental discovery. It turned out that actually there were important reasons to suspect that something interesting was happening in their venom, that included their effects on the pancreas, and also the fact that they had very long-lasting fasts and they only ate a few meals per year and could control their blood sugar levels despite that.

Jacob Trefethen: I also left this episode a fan of the Gila monster. The fact that even in the deadliest venom, we can find the most wonderful benefits for humanity. There’s got to be a lesson there, which we can leave to the listener.

Saloni Dattani: That’s very moving.

Jacob Trefethen: It’s very moving, slow moving, 1.5 miles an hour. I think that overall stepping- taking the GLP-1 example and then going further to repurposed drugs in general, I left this episode, I would say the pessimism I have is on effect sizes of repurposed drugs. I’m not sure many will turn out to be, stunning radical cures for a second indication. But I left this episode more optimistic about repurposed drugs in general. The fact that for drugs that already have been approved for one thing, you have an existing safety dataset that’s large. The fact that we can point to these economic reasons why companies themselves, wouldn’t be incentivized to pay for confirmatory studies for second indications, and all of that because of competition from generics and how patents work. I think that I am sort of cautiously optimistic there’s low hanging fruit for these beneficial second, third use cases for some drugs.

Saloni Dattani: I also, I think I started out as a skeptic. I sort of thought, well, observational studies are pretty misleading and lots of repurposing efforts are going to fail. Aren’t pharma companies already doing this internally anyway? But I think in doing research on this, I realized actually there are lots of economic reasons why there aren’t the incentives that there could be for doing more repurposing. That’s, as you said, the competition from generics, but also I think some diseases just not being commercially worthwhile to study.

I’m more optimistic about effect sizes, I think, than you are. I think sometimes we’ll have what look like moderate effect sizes, but there’s such a large patient population for them that they’ll be really beneficial. That seems to be true for the aspirin with cardiovascular disease, with colchicine for heart disease, for SGLT2 inhibitors, and for GLP-1s. But to be fair, those were tested commercially, aside from aspirin and colchicine. I think sometimes it’ll turn out that the secondary use is actually pretty big. With GLP-1 drugs, for example, the weight loss was the second use and those have a massive effect size.

Jacob Trefethen: Fair enough. Another thing I took away from this episode is just there are a lot of drugs out there already. Sounds basic to say, but there are thousands or over a thousand FDA approved medicines mostly from the last hundred years and we’re still finding out ways they work, and all the different things they do in the body, at different doses, for different people facing different problems or diseases.

Saloni Dattani: Yeah, it’s pretty cool.

Jacob Trefethen: It’s a bit punk that we don’t even know yet.

Saloni Dattani: I think that’s maybe especially true for the rare conditions or the tropical diseases where just someone hasn’t tried them out or hasn’t tested them. There must be lots of things that we just haven’t found out about yet. What was your favorite repurposed drug that you heard about today?

Jacob Trefethen: I think my favorite is the potential repurposed drug of the shingles vaccine. Maybe it turns out that it reduces your risk of developing Alzheimer’s. So I’m excited about that. But even better, if that ends up being true, I’m excited about me being right and you being wrong.

Saloni Dattani: I really hope you’re right.

Jacob Trefethen: Well you being 75% wrong because you think there’s a 25% chance that I’m right.

Saloni Dattani: Right. No, I really hope you’re right. I wish I could go out and get a shingles vaccine right now, but I am not old enough to. It’s one of those things where, when you’re a kid and you’re like, oh my God, I wish I was old enough to do whatever. Right now I’m like, oh God, I wish I was 50 years old so I could get the shingles vaccine.

Jacob Trefethen: Wow. For me, it was when I was 11. All I wanted to do, we stayed in a hotel once and I, well, probably more than once, but roughly once. They had a gym and I couldn’t go in alone unless I was 18. I was like, one day I’ll be old enough and I’m going to go into this gym. I had to go back to Ohio and then I can go into that gym.

Saloni Dattani: I didn’t know that there were age restrictions on gyms.

Jacob Trefethen: Yeah, I hate to give you such horrifying news this late in an episode.

Saloni Dattani: The other thing that I took away was I didn’t realize how important this was as an issue. I didn’t realize how large this social value of repurposing drugs could be. The estimates that I described, they were conservative estimates that put it at hundreds of billions of dollars in social value per year allowing for more repurposing to happen and under a hypothetical where patent terms were longer.

If you think about, okay, you extend patent terms to get more repurposing, that’s still only going to get you repurposing for diseases that are worth the commercial market. I think that’s still a conservative estimate. It doesn’t include very much like drugs that could be repurposed for tropical diseases, for example. Getting more repurposing could be really valuable. I think we’re missing out on knowing which other conditions many existing drugs might work for. And people need to go and find that out.

Jacob Trefethen: Yeah. One of the things in this episode that I think will stick with me is how much that problem is not scientific, but is about policy, economics, patents, and all of that. Just discussing, okay, how can reimbursement change? When should people run prizes for repurposed drugs? When should you, as a government or philanthropy, use push funding to fund off-patent trials and get more repurposing to happen? I think there’s a lot more activity that could happen in those different areas that would be really beneficial.

Saloni Dattani: I think also what I learned from reading for this episode was just, there are lots of these things already happening. Like there are incentives to some degree for repurposing your drug. You get an extra few years of drug exclusivity and stuff like that. Like, people have tried a bunch of these things already, but we could be doing a lot more of them. What was your favorite idea to get more repurposing to happen?

Jacob Trefethen: I think my favorite one is, honestly, my favorite one is modeling more trials like the RECOVERY trial. You know, have a platform trial, a shared control group, you can make it adaptive as you go. And have lots of off-patent drugs, but companies can chuck in their on-patent drugs too if they want and test things against each other. That is my most exciting takeaway from this episode.

Saloni Dattani: I’m going to disagree with that. I’m going to say prizes, I think, are better.

Jacob Trefethen: Prizes are better than the RECOVERY trial? The best trial of all time?

Saloni Dattani: Maybe not, actually. I think one reason a prize is better is that you don’t have to, as a funder, you don’t have to pick which drugs you think will succeed. Hopefully someone else has some better idea. But also, you could just get other companies to work on funding the trials themselves. You don’t have to pay for that. You can just pay for a prize, which is higher than the cost of one trial, but lower than the cost of funding all the trials. So why not?

Jacob Trefethen: Okay, I’ll meet you in the middle and say, let’s do both.

Saloni Dattani: I guess you do need someone to do both in the end. I guess the other upside of that is that if the drug already exists and it’s already on the market and maybe generics are already there, once you’ve given the prize for it, everyone can use it already.

Jacob Trefethen: True, true.

Saloni Dattani: The last thing that I found interesting was EvE Bio. I thought it was just really cool to have, one, this idea of initiative that is focused on one thing and then will planning to wind down after they finish that one project. But also just scientifically, this idea of testing out lots of combinations of drugs versus targets that haven’t been tested before and then publishing that as an open database that lots of researchers, academics, and pharma companies can use in the future. I think we need a lot more public goods like that and it’s just a really cool example of one.

Jacob Trefethen: Okay, we’ve left this episode with a lot to do. I feel like we both have to get back to work, Saloni.

Saloni Dattani: We should get back to trying out some of these repurposed uses for ourselves.

Jacob Trefethen: You and me volunteering for the sake of science. Each day we can do a different drug and measure what happens to each other.

Saloni Dattani: That’s how a randomized trial works.

Jacob Trefethen: I think so. It’s a shame about immortality bias or whatever you told me about because otherwise I could give all the data we need.

Saloni Dattani: All right. Thank you for listening. I hope you enjoyed this episode. If you did, please rate us on Spotify or Apple. We occasionally get comments on Apple podcasts, but we don’t have that many, so if you could add a comment, that would be really helpful to us.

Jacob Trefethen: Yes. Thank you very much. We would really appreciate that. Feel free to take this episode, chop it up, repurpose it for your own use too. Goodbye!

Saloni Dattani: Bye!

Show notes

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Acknowledgements:

• Aria Babu, editor at Works in Progress

• Graham Bessellieu, video editor

• Abhishaike Mahajan, cover art

• Atalanta Arden-Miller, art direction

• David Hackett, composer

Blogs

• Julia Rohrer (2018). The uncanny mountain: p-values between .01 and .10 are still a problem https://www.the100.ci/2018/02/15/the-uncanny-mountain-p-values-between-01-and-10-are-still-a-problem/

• Abhishaike Mahajan (2025). Mapping the off-target effects of every FDA-approved drug in existence (EvE Bio) https://www.owlposting.com/p/mapping-the-off-target-effects-of

Videos

• George Davey Smith (2026). Does the shingles vaccine prevent dementia?

Articles & reports

• Radwan Darwish et al. (2025). History of glucagon-like peptide-1 receptor agonists. https://doi.org/10.1016/j.phrs.2025.108045

• Brian L. Furman (2012). The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. https://doi.org/10.1016/j.toxicon.2010.12.016

• Eric Budish, Maya M. Durvasula, Benjamin N. Roin, Heidi L. Williams (2026). Missing markets for innovation: evidence from new uses for existing drugs. NBER Working paper. https://www.nber.org/system/files/working_papers/w34222/w34222.pdf

• Babak Sahragardjoonegani, Reed F Beall, Aaron S Kesselheim, Aidan Hollis (2021). Repurposing existing drugs for new uses: a cohort study of the frequency of FDA-granted new indication exclusivities since 1997. https://pmc.ncbi.nlm.nih.gov/articles/PMC7780607/

• BMJ (2020). Covid-19: The inside story of the RECOVERY trial https://www.bmj.com/content/370/bmj.m2670

• Stephan Guyenet (2021). The future of weight loss https://worksinprogress.co/issue/the-future-of-weight-loss/

• Kevin Hickey, Erin Ward (2024). The Role of Patents and Regulatory Exclusivities in Drug Pricing https://www.congress.gov/crs-product/R46679

• Alex Kesin (2025). The three-thousand-year journey of colchicine https://worksinprogress.co/issue/the-three-thousand-year-journey-of-colchicine/

• Samy Suissa, Laurent Azoulay (2012). Metformin and the risk of cancer: time-related biases in observational studies https://doi.org/10.2337/dc12-0788

• Nicholas Reville (2026). Proposing an NIH High-Leverage Trials (HILT) Program. Center for Addiction Science, Policy, and Research (CASPR) https://caspr.org/policy/papers/HILT/

Web

• Smithsonian’s National Zoo. Gila monster. https://nationalzoo.si.edu/animals/gila-monster

Growing up, I acquired a vague idea that medieval people did not view childhood as we do. I was told they saw children merely as defective or incomplete adults, and that they did not love their children as we love ours, perhaps as a way of coping with high infant mortality. As I grew older, I came to associate this idea with the name of Philippe Ariès, a French historian who argued in the 1960s that medieval childhood was profoundly remote in these ways. Ariès’s work never attained complete acceptance in academia, but it was vastly influential on the wider public.

As it turns out, however, Ariès’s view is just not true. This has been established beyond doubt by a wealth of later scholarship across Europe. Nicholas Orme’s Medieval Children is the leading study for England in particular. ‘It cannot be overemphasised that there is nothing to be said for Ariès’s view,’ Orme notes. It is mistaken ‘not simply in detail but in substance. It is time to lay it to rest.’

It is sometimes imagined that medieval people had a great many children. This was not generally the case. Very large families occasionally occurred, but most medieval people had only three or four children, somewhat more among the rich and somewhat fewer among the very poor. At least in England, this was partly because they married quite late, generally in their mid or late twenties. About 25 percent of children died in their first year and another 15 percent by their tenth. The median English child thus grew up in a home with one sibling and two parents in their thirties or forties, being in this respect just like the median English child today. Surviving grandparents often lived nearby, but rarely under the same roof.

Abortion was considered sinful, but the situation was more complicated than might be supposed. Medieval people did not think that early-term fetuses had souls, believing them to be alive but unconscious, like vegetables. Early-term abortion was thus not considered homicide, and was not punishable at common law, though a church court might impose a penance like regular fasting or almsgiving. Late-term abortion was thought to be a kind of homicide, but was not normally punished at common law either. This distinction persisted until the nineteenth century.

Medieval parents made immense sacrifices for their children, and seem to have expected little in return. Feeding a child consumed about 15 percent of average income, and parents often continued to support children throughout their adulthood. Older children often performed light work at home, but at just the age they might become a net economic asset – 13 or 14 – they were usually sent away to acquire skills and savings through apprenticeship or working in service. They may have remitted some of this income to their parents, but this was not standard, and in fact parents generally paid for their children’s apprenticeships. Grateful children sometimes supported their parents in old age, but again this does not seem to have been the norm.

Medieval England was often at war, and the government was desperately in need of soldiers. The Crown repeatedly issued decrees banning ‘dishonest and useless’ ballgames like football, requiring boys over the age of seven to practice archery instead. Needless to say, English boys could not be stopped from playing football, and the decrees were widely ignored.

Child mortality was high, but there is no reason to think that parents were indifferent to it. Few diaries or letters survive in which they expressed their grief, but it was sometimes recorded by others. The fifth child of Henry III and Eleanor of Provence was called Katherine. Katherine was born disabled and never learned to speak, and she died when she was three years old. Both her parents were heartbroken. The chronicler Matthew Paris wrote that Queen Eleanor fell sick with grief, ‘and could find no relief in medicine nor human consolation’.

Parents also took joy in their children, and vice versa. An Oxford schoolbook of the 1490s describes a schoolboy returning home for the holidays. Upon meeting his parents, ‘we wept for joy, each to other’. The thirteenth-century treatise Ancrene Wisse imagined Jesus playing with a Christian believer as a mother does with her child. ‘She runs away from him and hides herself, and lets him sit alone and look anxiously around, and call “Dame! Dame!” and weep a while. Then she jumps out laughing, with outstretched arms, and embraces and kisses him and wipes his eyes’.

The medieval people who emerge from Orme’s book are quite unlike the strange and cold figures that we have been led to imagine. ‘I believe they were ourselves, five hundred or a thousand years ago’, Orme writes. Perhaps we should ask why the Ariès hypothesis ever exercised such a hold over the popular imagination. Was it ever really plausible that children survived the terrible hardship of medieval life without devoted parents? Next time a scholar makes exciting claims about how some class of human beings is incomprehensibly unlike us, we would do well to ask similar questions.

Samuel Hughes is an editor at Works in Progress.

This piece was featured in Issue 24 of Works in Progress. Subscribe today to get Issue 25, and an issue every two months after, delivered straight to your door.

Ultra-Orthodox Jews may have something to teach us. They live squarely in the urban centers of the US and Europe, including 200,000 in New York City, but unlike most city dwellers, they have very high birth rates. Today, a Yiddish-speaking woman in the United States can expect to have 6.6 children, compared with 1.6 for the country as a whole.

Everything in ultra-Orthodox life is geared toward facilitating large families, from how children play to how couples have sex. In this piece, I’ll use the example of Chabad, the largest denomination of Hasidic Jews, although many practices mentioned here are shared by all the ultra-Orthodox.

It’s not clear that many modern people, Westerners or not, would want to adopt the family-friendly elements of Chabad life. What’s more, little of the Chabad lifestyle can easily be practiced in isolation. But understanding how this community encourages fertility can help to explain why it is falling in many other parts of the world today.

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Before marriage

1. Chabadniks start having children young: there’s almost no way to have six or more children if you’re starting after 30. Yiddish-speaking men in America have a mean marriage age of 22 and women 21, and couples will almost always have children shortly after, partly because contraception is broadly discouraged.

2. Since lifetime mates are chosen at a young age, Chabadniks believe the selection can’t be left to the couple alone. I don’t mean to be rude, but 18-, 19-, and 20-year-olds don’t have a reputation for great judgment in any area. Even so, Chabadniks would object to characterizing the way they date as ‘arranged’, but from a secular point of view, the level of parental and community involvement and the short duration of courtship make Chabad dating practice resemble arranged marriage.

3. Chabadniks segregate children and teens by gender, believing that it helps to make their short courtship with a small number of potential partners feel satisfying and selective. Teenagers can’t have boyfriends and girlfriends in middle school and high school, and children are forbidden from playing at the marriage experience. Even in my secular Jewish childhood, our Hebrew school teachers scared us with tales of rabbis who made children get real divorces after pretend weddings.

4. Sex before marriage is prohibited. Such restrictions have long been foisted inappropriately on American teens, but they are much less unreasonable when community members marry around 20.

After marriage

Starting early isn’t enough to guarantee many children. Parents need to have kids young and then continue to have them throughout their twenties and thirties. But how do couples continue to like each other enough to keep wanting to have more children (including having the frequent sex this requires)?

1. Gender segregation continues in many, if not most, areas of adult life. This helps maintain a sense of romance in daily life. As the Chabad-Lubavitch website says: ‘If we preserve the space and boundary between men and women we can cherish our times of closeness all the more’.

2. Men and women are prohibited from mixing because rabbis believe a love affair is around every corner. But the omnipresence of assumed temptation both makes extramarital affairs difficult and, according to Chabadniks, creates the sensual atmosphere it’s meant to dispel, while channeling it toward the only acceptable outlet: one’s spouse.

3. Sex becomes a pious act, permitted within a limited timeframe. While a woman is menstruating, and for the seven days after the end of her period, a couple doesn’t have sex at all. Some couples take this very seriously and won’t even touch lest contact lead to physical intimacy. This even includes handing each other an object in case their hands touch accidentally. At the end of this period, the woman goes to a ritual bath called mikvah. The mikvah visit happens at night, when the sun is down, and the bath is a communal facility, some of which are quite fancy. Upon returning home, the woman is supposed to have sex with her husband. Having sex on day 12 or 13 of her menstrual cycle is a great way to maximize the chance of conceiving!

4. Sex is especially encouraged on Shabbat, the Jewish day of rest. From Friday sundown to Saturday sundown, pretty much all that’s permitted is eating, praying, reading, socializing in your neighborhood, and napping. The faithful are commanded to enjoy Shabbat, and one of the recommended ways is to have sex with one’s partner. As one prominent halachic code (a compilation of rabbinic law) says: ‘Marital intimacy is one of the expressions of Shabbos pleasure’.

The life of a child and its parents

The gender segregation described above may seem alien, but we seculars also inhabit segregated worlds; they’re just not tied to our biological sex. We call them ‘professional’ and ‘leisure’, ‘public’ and ‘private’, or ‘adult’ and ‘child’.

In fact, people without children may not realize how totally we separate children into their own sphere and complicate their existence outside of that sphere. Not only does this discourage adults from having children, it also marginalizes those who do have them, especially women.

When children are permitted in public spaces, the expectation is that they be continuously and closely supervised by an adult, in a bubble of attention and control. A recent poll of five hundred children between the ages of eight and twelve found that 62 percent had never walked or biked somewhere without an adult. Even in the absence of actual danger and even when they’re not causing a nuisance, children are not allowed to roam, with parents sometimes facing prosecution when they leave their children unsupervised.

While Chabad life has gender segregation, the separation between adult and child spaces does not exist in the same way. Children are considered a blessing, and making it easy to raise them is a major purpose of life.

Walking into a Chabad congregation, one of the most surprising features for secular Americans might be that young children roam anywhere in the building apparently without limitation, playing games, squealing, and laughing, including at the front of the room where the service is being led. A leading Chabadnik rabbi, Zushe Greenberg, explains: ‘We not only recruit kids to come to shul [synagogue], but even encourage this phenomenon. As I always tell people, we allow the adults at Chabad because they’re the ones who bring the kids’. Some of these children belong to the rabbi. He might pick one up, or shush them in passing. If they’re very loud in the hallway, other congregants might shush them too, but children making noise or playing unattended in this space isn’t problematic. Rabbi Elisha Greenbaum says: ‘A shul without children is boring. What kind of organization would deliberately reject their own future and opt for a sterile, boring, child-free environment?’

Lastly, Chabad women do not carry the burden of childcare alone. Men and older male children are active contributors to childcare and to children’s education. Religious men, in general, do more housework and more childcare than non-religious men. And communal childcare is the default. In New York, for example, many more Orthodox Jews, including Chabadniks, send their children to daycare than non-denominational Jews do: 54 percent versus 15 percent aged 0–2 and 93 percent versus 18 percent aged 3–5. Nursery schools are run and staffed by women, but primary schools for boys have male teachers and leadership to a great extent.

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Learning from Chabad life

Copying Chabad life wouldn’t be easy in secular society. Religious belief adds weight to practices like the mikvah or sexual abstinence. But there is one pronatalist practice that we can adopt from ultra-Orthodox life and that all high-fertility subcultures share: assuming that everyone you interact with between the ages of 20 and 45 will have at least one child under five in their care. This assumption impacts every social and business function. Children are welcome in far more spaces, and where they aren’t, event organizers provide schedules and resources to facilitate the participants’ childcare needs.

This might seem like a tall order, but in the developed world we already expend tremendous consideration and public resources for a type of dependent: people’s cars. The host of an event, the owner of a store, the developer of offices or housing, an employer, or a local government will all assume their guests, customers, tenants, employees, and residents have cars, and take responsibility for providing a place to store and a convenient way to transport them.

We take on tremendous expenses to build huge parking garages and wide and smooth roads for people’s cars. This social support incentivizes driving. If we extended as much concern for people’s children as we do for their cars, we would, like Chabad, encourage more children than we have today.

Sonja Trauss is the Executive Director of YIMBY Law.

Some of America’s most famous land was reclaimed from the sea. The Lincoln Memorial, the World War II Memorial, and the Reflecting Pool all sit on earth reclaimed from Potomac River tidal flats in the early twentieth century. Treasure Island was built in San Francisco Bay for the 1939 Golden Gate International Exposition. Chicago’s Northerly Island was filled in from Lake Michigan to complete Daniel Burnham’s 1909 plan of the city.

In total, around eight percent of the land in America’s major coastal cities was underwater in the 1890s and has since been reclaimed. This includes the land under several major airports, like Newark, Logan, and SFO, as well as neighborhoods like the Financial District in San Francisco, the Back Bay in Boston, and Camden in Philadelphia. Some cities, like Boston and Charleston, have doubled in size by reclaiming land.

Today, reclamation should be more common than ever. Land values in some cities are thirty times what they were in 1950, and high-tide flooding is four to eight times as frequent. Reclamation could extend and protect our coastal cities as it has for centuries. But rather than reclaim more land, we have virtually ceased to reclaim any at all. Since the completion of Battery Park City in 1976, there has not been a single major urban land reclamation project in the United States and only a handful of port expansions.

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Two explanations are commonly proposed for this: first, that the easy spots have already been reclaimed, and second, that improved transportation has made reclamation unnecessary since we can expand cities further inland instead. But neither of these matches the evidence. Other countries still reclaim land at enormous scale, under conditions at least as challenging as those in the United States. The transportation story was once plausible, but not any more. Transportation has stopped improving, and downtown land values have risen so much that reclamation costs would be dwarfed by the value of the land created.

The timing points to a third explanation. Reclamation stopped abruptly in the 1970s when a wave of environmental regulations made it enormously expensive to reshape the landscape. And it halted at the same time in every other country that passed similar laws.

If the legal barriers to reclamation were lifted, we could build hundreds of thousands of new homes near the centers of our most valuable cities. We could build new airports to refresh ailing transportation infrastructure, and we could protect low-lying coastal areas from sea level rise. The disappearance of land reclamation is a choice that we have the power to undo.

Have we run out of good spots?

A common explanation is that we simply ran out of good places to reclaim. According to this view, there used to be plenty of shallow, semi-dry plots available, but they’ve mostly been used up.

There are indeed a finite number of shallow bays near major cities, and since land is often raised in one area by dredging the bottom of the surrounding waters, land reclamation can eat into its own expansion opportunities. But even so, many countries have been adding land for centuries without running out of good options. China has the longest reclamation history of any nation, stretching back to the Tai Lake Basin in the fifth century BC. Low-lying wetlands along the Yangtze river were made suitable for building by using dams and drains. If the US hit the limit of suitable areas for land reclamation within two centuries, China would surely have long since run out, having begun the practice over two thousand years ago.

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But China still leads the world in land reclamation, with close to 80 percent of all land reclaimed in the twenty-first century. Since 2000, Chinese cities of over one million people have reclaimed a land area equivalent to 39 Manhattans, with even more reclamation occurring outside city limits.

American history argues against this theory too: reclamation wasn’t confined to a few choice spots in the most valuable cities. It was common along both coasts, even in smaller cities like Charleston, Wilmington, and Portland.

Hundreds of square miles of water near major American cities are shallow enough to reclaim easily. When Boston’s Back Bay was filled in the late-nineteenth century, it had an average depth of 20 feet. Two thirds of the San Francisco Bay is shallower than this. The South Bay, adjoining Silicon Valley, is less than six feet deep. Outside the main navigation channels, most of New York harbor is less than ten feet deep. Almost all of the water between Miami and Miami Beach, and along the shelf extending south to Key West, is also less than ten feet deep. All of these could be candidates for reclamation.

Nor is depth a hard limit if land values are high enough. Monaco’s recent Mareterra project expanded the country’s land area by three percent by dredging down to 164 feet.

Soil and rock conditions also matter, but much of the American coastline has better conditions than sites where reclamation has already succeeded. Singapore’s Jurong Island is a massive industrial zone created on land reclaimed between 1995 and 2009. The water was more than 50 feet deep and atop another 50 feet of soft marine clay, which settles more than other materials under pressure. To reclaim the land, these layers had to be threaded with long plastic tubes to allow drainage and loaded with a large, heavy quantity of extra soil.

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It is possible that the United States could eventually exhaust its opportunities for land reclamation. But given how much further other countries have gone and how much suitable coastline remains, that point is likely a long way off.

Has transportation made land reclamation unnecessary?

Another explanation is that land reclamation was replaced by transportation. When walking was the main mode of travel, cities faced tight spatial constraints. Boston began as a tiny peninsula of about two square miles. The city quickly outgrew its isthmus, but land to the south was too far for commuters to walk from. If Bostonians wanted to build close to the city center, they had to expand into the sea.

Other cities faced the same problem even where land was more abundant. In 1890, while Manhattan’s population was similar to today’s, there were still farmhouses beside Central Park, only six and a half miles north of Wall Street. The need to build within walking distance of the city center made northern Manhattan effectively unusable, justifying extensions to the southern tip. Even with plenty of dry land available, the city kept filling in riverbeds and marshland around the island. In all, over a quarter of Manhattan’s land was reclaimed before 1979.

Over time, however, land reclamation became less useful. Better transportation unlocked lots of greenfield land that was cheaper to develop than dredging up new land from the water, while the elevator unlocked brownfield land from the sky.

This abundance of new land within the commuting zone of cities was a cheaper substitute for reclaimed land. Boston’s Back Bay reclamation in the 1860s cost about $400,000 per acre in 2025 dollars. Although the state of Massachusetts ended up selling the land for a healthy profit, by the 1910s there were cheaper ways to unlock land within reach of the city center. If each of the 332 stations of New York’s 1913 subway extension connected a half-mile radius to the downtown, this form of land reclamation cost only $65,000 per acre in 2025 dollars, five to ten times less than land reclamation from the sea.

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But this alternative source of land has proven difficult to extend indefinitely. First, while there may be land that we can access by expanding our cities outwards into virgin countryside, doing so is politically tricky in most countries, not least the United States. Adding more New York suburbs in New Jersey and Connecticut would mean a modern Robert Moses building more expressways through Manhattan.

Second, with enough population and economic growth, even the vast swaths of land accessible by modern transportation can eventually be filled. The edge of New York’s metropolitan area is already 40 miles from Midtown Manhattan at many points, over an hour’s commute. After rapid improvements in the twentieth century, transportation technology has stagnated. Average commute times have increased by a quarter since 1980, partly because cars haven’t grown much faster and partly because highway construction costs at least four times as much per mile as it did in 1960.

Finally, reclamation adds space near city centers, where land is far more valuable than at the suburban fringe. Cities are valuable because they concentrate economic activity, making it easier to find jobs, customers, and suppliers, and because they generate knowledge spillovers making everyone more productive. Better transportation increases their value by putting more workers, suppliers, and customers within reach. Crime and pollution pushed people out of city centers in America after World War II. But since 1990, this trend has reversed, and the value of land in city centers has grown quickly despite continuing suburban expansion.

Today, downtown land values are high enough to justify reclamation costs even in places where suburban land is plentiful. In 1955, the California Division of Water Resources estimated that reclaiming 23,000 acres of land on the west side of the San Francisco Bay would cost about $330,000 per acre in 2025 dollars. Today, the cost of an acre of single-family-zoned land in San Francisco County averages $24 million, more than 70 times the estimated reclamation cost. Even the cheapest county in the Bay Area exceeds $330,000 per acre.

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Despite the space opened up by cars, trains, and buses, America’s biggest cities face a massive land shortage. Even as the transportation explanation has weakened, reclamation hasn’t returned. Boston’s Back Bay reclamation was profitable when land sold for the equivalent of $40 per square foot. Land in major cities today sells for ten to a hundred times that, and dredging capacity has grown nearly tenfold since 1950. Yet urban reclamation has disappeared even in the most land-constrained cities in the country.

How reclamation went extinct

Neither explanation is convincing, especially where urban land values would plainly justify reclamation. But there is another problem: the explanations cannot easily account for the timing of land reclamation’s disappearance. A technological or geographic explanation would predict a slow and patchy decline, as different regions responded to different pressures at different speeds. But this is not what happened. In the 1970s, reclamation stopped virtually simultaneously everywhere in the country.

Of the 37 cities for which we can find data, every one reclaimed land more slowly after 1970, with many, such as Seattle and Chicago, slowing to zero. A few, including San Diego, Washington, and New York, do show some growth in land area after 1970. But most of this reflects changes in measurement or the completion of projects already underway.

The abruptness of the change shows up clearly in data on the amount of wetland that is lost per year. Most wetland loss is inland and agricultural, not the coastal urban reclamation we’re advocating. Still, the aggregate trend makes it clear that land reclamation ended suddenly around the 1970s. The annual rate of wetland loss in the 1960s was eight times higher than in the 1990s, and twenty times higher than in the 2010s.

In the 1970s, the United States passed a wave of new environmental laws, with perhaps the most far-reaching effects on land use in the country’s history: The National Environmental Policy Act of 1969 (known as NEPA), the Endangered Species Act of 1973, the Clean Water Act of 1972, the Marine Mammal Protection Act of 1972, the Resource Conservation and Recovery Act of 1976, and others. These laws hit the whole country at once, enormously raising the cost of reshaping the landscape, and are the real explanation for the end of American land reclamation.

Still in force, these laws largely regulate the federal government and not private development. But the moment a private project touches federal land, funding, or permits, it must comply with all of them. For land reclamation, NEPA is the most onerous.

NEPA requires covered projects to prepare a detailed report on the environmental impact of the proposed action and its alternatives. While NEPA itself sets no standards for how detailed these reports must be, decades of litigation have turned them into thousand-page behemoths that take years to produce. The environmental assessment for New York City’s congestion pricing plan, for example, is 900 pages long with 3,000 pages of appendices, despite the project requiring zero major construction. When potential harms are identified, agencies must undertake mitigation: buying and restoring 3,000 acres of panther habitat, say, or donating $16 million to conservation banks. In some cases, the project is simply blocked.

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Land reclamation must always go through the NEPA procedure because the Clean Water Act requires a federal permit for any discharge of dredged material into waterways or wetlands, including the entire coast. Because land reclamation projects do have significant environmental effects, every project must either complete a full environmental impact statement or produce an environmental assessment with costly mitigation measures before receiving a permit. Environmental impact statements filed by the US Army Corps of Engineers, the agency that oversees the permits for land reclamation, take an average of six years to complete, and the mitigation measures often run into the hundreds of millions of dollars.

The Craney Island extension in Norfolk, Virginia is a useful illustration of how these laws complicate land reclamation. Craney Island is a four-square-mile rectangle of dirt and sand surrounded by dikes at the mouth of the Elizabeth river, built solely to store material dredged from Chesapeake Bay navigation channels. In 1997, Congress approved a study of the possibility of expanding the island to the east, extending the lifespan of the disposal area and adding a container shipping terminal to the Norfolk port.

By historical standards, this would have been an easy project: the original 2,500-acre Craney Island was built in just two years between 1956 and 1958. But because the extension involved discharging dredged material into US waters, it needed a Clean Water Act permit. The Army Corps’s environmental impact statement took nine years and ran to 1,400 pages.

Virginia’s environmental quality department then issued permits in 2010, three years after the environmental impact statement was published. After a decade of delays and budget uncertainty, the Corps changed its discharge plans in 2023, which required yet another supplemental environmental assessment. Twenty-eight years after the feasibility study began, almost nothing has been built. The project is expected to finish ‘on schedule’ in 2065.

Craney Island is not an isolated case. Land reclamation ground to a halt across the country after the major environmental laws passed in the 1970s. Very few US reclamation projects started later in the twentieth century, and no notable urban reclamation projects have taken place in the twenty-first.

Evidence for environmental law’s role in the end of American land reclamation can also be found in other countries. It declined abruptly in the 1970s and 1980s across the West. What western nations shared was the rise of powerful environmental movements hostile to reshaping the landscape.

Germany reclaimed over 80,000 acres from the marshy Wadden Sea before 1990. Tens of thousands more were planned, but fierce environmental opposition ended the practice in the late 1980s, turning the Wadden Sea into a national park and making wetlands protected areas. In the 1960s, France used reclamation to develop its Mediterranean coast into a world-class tourist destination, but environmental protection laws in the 1980s banned all construction within 100 meters of the shore.

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In the early twentieth century, Canada reclaimed tens of thousands of acres of floodplain in British Columbia and the Maritimes, along with hundreds of acres of urban land in cities like Toronto, but large projects like these have stopped or greatly slowed due to environmental rules. In nineteenth-century Australia, hundreds of acres were reclaimed in Sydney Harbor, including the land under the Sydney Opera House, but twentieth-century environmental rules have prevented future expansion.

Even the Dutch, history’s most celebrated reclaimers, largely ceased the practice after the passing of their own environmental laws. From about 1917 to 1970, the Dutch undertook the largest reclamation project in history: the Zuiderzee Works, which expanded the Netherlands by five percent. The fastest phase, the 1927 Wieringermeer Polder, dammed and drained 50,000 acres in just three years. The 1957 Eastern Flevoland Polder then reclaimed nearly three times the area in less than eight years.

But only four of the five planned polders were filled. The fifth, the Markermeer, which was dammed and ready to drain in 1975, was never completed. It would have provided the closest land to Amsterdam, where house prices have risen 120 percent since 2010. In 1969, the Netherlands created a new approval process for large spatial planning projects similar to the NEPA. This process required extensive public consultation and referendums which, while not as explicitly environmental as NEPA, were still dominated by environmental concerns. While the debate dragged on, the 1979 European Birds Directive added another layer of environmental protection. Environmental groups campaigned to halt reclamation permanently and have the unfilled lake designated a Special Protection Area.

In response, the government eventually abandoned its land reclamation plan. In 1992, the Markerwaard was listed as a protection area, preventing any development on some of Europe’s most valuable water. (Some reclamation has resumed since 2014, but not for people: a €300-million, decades-long project is building swampy archipelagos in the lake as bird habitat).

Even the rare successes are instructive. The one major Dutch reclamation of the twenty-first century, an expansion of the port of Rotterdam called Maasvlakte 2, took eighteen years to complete, including an eleven-year planning and environmental compliance period before construction began. Its environmental review alone ran to some six thousand pages.

Reclamation has continued only in countries where environmental regulation is less onerous, like China, Singapore, and Japan. China has reclaimed over 5,000 square kilometers in the first two decades of this century, including a new city of 500,000 outside of Shanghai, and Singapore has expanded its territory by over a quarter since 1975.

Japan does have high environmental standards and a NEPA-style law requiring environmental impact reports. But Japan’s system has two advantages: clear numeric thresholds for when reports are required and courts that make it harder to overturn agency decisions. Japanese infrastructure projects don’t need the defense against legal challenges that make Western projects take decades. The result is abundant housing and infrastructure, including multiple airports, port facilities, and residential areas built on reclaimed land.

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Land reclamation has always faced obstacles, and the story of its historical fortunes is not simple. But the weight of the evidence points in a clear direction. In America, as across the West, land isn’t reclaimed today because of barriers of geography or technology, but because 1970s environmental regulations made it prohibitively expensive and slow.

The wrong solution for an old problem

Reclamation would be feasible and profitable in the West today if some environmental laws were changed. But those laws were passed to solve real problems. So is it worth bringing land reclamation back?

The postwar state had incredible power to act unilaterally and grade its own work. Robert Moses could demolish entire neighborhoods for expressways without accountability; urban renewal programs replaced them with awful housing blocks; the Cuyahoga River caught fire from wanton industrial pollution; the interstate highway system demolished half a million homes to make way for highways through urban areas; and indeed land reclamation was sometimes responsible for the loss of valuable wetlands. These excesses understandably created fear of unchecked development.

Environmental laws provided necessary curbs, but since the 1970s, the costs of compliance have grown as NEPA reports expanded from ten pages to thousands and spurred half a century of expensive litigation.

Simultaneously, the value of foregone construction has never been higher. Real housing prices are at least five times higher today than in 1970 in New York, San Francisco, Boston, and LA, and three times higher across the country as a whole. Land reclamation may be the most striking casualty of 1970s environmental law. Land reclamation makes housing cheaper, cities more productive, and transportation networks more efficient. It also addresses twenty-first-century environmental challenges: city dwellers produce far less carbon per person than suburbanites, and reclaimed land can make coastal cities more resilient to natural disasters.

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Despite the environmental costs, there are many places in the country where the benefits of land reclamation are too great to ignore, in particular in and around our biggest cities. In some cases, the environmental benefits of bringing more people into dense, efficient cities where they have far lower emissions per capita may outweigh the loss of aquatic habitat all on its own, leaving the direct benefits of more land as pure reward.

Land reclamation is not the solution to everything, but there’s no good reason we should be worse at land reclamation than we were 150 years ago. There is plenty of land that is easy to reclaim and plenty of areas where the value of land is far greater than the cost of acquiring it. The benefits of more land in our most productive cities are large enough to justify the effort of reforming the laws that currently prevent it. Let’s make more land!

Zigmund Forrest is an independent researcher. Maxwell Tabarrok is a graduate student at Harvard University.

Artwork by Filip Setmanuk.

The holy grail of cancer therapy. Roughly half of all cancers have a mutation in p53, one of the most important proteins in our body. It protects us against cancer by acting as a checkpoint: when a cell’s DNA is damaged, p53 can pause the cell to help it repair the damage, or trigger the cell to self-destruct before it becomes cancerous. Destroying mutant p53, or restoring the function of healthy p53, has therefore been something of a holy grail in cancer therapy.

So far, though, it has been incredibly hard to develop drugs against mutant p53. That is partly because p53 can carry a wide variety of possible mutations, and partly because mutant p53 proteins tend to be slippery, without an obvious pocket where a drug could bind.

A new paper by Jennifer Doudna’s lab, which pioneered CRISPR/Cas9 as a gene-editing technology, describes a new approach. Rather than trying to attach to and block the protein, why not kill cancer cells that carry the mutation? So they developed a system to do that, CRISPR-Cas12a2. It finds mutant RNA transcripts of p53 and switches into a destructive mode, shredding the cell’s DNA, which essentially causes the cancer cell to commit suicide.

The guides are highly specific: they target just a single-letter change in the RNA and leave other cells as they are. They are delivered as mRNA inside lipid nanoparticles, with components that steer them toward the lungs, unlike the standard lipid nanoparticles that tend to be taken up in the liver. And helpfully, the nanoparticles can carry several guides at once, so one treatment could target multiple p53 mutations or cancer-causing genes together.

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The first base-edited human embryo. Eight years ago, the Chinese scientist He Jiankui became infamous for using CRISPR-Cas9 to edit embryos from IVF that became children. This was more than an ethical scandal about gene-editing. The standard CRISPR-Cas9 system he used is technically risky: it cuts through both strands of DNA while making the edit, and since the break is hard for our cells to repair, it can result in losing long stretches of DNA or even entire chromosomes. Dieter Egli, a scientist at Columbia, tried it in a research setting in 2020 and found around half the embryos suffered from what he called ‘catastrophic consequences’.

Now, Egli’s group has tried another, safer approach, in the lab: base editing, which cuts only one strand of DNA instead of both, and replaces just a single letter of DNA. For certain mutations, this kind of single letter edit is enough to make a fix. The team base-edited two genes in donated embryos: PCSK9 (which regulates cholesterol levels) and HBG (which controls fetal hemoglobin), and found the edits were both efficient and free of causing the chromosomal damage seen with Cas9. But, the edited embryos weren’t implanted as He Jiankui had done.

The method resulted in some rare off-target edits, with segments aside from those of interest being edited too. And it wasn’t fully effective, as many embryos came out as genetic mosaics, with only some cells carrying the edits. (The phenomenon of being a genetic mosaic is also seen in rare cases in humans. It’s called ‘whole-body chimerism’, from two separate embryos merging into one, early in development. It’s mostly harmless and often discovered only by accident, during DNA testing, though some people with it have noticeable features like patches of differently colored skin or eyes.)

Although the technology is still in development, the idea could correct the single-letter mutations that cause many congenital diseases. Embryos found to carry such mutations during IVF, which parents might otherwise discard, could instead be repaired. Scientists have also been working on gene-editing technologies that could be applied ‘in utero’, not just during IVF, meaning gene-editing could correct congenital mutations that cause diseases like cystic fibrosis, but before birth, as fetuses grow.

The first CRISPR medicine, three years on. A few years ago, the first CRISPR medicine was approved: Exa-cel (exagamglogene autotemcel). It’s a gene-editing therapy for sickle cell disease and beta thalassemia. Both are inherited disorders of hemoglobin (the protein that red blood cells use to carry oxygen) and in both cases, the blood ends up carrying less oxygen than usual. Until recently, the only cure was a stem cell transplant from a healthy donor, but suitable matches are hard to find and transplants carry risks.

To solve the problem, the CRISPR medicine works by switching a fetal form of hemoglobin back on. People make this fetal hemoglobin naturally before birth and then switch to the adult form, and it carries oxygen just as well. In the therapy, doctors remove a patient’s blood stem cells, switch fetal hemoglobin back on with CRISPR-Cas9, clear out the remaining stem cells with chemotherapy, and then return the edited cells to the body.

A new paper reports the results of two phase 3 trials of exa-cel in children aged 5 to 11. Most children in the study were, in effect, cured: those with beta thalassemia no longer needed blood transfusions, and those with sickle cell disease became free of the painful episodes of blocked blood vessels; the remaining children hadn’t been followed up for long enough to tell. The result has led the FDA to expand the treatment to children as young as two.

But it’s a hard therapy to go through, with side effects that can be fatal. Every child in the trials had serious side effects from busulfan, the chemotherapy used to clear the bone marrow before the edited cells go back in; two developed liver disease, and one died. The edited cells themselves weren’t harmful but the process to clear out their original cells with chemotherapy, unfortunately, was. It doesn’t have to be this way: new technologies that could skip the chemotherapy step and directly edit cells in the body are in the pipeline, though they’re currently early in development.

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Lab-grown human eggs and sperm (with caveats). Two separate biotech companies – Paterna Biosciences and Conception Biosciences – have reported growing human sperm and immature eggs, respectively, in the lab.

The companies are trying to achieve ‘in vitro oogenesis’, or IVG, a technology in which adult skin or blood cells are ‘reprogrammed’ back into pluripotent cells, and then coaxed to form viable eggs or sperm.1 So far, this technology has only worked in mice, with just 1–3 percent of lab grown eggs leading to viable pups. If IVG ever works for humans, though, it would mean that just about anyone who wants to have biological children could do so, including two men or two women, or women who don’t have many eggs of their own.

How about men who lack sperm? About 10 percent of men with infertility, and about 1 percent of all men, have something called ‘azoospermia’, which means they have zero detectable sperm in their ejaculate. The condition can be caused by an inability to make sperm at all, or by a blockage where sperm fail to exit the body. Paterna, one of the biotech companies working on IVG, claims to have developed a technology that would solve either problem by isolating sperm-making stem cells directly from a patient’s testicles, via a biopsy, and then coaxing them into developing mature, functional sperm in a dish. These lab-grown sperm were able to create human embryos that appear healthy, though further testing would be required to find out if the embryos had any genetic (or epigenetic) abnormalities.

The holy grail in the field, though, would be to make viable eggs or sperm all the way from blood or skin cells taken from the body, after converting the latter into pluripotent stem cells. Paterna did not do that: they are using stem cells from the testes that already have the ability to make sperm inside the body, and then recreating those sperm-making conditions outside the body.

As for the eggs, Conception Biosciences, based in San Francisco, says they’ve ‘generated the first early human egg cells (‘primary oocytes’) derived from stem cells.’ The company writes: ‘After performing a simple blood draw, we converted blood cells into stem cells, and then coaxed those stem cells into becoming miniature human ovaries that contain the early eggs.’ Note that they are only claiming to have made early eggs, which are immature, rather than mature eggs that could be used to make a human embryo.

Neither claim has been published, and experimental data is scarce. But people we’ve talked about this with in the reproductive technology field say their claims are likely real, even though it’s not clear whether either could lead to a viable pregnancy.

The race to cure multiple myeloma. Treatment for multiple myeloma, a cancer of the plasma cells in the bone marrow, has advanced a lot over the years. Much of this progress has been down to antibody treatments that direct the immune system to fight the cancer. Some, like daratumumab, tag myeloma cells so the immune system destroys them. These treatments are grueling, though: they have to be taken continuously, they carry real side effects, and in many patients the cancer relapses eventually.

Ruxandra Teslo and Amol Punjabi recently wrote about a big breakthrough from another angle: CAR-T cell therapy, where a patient’s own T cells are removed and re-engineered to hunt the cancer. The standout, Carvykti, was developed in China, and is a cure for some. About a third of patients in the phase 3 trial, with relapsed or refractory multiple myeloma, were still disease-free five years after a single infusion, with no further treatment.

But the off-the-shelf antibodies are fighting back. Talquetamab is an example. It’s a ‘bi-specific’ antibody, which grabs myeloma cells with one arm and T cells with the other, and bridges them, helping the patient’s own T cells kill the cancerous cells. It’s been approved since 2023, but only for patients who have already been through at least four prior treatments. Now a new phase 3 trial suggests it can be given much earlier, after a first relapse.

How well does it work there? Very well! Added to daratumumab, it cut the risk of the cancer progressing by two-thirds against a standard regimen (with roughly 78 percent vs 52 percent of patients were progression-free at two years) and halved the risk of death within two years.

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Electron microscopes with laser beams 100 million times brighter than the surface of the sun. Electron microscopes can help visualize objects far too small to be seen through regular light microscopes, including individual proteins. They work like this: a ‘gun’ fires electrons down a column, and magnetic lenses focus them onto a thin sample. The electrons hit the sample, scatter off, and collide with a detector, which then generates an image.

This approach has a few problems, though. For one, it only works under vacuum, so researchers must kill cells before imaging them. Even the remaining material gets ripped up and slowly destroyed by the electron beams over time. And transparent things, including cells, barely scatter the electrons passing through, so most images look blurry.

When electrons pass through a specimen, they split into two populations: most pass straight through, but a small fraction scatter, shifting their wavelength by one-quarter. At the detector, these two populations of electrons overlap and interfere, and the sum of the ‘heights’ of their waves determine the final brightness of the image. Since waves that are a quarter-wavelength apart add up at nearly right angles, the electrons scattered by the specimen have almost the same brightness as the background, which means minimal contrast.

Now, researchers at UC Berkeley have taken a huge step toward solving this problem, by using an intense laser beam to shift the phase of the electrons themselves.

First, they built a laser beam 100 million times brighter than the surface of the sun. They generated this beam by trapping a laser between highly polished mirrors, which bounce it back and forth 10,000 times to build up intensity. Then, the researchers positioned the laser so that it only interacted with the straight-through electrons, rather than the electrons that collide with the specimen, so both populations would be shifted by the same quarter wavelength. When the populations then recombine, their interference produces a large brightness difference, increasing the contrast between specimen and background.

This enables huge improvements in cryo-electron microscopy. Before, researchers could image only about 10 percent of human proteins in purified form, and under 1 percent of proteins inside intact cells, mostly larger proteins like hemoglobin. The laser phase plate could push those numbers past 50 percent, while improving their resolution too. It means researchers can see which proteins bind to each other inside living cells. They are already studying mutated lysosomes, or the recycling organelles in cells, implicated in Alzheimer’s disease.

The EU will adopt streamlined approval pathways for lightly gene-edited crops. Until now, all gene-edited crops in the EU have been regulated, regardless of how minor the edits were, under the GMO pathway. This regulatory process required many experiments – like feeding the engineered plants to rodents for 90 days to see if they got sick, proving that added proteins could not be allergenic, and mapping out all possible effects the crop could have on the environment – before approval. This process took about five years of work, and cost between 10 to 16 million euros.

But this month, the European Parliament endorsed a new regulatory system where crops carrying gene edits that are modest enough to have arisen through conventional breeding can go through expedited approval pathways. Many other countries have already adopted similar regulatory pathways that distinguish between ‘gene-edited’ and ‘GMO’ plants, including Australia, Argentina, the United States, Japan, and Brazil.

Under the new guidelines, which will go into effect in two years, engineered plants that could have been made through conventional breeding techniques will have an easier path to approval. This new pathway applies to any plants carrying less than ~20 genetic changes and with no foreign, non-plant DNA. These plants won’t need to be labeled as GMO in supermarkets, either.

Many examples of ‘gene-edited’ crops will become easier to approve in Europe as a result, including non-browning mushrooms, which are typically made by knocking out a single gene encoding an enzyme that causes that browning, and are cleared US regulatory review back in 2016. Another example is wheat resistant to powdery mildew, made by knocking out a mildew-susceptibility gene.2

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A synthetic cell that can eat, grow, and divide. For the first time, scientists have made a synthetic cell (called SpudCell) that’s capable of ‘feeding, growth, replication, division and selection [...] entirely using components scientists put there.’ Although SpudCell is definitely a cell, it is not alive, because it can only divide a couple times before expiring.

It is basically a bag of lipids filled with proteins and DNA. Its genome spans 90,000 basepairs of DNA across seven plasmids. Its DNA replication is simple, using a DNA polymerase called Phi29, which floats around, randomly grabs plasmids, and copies them. This happens continuously. Its protein synthesis is more complicated, involving dozens of proteins. And SpudCell cannot make its own ribosomes; researchers must supply them from outside.

Whereas normal cells consume nutrients and convert them into useful molecules, SpudCell feeds by fusing with lipid bubbles called ‘feeder liposomes’, which are filled with ribosomes, using a protein engineered to carry short strings of histidine amino acids. These strings latch onto the feeder liposomes and coax them to merge into SpudCell to bring their ‘food’ inside.

Cell division in SpudCell involves a clever trick of biophysics. It turns out that, if you stud the outside of a lipid membrane with bulky proteins, those proteins will crowd each other and repel the cell membrane, forcing the cell to bend and eventually split. And that’s how SpudCell divides.

The next step will be to engineer SpudCell so it divides dozens of times, reliably. Metabolism is probably the biggest requirement for long-term growth. As SpudCell can’t make its own ribosomes or energy, the researchers currently have to pump in fresh supplies constantly. This is fine, in principle, but SpudCell can’t recycle its broken proteins either. So when the ribosomes wear out and its proteins ‘break,’ they simply sit there and fill up space. It has no way to export its waste, so with each cell division, a larger and larger fraction of the cell’s internal volume becomes packed with junk.

Cover illustration: Escherichia coli.

Print subscribers received the full edition in the first two weeks of June. Most articles in the issue have previously been released online; the remainder of the issue is available on the website today. The issue contains pieces on:

• Why British NIMBYs in the 1600s smashed themselves;

• Why we only discovered plate tectonics around the time we went to the moon;

• How p-hacking is ruining nuclear regulation;

• Why Western countries stopped reclaiming land from the sea;

• What’s really slowing down the AI buildout

• How Europe eliminated fox rabies by dropping vaccines from helicopters;

• Alberta, the only place in the world without rats;

• The most unusual housing development in the world; and

• The prison city that kept Japan peaceful for centuries.

You can get a year of the print magazine for $100 here. New subscribers will receive Issue 24 immediately, plus a new issue every two months after that.

Many people know that the Glorious Revolution was central to Britain’s economic divergence from the rest of Europe. The common story holds that the revolution did this by restraining what the government could do. Ben Southwood and Kara Dimitruk argue the opposite: by creating a form of government controlled by landowners, the British state became far more interventionist, capable of overriding encrusted property rights that prevented farmers from investing in their land, travelers from paying for their roads, and landowners from digging canals and building houses. Like in eighteenth-century Britain, maximizing economic growth today may depend on building a pro-change coalition among rightsholders, rather than on trying to override them.

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Without plate tectonics, we cannot explain mountains, deep sea trenches, earthquakes, or volcanoes. It tells us where to expect oil and why fossilized sea creatures show up in the middle of the desert. Given its extraordinary simplicity, it is surprising how long it took for plate tectonics to become consensus, writes Elizabeth Van Nostrand. People had noticed for centuries that South America and Africa fit together, but most geologists remained dismissive until the second half of the twentieth century. Only in the 1960s, when the US Navy funded research for submarine navigation did the consensus change. Plate tectonics may be the Platonic ideal of a scientific paradigm.

Is it better to drink one beer every evening for a year, or drink 365 beers in one evening? The answer may seem obvious, but the rules governing nuclear power are based on the idea that, when it comes to radiation, both doses are equivalent, explain Alex Chalmers and Ben Southwood. The studies often cited to justify treating any radiation exposure as intolerable turn out to be textbook cases of p-hacking; even the worst nuclear accidents have never had the long-term consequences these studies predict. Low doses of radiation are almost certainly safe, and a regulatory system that reflected that truth would make nuclear power far cheaper to build.

Since 1985, North Korea has reclaimed 14 times more land than the entire United States. America isn’t uniquely bad at this: across the entire Western world, land reclamation halted almost completely in the early 1970s. The timing of this change, argue Zigmund Forrest and Max Tabarrok, suggests that it was modern environmentalism that killed it. Land values have risen enormously in the last fifty years, and reclaiming land is technologically feasible near almost every major American and European city. To build more land, all that needs to happen is for it to become legal again.

The limit on building data centers is the time it takes to get connected to the grid. Replacing the current first-come, first-served system with something closer to an auction and letting data centers plug in immediately if they agree to power down for a few hours a year could unlock far more capacity than building new plants alone, writes Chris Gillett. These changes would be almost free, bring down electricity prices, and dramatically speed up the construction of new data centers across America and much of Europe.

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We commonly vaccinate humans and pets. But more than half of all infectious diseases are zoonotic, and a majority of those originate in wild animals, rather than pets or livestock. Rather than wait for diseases to spread, vaccinating wildlife directly is the cheapest way to protect humans, save species from extinction, and spare animals painful deaths, explains Michelle Ma. For some diseases, we’ve already done it: airdropping vaccine-laced chicken heads over the Swiss Alps and trapping koalas to vaccinate them against potentially fatal chlamydia.

In a world map of rat habitats, only one blank space sits amidst a sea of red: the Canadian province of Alberta. Alberta has been free of rats for more than seventy years, making it a rat-free expanse second in size only to Antarctica, writes Deena Mousa. It did this by preventing them from settling at all: anticipating the corridors through which rats could enter, poisoning their potential habitats, and maintaining a state of permanent vigilance.

In 2002, a Canadian indigenous tribe, the Squamish Nation, managed to recover 11 acres of land in central Vancouver that had been seized from their ancestors in 1913. Freed from the zoning rules that keep the rest of Vancouver low-rise, the Nation voted to maximize density, and are now building eleven towers which will eventually house 9,000 people, writes Anya Martin. The story of the Squamish teaches us two things: when they benefit from development, people will vote for it, and when a development enjoys legitimacy, other parts of government will hesitate to block it.

Between 1600 and 1868, Japan’s ruling family kept the country almost entirely free of war. It did this by forcing its warrior aristocracy to live in a single city, writes Samuel Hughes. At its height, Edo, now Tokyo, was the largest city on Earth. It was less a functioning capital than an extremely effective, extremely expensive prison, sorting samurai, daimyo, and commoners into walled quarters sealed by checkpoints that closed every night. Edo was an enormous drain on taxpayers around Japan; in exchange, the country lived through a quarter millennium of peace.

Notes on Progress

We released a few Notes on Progress since the last issue:

• The miracle of modern epidurals, by Phoebe Arslanagic-Little

• How bacteria solved the mystery of inheritance, by Kevin Blake

• European housing politics should be Americanized, by Samuel Hughes

• Why Spain has the best cities in the world, by Harry Law

• The flattening of American city flags, by Ned Donovan

• What we can learn from a Chinese cure for a brutal blood cancer, by Ruxandra Teslo and Amol Punjabi

• A review of Tyler Goodspeed’s book, Recession, by Mark Koyama

• An architectural review of Washington, DC, by Samuel Hughes

• The education of Ben Southwood, by Ben Southwood

• How daraxonrasib made pancreatic cancer treatable, by Ruxandra Teslo

The Works in Progress podcast

We’ve released podcasts on;

• Local government

• Sculpture

• How nineteenth century cities expanded so quickly and so well.

• The articles in this very issue

This season of the Works in Progress podcast is now over. Keep your eyes peeled and ears pricked for the things to come.

Events

We hosted lightning talks on housing and infrastructure in Berlin; a party to celebrate Issue 24 in Washington, D.C.; and a behind-the-scenes glimpse at the design of the print magazine in New York.

Coming up soon:

• Cambridge, UK: Subscriber-only Issue 25 launch party, Friday 21st August

• Brussels: How can Europe catch up on AI?, Tuesday 8th September

Plus subscriber-only events in San Francisco and London. Sign up to the print magazine to get the details!

What we’ve been up to

• Sam finished up as a judge on the Orwell Prize for Political Writing.

• Saloni has been writing regular round ups of biology breakthroughs with Niko McCarty. She also wrote about why Covid vaccine trials were so fast, and interviewed the inventor of the second malaria vaccine, which is much cheaper and scalable than the first.

• Pieter got into an argument with Paul Krugman and wrote two pieces about how Europe should think about AI.

• Aria was on the Inkhaven podcast talking, yet again, about sexiness.

• Rachel has been obsessively reading the work of Antal Szerb, a Hungarian novelist and literary critic, and translating some of his essays into English.

• Ellen stayed in a capsule hotel in Berlin and spent the heatwave trying to brew the perfect iced tea.

• Ruxandra recently visited Washington, DC to advocate for clinical trial reform and she was very happy to see the recent initiative from the HHS focused on making Phase I trials faster.

Chernobyl was the world’s worst ever nuclear disaster. The reactor was built to a flawed design. In 1986, its operators disabled automated safety systems and removed control rods to perform a late-night test. The coolant water overheated, speeding up the reaction until it flash-boiled into steam and violently shattered all the nuclear fuel in a matter of seconds. The graphite in the reactor then caught fire.

Six hundred workers were present when this occurred. Of these, 134 received high doses of radiation, between 800 and 16,000 millisieverts, mostly within hours. Twenty-eight of these died in the first three months, and another 19 died before 2004, though not all from radiation-related causes. While first responders have shown a slight increase in rates of leukemia, there has been no increase in solid cancers.

When the reactor exploded, it released massive amounts of radioactive material into the atmosphere. This ash settled onto the grazing regions of Ukraine. Dairy cows ate it and secreted it into their milk. Every person who drank this milk ended up with some quantity of radioactive iodine concentrated in their thyroid gland. Since children have smaller thyroids, their effective doses were much larger. The hundreds of thousands of children exposed have been closely screened in the years since, and authorities have identified 6,000 thyroid cancers. Fifteen people have already died of these cancers, and 200 might in the long run. These thyroid cancers were completely avoidable because the iodine has a half-life of eight days. After the Windscale fire released radioactive fallout onto grazing land in 1957, Britain discarded contaminated milk for 44 days, thereby avoiding any harm.

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Chernobyl is the only accident in commercial nuclear history that has exposed people to large enough doses of radiation to poison and kill them. But even it has caused only hundreds of early deaths, despite the exposure of millions of people in the exclusion zone and nearby. Radiation impacts on Scandinavia and Germany, where there were major fears about the effects of the fallout, were nugatory. Evacuations and relocations to avoid small additional background radiation levels may have caused more harm than they averted. The same is true of Fukushima and Three Mile Island, the other two large nuclear disasters, but to an even greater extent: neither saw any responders die of the direct effects of radiation, and neither shows any clear impact on cancer rates.

Two years before Chernobyl, an explosion at a pesticide plant in Bhopal, India, released toxic methyl isocyanate gas that killed at least 2,000 people instantly, permanently disabled another 4,000, and caused 550,000 injuries in total. In 1975, the Banqiao Dam in China failed, flooding 12,000 square kilometers, drowning at least 25,000 people, and destroying perhaps five million houses.

Whereas Chernobyl is a household name, Bhopal and Banqiao are mostly familiar only to specialists. People have much greater familiarity with and concern about the risks created by nuclear power, and the world’s international radiation protection regime is based on the idea that any release of radioactive material from a nuclear power plant is intolerable. This has led to regulations that have increased the costs of nuclear electricity over time to the point where it is widely considered a slow, backward, and ineffective technology.

The idea that any release of radioactive material is an intolerable disaster rests on the claim that radiation is harmful even in small, spread-out doses. But this claim is not well supported. The studies that claim to show harms from slow, drawn-out ionizing radiation are unconvincing. By giving them undeserved credence, we may be foreclosing one of the world’s most powerful technologies.

Trouble in Taipei

Between 1982 and 1984, recycled steel contaminated with cobalt-60 was unknowingly used in the construction of more than 180 buildings in Taiwan, including schools, businesses, and approximately 2,000 apartments. Cobalt-60 emits deeply penetrating gamma radiation, which in high doses is fatal: in 2000, three people died from acute radiation poisoning when a Thai scrap merchant took apart a radiotherapy machine containing large amounts of it. Over two decades, more than 10,000 people occupied these buildings, receiving an average total radiation dose of 400 millisieverts, about seven times more than the average American would receive over the same period from background radiation. This makes the Taiwanese buildings a good test of the claim that chronic background radiation at low daily rates damages human health.

A series of academic papers reconstructed the doses that different affected inhabitants experienced, combining thousands of on-site readings with estimates of their time spent at home. CJ Tung and colleagues built a model in 1998 of 24 of the 1,327 apartments that had then been identified as irradiated, breaking them down into one meter by one meter squares, and using dosimeters to measure radiation in those squares, to get an idea of how residents might have been affected.

Doses varied substantially. Most units received trivially low doses, less than the radiation exposure from one full-body medical CT scan per year (ten millisieverts). A small fraction of units received nearly 1,000 millisieverts per year, equivalent to a hundred CT scans. Later studies that mapped out these doses in more detail found that some sections of rooms were exposed to over 8,000 millisieverts per year, equivalent to about two CT scans every day.

A 2004 preliminary report, followed by a 2006 study (Chen et al), was the first to attempt to measure the health effects in this group. There were no cases of radiation sickness nor any major chromosomal aberrations. Affected Taiwanese had biomarkers of cellular stress nearer the upper end of normal reference ranges, but none linked with observable health effects. Cancer rates were, unexpectedly, dramatically lower than in the population at large.

Chen interpreted this as evidence of the health benefits of radiation. This theory, known as hormesis, holds that low doses of stressors, including ionizing radiation, can improve health (in this case, reducing cancer risk) by triggering the body’s repair systems in much the same way that exercise improves fitness by stressing the cardiovascular system. While popular among a small community of researchers, it has not gained widespread acceptance due to limited and conflicting evidence in humans.

This interpretation of the Taiwan data is dubious because it wasn’t able to control for age. Those affected by the cobalt-60 radiation were far younger than the average Taiwanese. Since younger people are less commonly diagnosed with cancer, this is a very significant limitation. A US Environmental Protection Agency (EPA) review, describing the Taiwanese apartment data alongside some similar cases, warned that ‘studies on these populations are ongoing and suffer from various shortcomings, including incomplete follow-up, dosimetric uncertainties, limited statistical power and confounding’.

Torture the data and it will confess

Later studies fixed most of these problems, linking good estimates of the doses individuals experienced with their health outcomes and adding the missing age data. Contrary to the previous report, the studies generally claimed to find that low doses of ionizing radiation can cause cancer. But drawing this conclusion from them requires an unreasonable manipulation of statistics.

A 2006 study (Hwang et al) in the International Journal of Radiation Biology, for example, found slightly elevated incidences of thyroid cancer in women and leukemia in men across a sample of 7,271 people. But overall cancer rates were still lower in this group than in the general Taiwanese population, even after controlling for age.

The way the researchers found these higher rates of cancer was to break cancer cases down into 77 subtypes, such as tongue cancer in men or kidney cancer in women, and see if any of these had higher rates than expected. This approach has two problems. The first is that when you divide cancer cases into 77 buckets, even small and random variations in one or two of the buckets can create the appearance of a relationship. Every statistically significant site-specific result showing higher cancer incidence relies on seven or fewer observed cases. Across 77 different statistical tests, we would expect to see statistically significant results in four cases purely due to random variation. The second problem is that the authors did not register their hypotheses in advance: we have no idea whether they sliced the data into hundreds of different tests before cherrypicking those that gave them statistically significant correlations.

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The biggest issue with drawing the inference that low-level radiation harms human health is that the exposed population actually have lower cancer rates than unexposed people. Just like in Chen et al, the number of total cancer cases observed is substantially lower than expected.

Don’t back down, double down

A 2017 study in the British Journal of Cancer (Hsieh et al) follows up on this result, with ten years more data on whether affected people got ill, again using more accurate dose-rate profiles, more closely associated with particular individuals. Like Hwang et al, they claim their findings show that ‘low-dose-rate radiation exposure increases risks of breast cancer and leukaemia’, but the data is similarly brittle.

Within their sample of around 6,000 exposed Taiwanese apartment dwellers and schoolchildren, female breast cancers were higher at higher levels of exposure: 100 millisieverts of exposure was linked to an 11 percent higher cancer risk. This result is statistically significant. The study finds a few other results that are narrowly significant, but only out of a table of dozens, just like the previous study.

But again, the studies fail to state which tests they planned to do beforehand or that they began the analysis with the hypothesis that leukemia (but excluding multiple myeloma and chronic lymphocytic leukemia) would go up after a delay of two years, whereas rectal, stomach, liver, and thyroid cancer would be unaffected – or that cancers overall would be no higher in the study group than among totally unaffected Taiwanese. If they’d entered their research with this hypothesis, it might make the results more credible. Instead, they appear to have stumbled across a handful of correlations by chance.

And once more, the authors don’t highlight that the irradiated group has significantly lower overall cancer rates than the general Taiwanese population.

While we can comb through the data and infer that the average age of the subjects in Hwang was 33. The samples are slightly different, so we can’t just add ten years to get an average age of 43 for Hsieh. The UN Scientific Committee on the Effects of Atomic Radiation estimated that the average age of the Hsieh sample was about 45, seven years older than Taiwan’s population overall in 2012. By 2012, the irradiated apartment dwellers had experienced 247 cancers, across 97,106 person years. Yet the cancer rate for Taiwan as a whole between 2008 and 2012 was about 390 per 100,000 person years.

Overall, cancer rates seem to be almost 35 percent lower in the affected group. If being irradiated with hundreds of millisieverts per year appears to have no effect, or even reduces cancer rates compared with the general population, this strongly implies that the links these two papers identify between much smaller doses of radiation and particular kinds of cancer are random noise.

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Made aware of this, Hsieh responded (as did Hwang) that these gaps must be down to socioeconomic status. Is this true? The best argument provided is that these were residents of new buildings constructed during an economic boom, suggesting that the apartments were relatively expensive. Though no data on the actual socioeconomic status of their residents exists, we can make some educated guesses.

First, though new, some of the buildings were public housing intended for poorer residents or public employees. This makes it unlikely that their inhabitants were wealthier people projected to have better health outcomes than the rest of the population.

Second, even if it were true that the residents were richer than average, this still wouldn’t account for the decreased cancer rates. Existing data suggest that Taiwanese health differences by socioeconomic status do not close this gap: overall cancer incidence is ten percent lower among doctors than in the general population. The incidence of colorectal cancer, one of the most common cancers, is actually lower (by about 20 percent) at the bottom of the wage ladder in Taiwan, though it is higher among those with the lowest education. None of these variations approach the 35 percent lower rates of cancer seen in the irradiated apartment residents.

This is not to claim that Hsieh’s paper provides strong evidence for the health benefits of radiation, as some fans of nuclear power have suggested. Most likely, these results are evidence of nothing.

The perils of low-dose science

From 2011 onwards, scientists began to realize that significant numbers of famous, eye-catching findings were unreplicable, in what became known as the replication crisis. Starting in psychology – once-popular ideas like power posing or the brain-enhancing effects of classical music began to be debunked – before the same occurred across every discipline.

The Taiwan papers have the classic tell of such findings, using tricks to turn random noise into statistically significant results, a phenomenon known as p-hacking. One such trick is dicing a population up into as many different subgroups as possible, expanding a researcher’s likelihood of finding something by chance.

It is inherently difficult to find out if low doses of radiation affect health. Populations vary hugely in all sorts of health, lifestyle, and genetic factors. The anticipated cancer effects of radiation would be low, even for those who expect to find them. Researchers would need a huge sample size and very carefully designed analysis to have any hope of detecting a signal amid the noise. INWORKS, first published in 2015 and updated in 2023, is the most serious attempt. It looks at cumulative low-dose radiation among 300,000 nuclear workers in France, the US, and Britain, measured by badge dosimeters, and finds that each additional 100 millisieverts of lifetime ionizing radiation exposure is associated with five percent higher cancer mortality rates, adding about one percent to the lifetime risk of dying of cancer (compared to an average of about 34 percent).

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For comparison, 100 millisieverts is about ten full-body CT scans, whereas the median INWORKS worker experienced a four-millisievert dose. Eating 50 grams of processed meat per day is associated, after controls, with a lifetime colorectal cancer risk 18 percent higher, and smoking with a lung cancer risk 1,500 to 3,000 percent higher.

The INWORKS study is the best single piece of evidence for an effect of cumulative low-dose-rate radiation on health, but the size of the effect is small enough that it is far from a given. For one, the INWORKS study does not attempt to account for background doses, despite the fact that different people will have different levels of background exposure, depending on factors like where they live and how many medical scans they have. The average lifetime background dose in the UK is about 70 millisieverts, similar to that in the US and France, meaning that more than 90 percent of INWORKS subjects got most of their exposure from natural background radiation.

Another problem is that INWORKS’s significant result is driven by subjects between the 75th percentile, meaning lifetime exposure of roughly 20 millisieverts, and the 90th, at roughly 50 millisieverts. The relationship between exposure and cancer is not significant for doses between 0 and 20 millisieverts. Only when expanded to doses between 0 and 50 millisieverts does a significant effect appear, before weakening steadily as higher doses are added in, though not to the point of becoming insignificant.

This sensitivity makes the results fragile and is one reason why many look instead at studies with higher doses. The median INWORKS worker received a dose of four millisieverts, which according to INWORKS’s model, would correspond to increasing the lifetime risk of dying from cancer from the US average rate of 17.2 percent to 17.23 percent. An effect this small is hard to confirm even with 300,000 subjects, given so many unmeasured confounders.

Historically, many people have received doses of thousands or even tens of thousands of millisieverts, similar to those of the Taiwanese apartment dwellers. There are cases of Keralans exposed to sand containing thorium; Manhattan Project scientists who inhaled so much plutonium that they peed it out; early British radiologists who worked without any protection from the X-rays they worked with. These groups suffered long-term health effects only if they absorbed high dose rates.

One of the most horrific and notorious cases of radiation exposure was that of women employed to paint radioactive radium onto watches for glow-in-the-dark dials. Early dial painters were told to lick their paintbrushes for greater precision. Those that did ingested radium at extremely high internal doses and developed necrosis of the jaw and often-lethal bone cancers. But the thousands that did not lick their brushes, despite receiving doses that were often hundreds of times higher than normal, did not see any higher rate of cancer.

Though unlikely, it is possible that future studies will reveal a more substantial correlation. In the meantime, the lack of any strong signal in the Taiwan data is one of many good indicators that low-level radiation is not a cause for concern. Where radiation does harm people is when they are exposed to high, acute levels that even the worst nuclear disasters seldom release. When people are looking this hard, absence of evidence is, in fact, pretty good evidence of absence.

Alex Chalmers is a staff writer at the Cosmos Institute and a former editor at Works in Progress.

Ben Southwood is an editor at Works in Progress.

One of the most expensive projects in history is under construction in Abilene, Texas. This joint venture, Stargate, is the flagship of a bigger project by the same name led by OpenAI and Softbank, and is expected to cost well over $40 billion for a high-performance computing campus that will train new generations of AI models.

Stargate is just one major project in one of the biggest investment booms in history, driven by the belief that increasingly powerful AI models can deliver explosive economic growth. But it will require enormous amounts of electricity to work: Stargate is expected to draw 1.2 gigawatts, as much as 313,000 median American family homes, at peak load. A report by EpochAI and an energy research institute projected that total AI computing power would reach 100 gigawatts worldwide in 2030 if the 2025 growth rate stays steady. And data centers aren’t the only energy-hungry element of the AI revolution. The biggest battery manufacturing plants in the US draw energy at a rate of 115 megawatts, and the first phase of TSMC’s Arizona semiconductor plant will draw 200 megawatts.

The primary bottleneck to this growth is the availability of electricity. But this doesn’t mean there is an energy shortage. Instead, the constraint is connecting the flood of new data centers and the plants to power them to the electric grid. Before any new piece of infrastructure can be connected, grid operators must study how it will change power flows around the grid and determine whether upgrades to the system are required. That process is significantly backlogged. Though the median power plant in 2005 waited less than 20 months for interconnection, this had jumped to 55 months by 2023.

The interconnection process wasn’t created for today’s world. Grids use an inflexible first-come, first-served queue that leaves some of the most valuable projects stuck behind less important ones. They also evaluate according to rigid conditions that don’t reward plants for being willing to cover their own power needs for short periods. To prepare for the AI age, grid processes need to change.

A power-hungry future

Estimates vary for how much power will be needed by the data centers and chip manufacturers of the future, but the heads of every major AI company agree that they will need more than they are currently able to get. Jensen Huang, CEO of Nvidia, has said that ‘every data center in the future will be power-limited’. Mark Zuckerberg said Meta ‘would build … bigger [AI training] clusters … if we could get the energy to do it’. And OpenAI CEO Sam Altman told Congress that ‘the abundance of [AI] will be limited by the abundance of energy’.

Regardless of how the data center boom plays out, there is a long-term shift towards electrification across the economy. Electricity can be converted into work instantly, unlike fuels, and with little energy loss. Electricity creates motion directly, while fuels must first be combusted in an engine. This is why electric vehicles can cost half as much to fuel even though electricity is more expensive than gasoline. The simplicity of electric motors also means that electric vehicles have half the lifetime maintenance costs of gas-powered ones.

Electricity also transmits information. Transistors switch on or off depending on the voltage applied to their gates, which allows circuits to perform logical operations. Radios, screens, and computers cannot run on gasoline alone.

Between 1990 and 2024, the price of electric motors declined by 97.5 percent. Power electronics fell 99.5 percent in price, processors built into devices by nearly 99.9 percent, and batteries 98.8 percent. As prices have declined, performance has improved. For example, the amount of energy a battery can store per kilogram has increased five-fold over the same period.

These trends allowed the progression from the Walkman to the iPod and then the iPhone, as well as enabling battery-powered cars, delivery vans, and bicycles. At the same time, the increased computing power built into devices is giving autonomy to newly electrified cars and trucks, robotic vacuum cleaners and mowers, and drones. The commercialization of humanoid robots may also be on the horizon. The future will be largely defined by technologies that run on electricity.

The grid bottleneck

This growth in demand is already straining power grids. Operators are increasingly forced to use expensive local plants because of what grid operators call congestion: cheaper plants are on the other side of transmission bottlenecks and there aren’t enough cables to get the electricity through. In the United States, the additional costs incurred because of grid inefficiencies like congestion ran to $11.5 billion in 2023, an increase of 45 percent from the year before.

ERCOT, the grid that provides 90 percent of Texas’s electricity (including for the plant being built in Abilene), forecasts that it won’t have enough power to meet demand in summer 2028. PJM is the US’s largest grid, both by the amount of electricity it provides and the population in its coverage area, serving an area between Chicago, New Jersey and North Carolina. In 2025, PJM was not able to buy enough future generating capacity to meet projected demand. MISO, another large US grid operating between Louisiana and Minnesota, concluded in one study that ‘resource adequacy risks could grow… absent increased new capacity additions’. PJM’s CEO put it more plainly: ‘We need capacity – a lot of capacity.’

Discussions about expanding electricity supply to power the future often become debates about which source is most suitable: gas, nuclear, solar, or something else. But these are a distraction. Far more fundamental is ensuring power can be efficiently delivered where needed.

When different generation technologies coexist, they can average out to a grid that is cheaper, more reliable, and less polluting than any single type alone. The question isn’t which technology to use, but what balance. But this question isn’t best answered in the marketplace of ideas. Instead, it should be addressed in the marketplace for electricity.

The market for electricity

In the US and Europe, power grids are largely liberalized: provided they can get the necessary permits, independent developers build power plants, and the local utility is required to connect those plants to the grid. In the United States, 88 percent of large-scale power projects currently in development are privately organized and funded.

The power market is run by the grid operator’s economic dispatch software. Each power plant tells the operator its costs, and the operator commissions the cheapest plants, accounting for transmission constraints. As load increases during the day, the operator keeps commissioning the next cheapest plant. The price of power is set at the marginal cost of the next cheapest plant, and that’s the price every power plant is paid.

Market prices signal to power plant developers about levels of supply and demand. In the same way, prices balance different energy sources based on the strengths and weaknesses of each. For instance, as more solar panels are built, the value (and therefore price) of power during the middle of the day, when the sun is shining most, adjusts downward. From December 2020 to September 2025, maximum solar output in ERCOT increased from 4 to 29.8 gigawatts. And from 2020 to 2025, the value of power at 1pm relative to the highest-priced hour decreased from 92.9 percent to 38.7 percent. As one technology type becomes overbuilt, prices reflect that and developers react accordingly.

The evolving daily price shape in response to the abundance of solar energy was a signal that the grid needed storage capacity, and power plant developers responded. From 2020 to October 2025, ERCOT went from having almost no battery storage to a combined battery discharge of 8.6 gigawatts. The same process has played out in California and many European markets.

One might assume that the price of electricity for consumers is dictated by market forces, like those that regulate supply and demand across different power plants. But to a large extent, it is not. Grid infrastructure, like large power lines, is generally planned by the grid operator, and the cost is passed on to consumers at a price approved by state and federal regulators. In one typical utility territory within ERCOT, the portion of regulated costs on the average residential customer’s bill has grown from 28 percent in 2002 to 40 percent in 2025.

Regulators of all major grids have set caps on wholesale prices in response to public outrage at price volatility. As a result, the generators needed to keep the grid reliable are sometimes unprofitable. Under normal market circumstances, generators would stop running when it wasn’t profitable to do so. Instead, regulators put further policies in place to prevent this. Markets for capacity mean that generators are paid not for energy itself but for committing to be available if there is extra demand. Must-run agreements pay unprofitable generators to keep running if they keep the grid reliable. These are negotiated bilaterally between generators and the grid operator, outside of any wider competitive process.

Policy choices also shift the equilibrium. For example, America’s Inflation Reduction Act gives a $30 tax credit for every megawatt-hour produced by qualifying renewables. Power plants that opt in, typically wind, paradoxically often offer their power at negative prices, making money from the tax credit even when they literally pay consumers to use them. At times, a large enough share of the market offers electricity at a negative price that electricity overall (not just from one supplier) can have a negative price. A similar dynamic is playing out in some European countries.

Despite these interventions, which make them less efficient, markets still find an equilibrium. The interaction of supply and demand creates prices that power plant developers use as indicators for what the market does or doesn’t need more of. If prices are high, new power plants enter. That’s why arguing about the best power generation method is overrated. Well-designed energy markets answer this question automatically. The real bottleneck is connecting to the grid at all.

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Power struggles

xAI’s Memphis data center operated partially off-grid for months. When it first came online in 2024, it could reportedly draw only eight megawatts from the grid (enough to power a few thousand electric toasters). Rather than wait for its grid connection to be upgraded, xAI installed 422 megawatts of on-site gas turbines. Once transmission upgrades were completed, the project would shift to consuming grid power and the on-site generators would be used only for emergency backup.

Such off-grid generation is a temporary solution. Grid power is more reliable and, on average, cheaper. But thanks to the long queue of projects waiting for connection, 62 percent of data centers are considering off-grid solutions, either to get up and running faster or to improve reliability. Google is even exploring the possibility of a data center in space powered by solar panels. Grids connect to new generators and energy-hungry infrastructure only after studying how to do so using an engineering model that simulates power flows during peak load scenarios. If the new infrastructure would cause overloads on any parts of the system, then those elements need to be upgraded. The utility then needs to estimate the cost of those upgrades and build them.

The grid operators who run these studies are typically public bodies charging a small fee on electricity sales to fund their operations without seeking to make a profit. State utility commissions and the Federal Energy Regulatory Commission have determined that grid operators should run the interconnection queue as a first-come, first-served process that is essentially free.

That process is moving very slowly, creating a huge backlog of mostly phantom projects. Every US grid has more power plant capacity waiting to be connected than there are gigawatts of peak demand. The backlog also exists for the separate but similar queue of infrastructure not yet connected to the grid. Across ERCOT, there were 143.5 gigawatts of data centers seeking to connect as of October 2025. This compares to ERCOT’s highest ever total demand of 85.9 gigawatts in August 2024.

This system was designed for a different era. The last time electricity use grew five percent annually or faster was between the 1950s and 1970s, during the adoption of air conditioning, refrigerators, dishwashers, and washing machines. From 2005 to 2023, electricity use was almost completely flat. But as that lull in growth comes to an end, the grid will have to adapt.

Crossed wires

The main flaw of the interconnection process is that it uses a first-come, first-served queue. This means that high-priority requests can spend years stuck at the back of the line behind other less important ones.

Some requests are speculative, submitted by developers before they have ready customers. Some are duplicative, meaning a developer fishing for a good spot has requested to interconnect the same project in multiple locations. These are among the reasons that 72 percent of requests to connect submitted since 2000 were ultimately withdrawn. Other requests are high quality but small and low value. This creates a feedback loop: the harder it is for developers to estimate the cost to interconnect, and the longer they have to wait for an answer, the more speculative requests are made, further clogging the system.

Every major grid has a roughly similar process. The system impact study comes first. The operator models the grid during peak demand conditions and assesses the cost of any necessary upgrades. After reviewing those costs, the interconnection customer (the developers of the power plant or power-hungry infrastructure) decides whether to proceed. Almost 40 percent of withdrawals between 2020 and 2023 were at this stage. If the customer proceeds, the grid operator then determines how to physically connect the project to the grid. Again, it delivers a quote for these costs to the customer, who then decides if they want to proceed. If so, they sign an interconnection agreement, and the utility begins work on the upgrades.

There are some opportunities to automate these workflows, but each request takes time. The median delay from initial request to the interconnection agreement was 34.2 months for agreements signed in 2023.

Another major issue is restudies. Once a system impact study identifies required network upgrades, those upgrades are added to the grid model that’s used to study subsequent projects in the queue. If those upgrades are not built because the earlier project withdraws, any subsequent studies may need to be redone. In one extreme case, a restudy increased a 242-megawatt wind project’s network upgrade costs from $33.5 million to $99 million after the project was already operating.

The slowness of the interconnection queue adds to households’ energy costs. The clearest example of this is found in PJM, which has the slowest queue of the US grids. In 2025, PJM’s electricity suppliers paid $14.7 billion at auction to make sure they’d have enough power to supply their customers, a huge jump from $2.2 billion the year before. Meanwhile, many gigawatts of renewable power projects have been sitting in the queue for five years or more. If just 30 percent of those projects had been interconnected, the auction’s cost would have been 63 percent lower.

Grids have adopted many sensible reforms to the interconnection queue, such as requiring higher deposits to enter the queue and forcing developers to prove they have land to build on and to disclose if they’re making duplicative requests. The most significant reform has been transitioning to cluster studies, which study multiple projects in the same simulation. This reduces restudies because removing any one project has less impact on the overall solution. Clusters also allocate costs more fairly. This prevents a single project triggering a major transmission upgrade that renders it uneconomical. In cluster studies, the cost of these backbone upgrades are shared among all the projects that would benefit from them. While these were necessary reforms, the backlog has only grown as they fail to address the fundamental irrationality of the interconnection process itself: the inflexible first-come, first-served queue.

Tragedy of the commons

In the early 2000s, regulators wanted to level the playing field between new independent producers and incumbents. They worried that utilities might preference their own projects. As there was plenty of spare capacity at the time, the first-come, first-served system seemed both simple and fair.

But today, transmission capacity is a limited resource and independent power producers are thriving. This means there is much less concern around the power of traditional utilities. In response, many grids are proposing mechanisms to allow more valuable projects to jump the queue. MISO, PJM, and SPP, three large grids in the US, have proposed mechanisms to prioritize projects that are most viable or most necessary for the system’s reliability. But these mechanisms are band-aid solutions.

The flood of requests is a typical ‘tragedy of the commons’. Everyone is incentivized to spam the queue with requests. Auctions can fix this.

In the fishing industry, when tradable fishing quotas were introduced worldwide in the 1970s, what had been a mad dash for fish became an orderly and efficient process. Before the quotas, the whole season’s supply was caught in a few days of dangerous, non-stop fishing. Market share went to whoever bagged the fish fastest. Once quotas were introduced, fishers could time their catches with market demand instead of catching everything at the start of the season and then freezing it. And since more efficient fishermen made more money, they were willing to pay more, and quotas went to them rather than the fastest fishers, lowering prices for consumers.

Auctioning new grid capacity could bring similar benefits. The scramble for interconnection would be replaced with an orderly process in which the highest quality projects would get priority. Developers’ bids would reflect both the likelihood that the project will come online and the projected value of the project to the grid if so. Less viable and less valuable projects would be weeded out.

The simplest way to implement an auction would be to create small ‘fast-track clusters’ that receive expedited studies throughout the year. Projects in the regular annual cluster could bid to enter the fast track, and the highest bidders up to some preset number would be admitted. The fast-track proposals recently adopted by some grid operators follow this structure, except that admittance to the fast-track cluster is based on an administrative scoring mechanism, not developer bids. But administrative scoring mechanisms could never capture the subtleties that a developer’s bid would. For example, developers have private knowledge about a project’s chances to get permitted, like whether the site has trees with endangered bird nests or unhappy neighbors generating pushback.

Only connect

Another inefficiency of the current transmission system is that it’s built for peak load conditions that occur only a few hours per year. The rest of the time, much of the grid’s generation and transmission capacity is sitting idle. In 2024, 42 percent of ERCOT’s capacity went unused for half the time.

Building the network upgrades that allow for this very high peak capacity can take years. But new power plants must wait for that construction to be completed before they can join the grid, even though the equipment being constructed will rarely be necessary. A survey of power developers found that transmission construction was the top cause of project delays.

The solution is to let the power plant come online before the upgrades are constructed on the condition that it agrees to turn off during peaks. The power plant doesn’t contribute to the reliability of the system since it won’t be available when the system is under stress. But it will produce electricity the rest of the time, which will lower costs. This is known as energy-only service.

ERCOT has made this energy-only service, also known as non-firm transmission because it implies no guaranteed ability to export or import power, their default. They call it connect and manage. That’s a large part of why projects move through ERCOT’s queue faster than any other grid operator.

But despite being an option in all organized US grids, 87 percent of interconnection requests by capacity opt for the slower firm transmission service. That’s because non-firm service disqualifies power plants from the payments they could otherwise receive in exchange for being available at times of high demand. Other grids could adopt connect-and-manage if they eliminated this payment system and, like ERCOT, raised price caps to allow energy prices themselves to reflect scarcity value. Short of that, they could make non-firm service more popular by allowing generators to apply for firm service after being interconnected on a non-firm basis.

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Can’t we just use less energy?

These proposed reforms would allow fast interconnection of new power plants. But if AI is a race with national security implications, they won’t be fast enough.

The fastest way to increase capacity for new large loads would be to decrease demand from existing sources. Demand reduction is the option energy planners have always reached for in a pinch. The concept of energy conservation originated in the late 1960s as the US power grid faced resource constraints for the first time in its history. Energy conservation became a national imperative. For the first time, utilities began promoting things like turning off lights and using less air conditioning. Christmas lights were framed as being wasteful and unpatriotic, and in 1973 the National Christmas Tree had only a single light.

Yet while short-term crunches can be fought with conservation, they are difficult to sustain, and increased energy efficiency can simply lead people to using more energy for other purposes. What’s more, the vast majority of electricity users are completely indifferent to the real-time cost to produce electricity, because they’re on fixed rates for terms of months or years. The wholesale cost of a clothes dryer load, which could consume four kilowatt-hours, could range from negative $0.12 to $20, but the retail customer always pays $0.64 at the average US residential rate of $0.16 per kilowatt-hour. This creates irrational behavior, like someone starting a load of laundry while the grid teeters on the edge of a brownout. If customers faced prices more closely linked to real-time costs, they would adjust their energy use accordingly. Prices would be more stable and, on average, lower.

Already, we’ve seen that power costs change throughout the day because of the increasing availability of solar power. Some power suppliers offer time-of-use rates that charge a different rate at each hour of the day to reflect what it costs to provide. As these are adopted more widely, the highs and lows of demand will increasingly follow the same daily pattern as wind and solar availability. Few customers think about their bill enough for small price differences to influence their behavior, but their power-hungriest devices, like their thermostat or EV charger, could schedule themselves to automatically run when the cost is lower.

Daily reconfiguration could be helpful. More helpful would be reducing demand during the few hours per year with extremely high wholesale costs, when the grid is under greatest stress. Even without time-of-use rates, customers can give their utility provider control of their most power-hungry devices, and the utility can turn them down during grid emergencies in exchange for a reimbursement on their bills. The US had 30.5 gigawatts of this capacity, called demand response, in 2022. But the headroom this gives is unreliable because participants may override the utility’s control, turning their air conditioning back up if they are too hot, for instance.

That’s what makes batteries, installed at customers’ homes, the ultimate load-managing tool. Electronic devices continue to work as normal in periods of high demand, just switching from grid to battery power. And batteries offset the demand of the entire home, not just one or two devices. Combined with rooftop solar, they can significantly reduce a home’s reliance on the grid, making room for new large loads. Perhaps the greatest advantage of all is that these at-home power resources don’t have to go through the interconnection queue; the installation process takes weeks to months, not years.

But devices like this free up relatively little grid capacity compared to the huge amounts that will be needed to power the AI revolution. They’re also relatively expensive, as the cost of installation has to be repeated on every home individually. Matching the demand of a single two-gigawatt data center, which could be handled by a handful of utility-scale projects, would require installing solar and battery systems at nearly 175,000 households.

The data center trilemma

Most data centers have on-site generators as backup power for if the grid goes down because they need a stronger guarantee of reliability than the grid alone can provide. But this capacity could have another significant benefit.

Like generators, power-hungry infrastructure could come online on a connect-and-manage basis, interconnecting before all transmission upgrades are complete on the condition that it disconnects from the grid during peaks. Instead of turning off entirely, it would switch to their on-site backup power. And just like connect-and-manage lowers grid costs, flexible data centers would also lower costs for consumers by ensuring less capacity sits idle outside of peak usage.

Because grid peaks are brief and infrequent, data centers would have to disconnect for only a few hours per year. One study found that 76 gigawatts’ worth of new loads could be added (across an area covering most of the US) if these new loads were willing to disconnect during just 22 hours per year. And those 22 hours of disconnection aren’t consecutive. Each disconnection would last a few hours at most, meaning that data centers could rely on batteries rather than thermal generation. The National Renewal Energy Laboratory estimates that grid-scale, four-hour batteries can be built for $1,300 per kilowatt, as compared to around $2,500 for combined cycle gas turbines.

Disconnecting from the grid isn’t exactly ideal, but given the constraints, developers face a trilemma: data centers can be large, they can come online quickly, or they can receive firm grid service, but not all three. If large data centers want to come online quickly, they’ll have to be flexible.

The powerful shall inherit

The data center boom has exposed the weakness of Western grids. But these are not the only new source of demand for electricity that we can expect in the coming years. Industrial electrification, hydrogen production, water desalination, heat pumps and air conditioning to cope with climate change, electric vehicles, and perhaps even electric aircraft are all likely to increase demand.

The twenty-first century will belong to those who make the most of these developing technologies. Without sufficient power, this will be impossible. And the main constraint to supplying power-hungry infrastructure is not power generation – it is getting that power where it is needed.

This is a blessing: insufficient power would be a much harder problem to solve. Instead, the solutions are simple. The queue of infrastructure that needs to connect to the grid should become more flexible, allowing fast-track slots to be auctioned so that the most valuable and viable projects can start sooner. And payment systems should reward both producers and large-scale consumers that are willing to disconnect for a few hours per year when demand is highest. These simple fixes can give America a power grid fit for the future.

Chris Gillett is a market analyst in electric power. His views don’t represent his employer.

In Irish mythology, a man forces his heavily pregnant wife, Macha, to race the King of Ulster’s horses on foot. She wins, gives birth to twins at the finish line, and then curses the warriors of Ulster: for nine generations, they will be afflicted with five days of labor pains in times of war.

Childbirth is very painful, as Irish storytellers knew when they described this curse upon the men of Ulster two thousand years ago. For many women, it will be the single most painful experience of their lives, frequently described as ‘excruciating’ and ‘unbearable’.

This pain can last a long time. Laboring women first experience increasingly frequent and intense muscular contractions, which open the cervix (the entrance of the womb) over a period of hours to days, before the baby is finally pushed out through their vagina, a process that leaves many with injuries ranging from minor to severe. In total, labor normally lasts somewhere between five and eighteen hours.

Just because that suffering is natural does not mean it is without consequence. Experiencing significant pain during labor may have enduring effects upon women; it is thought to be a risk factor for developing postnatal depression or PTSD. Women who have had traumatic births can find it more difficult to bond with their new baby and are less likely to have another child.

In Genesis, God tells Eve that ‘in sorrow thou shalt bring forth children’, but today the pain that many women experience in childbirth is effectively optional. Though a number of different pain relief options exist for laboring women, by far the most effective is epidural anesthesia. Epidurals safely remove much of the pain of childbirth for most women, while leaving the mother fully alert for the arrival of her baby.

In an epidural, a flexible tube is inserted under local anesthetic between the spinal vertebrae after the mother has begun having contractions. The analgesic, a combination of local anesthetic, opioids, and occasionally steroids that varies between hospitals, is pumped through the tube directly into the epidural space, located just outside the sac surrounding the spinal cord, where it numbs pain signals from the uterus and pelvis.

This relieves the entire lower body of pain within around half an hour. The analgesic is then continuously infused through the tube; with modern epidurals, a laboring mother can safely increase her dose at any time by pressing a button.

Epidurals have been available in some form for over a hundred years. The first successful spinal anesthesia was given in 1898 by German surgeon August Bier, who termed his method ‘cocainization of the spinal cord’, and two years later Oskar Kreis used this technique to give pain relief to six laboring women in a Swiss hospital. A technique more like the modern epidural, with medicine injected into the epidural space, was developed by Spanish military surgeon Fidel Pagés in 1921, and continuous epidural analgesia for labor was first described in 1931 by Romanian Eugen Aburel.

The modern epidural

When I gave birth to my first child on Christmas Day 2024, I asked for an epidural. Having it placed was uncomfortable, akin to a mild electric shock. But once it began to work, I felt supremely relaxed, napping and drinking tea through what should have been the most painful parts of labor. At one point, I felt some pain on the left side of my abdomen and, with a midwife’s help, turned onto my side, helping the drugs to reach those nerve roots and rapidly stopping the pain.

The epidural did not numb my lower body: I could feel the touch of my husband’s hand, contractions, and the pressure of my daughter’s head. The only missing sensation was pain. That’s because pain fibers are blocked more easily than the larger fibers that carry touch and movement. As I labored, the lack of discomfort was surreal. Perhaps because it was pain-free, I remember my daughter’s birth extremely well. I did experience one unpleasant and fairly typical side effect from the epidural: 20 minutes of shivering and itchiness shortly after it was put in place. But in comparison to what most women go through without an epidural, this seems like a very good deal.

Epidurals have other side effects. They can make birth take longer, by somewhere between fifteen minutes to an hour. In up to 20 percent of women, an epidural causes low blood pressure, though this is generally resolved with simple interventions like repositioning the woman onto her left side or giving her intravenous fluids. In up to 1 percent of women, an epidural can cause a severe headache when the needle is inserted slightly too far, puncturing the membrane around the spinal cord so that cerebrospinal fluid leaks out. This is treated by injecting a small amount of the patient’s own blood near the epidural site, which clots and seals over the puncture.

There is debate over whether or not epidurals raise the risk of an unplanned Cesarean section, but this is probably not the case. In general, establishing a causal relationship here is complicated, as women who have difficult births are more likely to have an epidural. However, one rigorous review from 2018 found that receiving an epidural does not increase women’s chance of a Cesarean section but that it does increase the risk of an instrumental birth, meaning the use of forceps or ventouse (vacuum cup) to help deliver the baby, which is associated with a higher risk of injury to the mother. However, this increased risk of instrumental birth generally does not appear in studies post-2005, possibly reflecting improvements to how epidurals are delivered, particularly the use of lower doses of pain medication so that women retain more sensation, allowing them to push the baby out more effectively.

Having an epidural can also change the way a woman is able to give birth. Moving and walking around during labor can be hampered by an epidural because the medication can make the legs feel heavy and weak, and because of the physical restriction of the epidural tube itself. But hospitals increasingly offer ‘mobile epidurals’, a technique that uses a lower dose of pain medication to preserve feeling in the legs and, thus, women’s ability to move around.

Because the epidural tube is inserted near the spinal cord, a common fear is that it might cause paralysis if misplaced. But this risk is extremely low: a 2009 study looking at serious complications from obstetric epidurals found that among the over 160,000 women who received one in NHS hospitals in Britain between 2006 and 2007, there were zero cases of permanent paralysis.

The final caveat is that epidurals do not work to the same degree for every woman. Up to 13 percent of women need their epidural tube repositioned because it has not provided full relief and around a third experience uneven or patchy pain relief, which may necessitate a higher dose of analgesic. How well an epidural works can also vary based on how quickly a woman metabolizes opioids, how much she moves, and the shape and size of her epidural space. But even women for whom an epidural does not fully work still receive some pain relief. And for most women, breakthrough pain is mild and easily fixable, as it was for me.

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The popularity of epidurals

In many developed countries, epidurals are popular, with the majority or a significant minority of laboring women choosing one, especially if giving birth for the first time. Today, 79 percent of American first-time mothers, 64 percent of Irish first-time mothers and just over 50 percent of Norwegian first-time mothers have an epidural. In France, epidurals are even more popular, with 82 percent of all women giving birth vaginally receiving one.

In poorer countries, use of epidurals is often much lower, due to a lack of awareness among women, cost, and a lack of necessary equipment and staff. In China, 70 percent of women deliver with no pain relief, and the government has targets in place to improve access and so make giving birth better for Chinese women. One report suggests that in India, only around 11 percent of women receive pain relief in labor and awareness is low. A study of 200 pregnant Indian women attending one clinic found that 98 percent did not know it was possible to relieve labor pains and that none had ever heard of anyone using an epidural.

But there are also rich countries where epidurals are not the norm. Only 22 percent of Scottish women and 31 percent of English women receive an epidural for a vaginal birth. This is partly because there aren’t enough anesthetists, but also because British maternity care has a long history of promoting ‘natural birth’ and portraying epidurals as unnecessary or best avoided. In Japan, where there is also an emphasis on natural birth, only around 14 percent of women receive an epidural, though this is a sharp increase from 5 percent in 2018. Epidurals are not covered by Japanese public health insurance. In countries like Britain and Japan, where cost is not a constraint, cultural factors still limit women’s ability to freely choose a painless birth.

Childbirth is as unpredictable and exciting as it is arduous and gruelling. But Macha’s curse has lost its sting: the pain that our female ancestors had no choice but to endure is now avoidable. Epidural anesthesia gives women the choice to safely opt out of what might otherwise be the most painful experience of their lives.

Phoebe Arslanagic-Little researches ways to make it easier for people to start families.

Illustration by Shuyan Chen.

Industrial modernity was invented in the English midlands around the end of the eighteenth century, kicking off an unprecedented global rise in living standards that continues to this day. But what made this revolution possible was a lesser-known political revolution that took place in the previous century: a period known in English history as the Glorious Revolution.

Today, the Glorious Revolution is remembered for having introduced the system of constitutional monarchy, which subordinated the power of the monarch to Parliament. What is really interesting, though, is how Parliament used its new power: to untangle excessively strong and complex property rights, making it possible for the first time for sustained investments to take place in infrastructure and agriculture across England. And unlike in most other political revolutions, this happened almost entirely peacefully and with the consent of the people whose rights were being redrawn.

Fragmented political and property rights have again become one of the Western world’s biggest problems, leading to the ‘vetocracy’ that paralyzes many developed countries. Could we foment a Glorious Revolution of our own?

Multiple scleroses

Seventeenth-century Europe was economically stagnant. Despite intellectual advances like the creation of patent systems, the flourishing of mathematical schools, and the founding of learned societies like the German Leopoldina and France’s Académie des Sciences, the physical world saw only plodding progress.

Agriculture was practically the only game in town. Almost everyone lived in small rural settlements: fewer than ten percent of Europeans lived in towns of more than 5,000 people in 1500. By 1700 this had grown to just 12 percent; and by 1800, to 15 percent. In France, Europe’s most populous country, nearly 70 percent of the workforce worked in agriculture between 1695 and 1790. Germany was similar, and Scandinavia, Russia, Eastern Europe, Southern Italy and Spain were possibly more agrarian.

The default was for countries to continue for centuries with virtually no growth. Spanish output per capita was flat for half a millenium between 1300 and 1800. Other areas saw temporary bursts of growth, followed by stagnation or reversion: Swedish and Portuguese incomes were lower in 1800 than in 1550, and the Italian efflorescence during the Renaissance was followed by steady decline for centuries. Even the Dutch golden age of 1500 to 1680, which saw the Netherlands buck the European trend with a large majority of its population working in industry or commerce and living in towns, was followed by more than a century of relative stagnation.

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Property ownership was so fragmented that nobody investing in improvements could expect to make a return. Splintered ownership of farmland discouraged the adoption of new crops and rotations. Rigid inheritance rules made it prohibitively difficult to invest in improvements to land or infrastructure. Roads were bad because nobody took responsibility for them, hindering the transportation of manure for fertilizer and preventing the trade that would allow different areas to specialize in different crops. Agricultural yields were so low that nearly everybody had to work to produce food instead of in other industries like mining or manufacturing.

Many European states tried to solve these problems, and nearly all failed. The reason was usually the same: monarchs depended on the support of landowning aristocrats and clergy, and those landowners had no confidence that reforms would leave them better off.

In 1746, Spain’s King Fernando VI tried to replace his country’s complex tax system with a single income tax to fund public investment, but was blocked by nobles, the church, and municipal oligarchies. In 1776, French Minister of State Anne-Robert-Jacques Turgot tried to liberalize the property system and replace the patchwork of taxes with a single land value tax, but the Parlement of Paris refused to register his reform edict. In 1781, Austrian Emperor Joseph II abolished formal serfdom, but ex-serfs remained effectively bound until 1848, since the crown enforced landlords’ prerogatives.

Only one country succeeded in modernizing its property rights in this period: England. The Glorious Revolution resolved the conflict between landowners and the Crown by handing the country to the landowners. One might expect this to have produced an oligarchy that jealously guarded its privileges. But the landowners, precisely because they were empowered, did something their continental counterparts could not. They dismantled the fossilized property arrangements that had blocked development elsewhere, and in doing so, set the stage for the Industrial Revolution.

The Glorious Revolution

In 1685, James II ascended the English throne. Several previous kings had faced accusations of covert Catholicism, but James II made no secret of his faith. He appointed Catholics to a range of government posts and tried to assert control of local governments, so that he could appoint the officeholders who oversaw elections to pack Parliament with loyal stooges. All this fueled fears that James was imposing Catholic, absolutist rule. According to one contemporary, at least 20,000 opposition pamphlets were circulated across the country during James’s short reign.

In June 1688, seven aristocrats wrote to William of Orange, inviting him to invade England with their support. William was the Dutch Republic’s head of state, married to James’s eldest daughter, Mary and, crucially, a Protestant. In their letter, the seven wrote that ‘the people are … generally dissatisfied with the present conduct of the Government in relation to their religion, liberties, and properties (all which have been greatly invaded)’.

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William landed at Torbay on 5 November that year with 20,000 Dutch soldiers and English exiles. The English defending army defected or melted away without a fight, and James fled to France, effectively abdicating. William and Mary were crowned as joint monarchs in April 1689.

A new political settlement quickly emerged. Parliament passed a Bill of Rights, reestablishing its own legal supremacy; the Mutiny Act of 1689 forbade a standing army without parliamentary assent; and taxes were decreed to expire after a year, requiring the monarch to call Parliament for renewals. Later acts established regular elections.

Today, this cementing of Parliamentary supremacy is what the Glorious Revolution, as William’s invasion came to be known, is most remembered for. But a second consequence was even more important: dramatically increased legislative productivity.

In the lead up to the Glorious Revolution, James II and his predecessor, his older brother Charles II, had been trying to rule without Parliament, dismissing it before it could pass legislation or simply not calling it. Parliament met infrequently at the end of Charles II’s reign, especially after the Exclusion Crisis of 1679, in which it had sought to pass bills excluding the future James II, by then a known Catholic, from the line of succession. Following this, it did not meet again for nearly all of James II’s short reign.

Before 1688, bills frequently failed because the monarch cut sessions short. After it, Parliament became an extremely active legislature, passing thousands of acts. Before the Glorious Revolution, legislative sessions had been short and variable: the average number of working days per session was 61 between 1660–85 and 57 for 1660–89. While some sessions lasted over 400 days, most lasted fewer than 50. Afterwards, legislative sessions met annually, owing to the requirement to renew military funding and the right to court-martial deserters. They began in autumn or winter and continued for more than 100 days.

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From 1660 to 1689, about 25 acts passed per session. Between 1688 and 1724, the average increased to 50–75 acts per session, rising to over 100 and eventually 200 per session in the late eighteenth century. Access also broadened. Before the Revolution, only the largest landowners brought bills to Parliament. Afterwards, many more minor gentry with no obvious political connections applied. The vast majority of these bills sought to reform landholdings or property rights in some way, either consolidating them, removing legal restrictions on how the land could be used, or allowing developers to charge for access to new or improved infrastructure.

Fragmented ownership

Across early modern Europe, plots of land were small as a result of the traditional open-field system, in which tenant farmers held many small strips of land scattered across different fields, as well as inheritance laws that divided landholdings equally among descendants.

The problems with small fields grew as technology improved, creating the potential for new economies of scale. The horse plough was faster than a team of oxen, but on a farm of many small plots, the ploughman spent more time turning and moving between them, so the advantage was dwarfed by a horse’s greater food cost. Under Russia’s equivalent system, peasants wasted as much as half their time moving between land strips. English farmers faced similar inefficiencies.

Small farms and the open-field system also made it hard to adopt better crops. The medieval three-crop rotation left each field fallow every third year to restore nitrates to the soil. The Norfolk four-course rotation eliminated this dormant period by sowing clover and turnips in the off year, which served equally well to replenish nitrates. But this was almost impossible on shared fields. Turnips and clover were hard to protect from neighbors’ grazing animals, which would not stay within strip borders. And in a fragmented system, anyone who wanted to sow a new crop would have to duplicate the work already shared by those sowing other crops, meaning that switching over required near-universal agreement.

As well as small farms and the open-field system, a third problem was common land: an uncultivated area on which local landowners had the right to graze their animals. The free mingling of livestock made selective breeding difficult, since owners couldn’t control which mated with which. It also meant this land was often overgrazed, since everybody was incentivized to overuse it. Since it was owned collectively, it was difficult to agree to do anything else with it: it could be reorganized or improved only by sending a petition to Parliament showing unanimous support of local landowners. A single holdout could block any change.

Over the century following the Glorious Revolution, Parliament steadily grew more confident in reorganizing land rights, drawing on the legitimacy generated by being elected by, for, and of the landowning classes. It gradually eased the process for enclosing and consolidating landholdings, with petitions eventually needing support only from a supermajority of landowners rather than all of them. By the 1740s, it was passing enclosure laws with 90 percent support of the landowners affected; by the 1750s, 80 percent; and later in the century, 75 percent. The process was formalized in 1801, and the General Inclosure Act of 1845 set up a standing body to enclose remaining fields.

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Enclosure was sometimes acrimonious, since a minority of rightsholders had their property restructured against their will. Some rights to common land were ill-defined, and some people lost them without adequate compensation. On the whole, however, enclosure benefited most people: it made land more productive, and nearly everyone ended up with more valuable holdings than they had before.

Between 1600 and 1815, Parliament passed 3,682 enclosure acts, almost entirely after the Glorious Revolution. This became possible partly because of the government’s increased legitimacy – as government by, for, and of landowners – partly because of the government’s increased legislative productivity – since Parliament sat longer and more predictably – and partly because each reform made sure to have overwhelming local support.

Other countries took centuries longer to solve the fractured land problem. German land was not consolidated until after the Second World War, when millions of acres went through a process like England’s and wheat yields tripled. Taiwan, Korea, and Japan used similar supermajority schemes to consolidate their small fields around the same time as Germany. In early 1900s Russia, Pyotr Stolypin’s land reforms used supermajority petitions by peasant farmers to divide their landholdings, boosting productivity so much that the country became the world’s top grain exporter. The Punjab is the breadbasket of both India and Pakistan in part because both sides consolidated their fields into rational squares, unlike the rest of the subcontinent.

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Modern agriculture requires consolidated fields, and consolidated fields require someone with the power to reorganize landholdings on a large scale. But before 1800, only the English Parliament, armed with new authority after the Glorious Revolution, managed to carry out a successful program of enclosure.

The dead hand of entail

The Revolution also addressed a second problem: the large quantity of land locked up by strict inheritance laws. European aristocratic families were obsessed with preserving their estates in perpetuity, and horrified by the idea that spendthrift heirs might sell, mismanage, or dismember them. They also wanted to provide for family members outside the direct line without splitting the estate, which would eventually destroy the family.

The details varied, but in England this was achieved through a legal device called a strict settlement. These devices guaranteed payments to widows, younger sons, and daughters marrying out of the family, while preventing an heir from mortgaging, subdividing, or selling any of the estate without their own heir’s consent.

Settlements also included an entail, a long list of successors to whom the estate would be passed. These legal devices are well known in fiction: they disinherit the Bennet sisters in Pride and Prejudice and Lady Mary Crawley in Downton Abbey, and drive the plot of The Quincunx.

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Over the 1600s, settlements became increasingly restrictive and harder to break. Conveyancers invented a device that prevented current landholders from undoing the entail. On its own terms, this worked. Large estates tended to be held together. Heirs could not squander their money on gambling and prostitution, and were more likely to marry and have children: owners of entailed estates were nearly 15 percentage points less likely to be childless.

But settlements were inflexible. Landowners could be prevented from selling, mortgaging, or improving their estates without the consent of an heir – even if no heir had yet been born.

This inflexibility could reach absurd extremes. In 1697, Zenobia Hough petitioned the English Parliament for the rights to sell land. Zenobia had a willing buyer, but could not sell her houses, fields, and water mill near Manchester because the settlement gave her husband Daniel the right to manage the property. But Daniel had been missing for 14 years, and no one knew whether he was alive or dead.

An investigative commission in 1829 reported a similar case. A barrister, Hasler Capron, explained that his client had inherited land in 1762 at the age of eleven. The settlement did not include the right to harvest timber. So for 67 years, ‘not a stick [had] been cut’ and ‘all the old trees, with scarcely an exception, [had] become decayed and valueless’.

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This inflexibility left swaths of estates in a bind. An owner might want to mortgage one field to raise the funds to drain others, almost certainly creating a large return. Any conceivable heir would want this too. But if the heirs were underage or not yet born, no mortgage could proceed.

A modern reformer might expect the solution to be simple: abolish entails and grant landowners the freedoms we now take for granted, accepting that many estates would be squandered and tens of thousands of widows and unmarried daughters would lose the stipends promised them.

Parliament, now sitting far more often and able to consider many more proposals than it had before, did nearly the opposite. It heard petitions from both sides, following the longstanding principle of expropriation with compensation, and broke settlements only when the living owner was proposing improvements expected to benefit their heirs as well. Perhaps that is why undoing the property rights of landed elites in this way faced so little opposition, allowing Parliament to pass 3,233 estate acts between 1689 and 1830, each tackling a single estate. These acts clustered around London and the industrializing North West, where the returns from changing land use were highest.

The practical consequences were considerable. In 1695, William, Duke of Bedford wished to build a wet dock on land he owned at Rotherhithe in Surrey, now part of London. His son was dead, which under the old settlement would have prevented any change of use. He and other family members petitioned Parliament, which promptly passed an act vesting the Howland family’s property in trust to raise the necessary funds. The Great Wet Dock (later called the Greenland Dock in the eighteenth century because it was used by whaling ships coming from Greenland) was completed in 1700. It was leased to the South Sea Company in 1725. By 1756 Rotherhithe had three shipbuilding docks; by 1892, eleven, building ships for the East India Company among others.

Estate acts enabled many grand projects. They raised the capital to improve the Bridgewater Canal, often considered England’s first true canal because it did not follow an existing river. The same powers helped finance railways and turnpikes, allowing parts of estates to be sold or repurposed.

Estate acts also helped ‘adventurers’ convert hundreds of thousands of acres of marshy fenland in eastern England into prime farmland. The Grosvenor, Portman, and Bedford families used them to develop Mayfair, Belgravia, and Bloomsbury by selling 99-year leases to developers, long enough to allow them to recoup their costs while eventually falling back into landowner control. Without estate acts, they likely could not have granted leases longer than 21 years.

As with communal land, other European countries failed to solve this problem for decades or centuries. Perhaps a third of the Castile region was entailed by the late-eighteenth century; Spain abolished entails only in 1841. Italy repealed its equivalent in the 1865 Civil Code after unification, and Germany only with the 1919 Weimar Constitution. England’s approach – led by landowners, and taking care to make changes to property rights only when those affected benefited – seemed to lead to much faster reform.

It was possible to fix settlements without landowners’ consent. Napoleon’s Code Civil of 1804 restricted entails on the grounds that they constrained credit, reduced incentives to improve land, and pulled property out of markets. But the top-down approach caused a different problem across the territories where it was imposed: morcellement, the excessive subdivision that entails had been designed to prevent, and the very problem England’s approach avoided.

For whom the road tolls

The Revolution’s third achievement was infrastructure. The division of labor is limited by the extent of the market. Even today, the transport costs of heavy, low-value goods like gravel and sand mean that they are usually produced locally rather than being manufactured at scale in one place and shipped around the country or the world.

This was far worse in early modern Europe, when canals were rare, many rivers were not yet navigable, railways did not exist, and, above all, roads were terrible. In sixteenth-century Spain, wheeled transport was virtually useless; it was faster to travel across open country than to use a road. In late Ancien Régime France, roads were routinely obstructed by quagmires.

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In 1700, English road speeds, which were similar to those on the continent, averaged 2.3 miles per hour in summer and 1.5 in winter. In 1705, the journey from London to Birmingham, a distance of about a hundred miles, took 65 hours. As the historian Cyril Hughes Hartmann put it in 1927, Britain’s roads had been better in Roman times.

The underlying problem was incentives. In the Holy Roman Empire, local governments could charge tolls on roads and rivers. But this led to overcharging without investment. Each stretch had a different authority, and each charged as much as possible while feeling little incentive to improve its own section, since no single section made much difference to the journey as a whole. Timber merchants on the Rhine between Andernach and Dordrecht complained that they had to pay around twenty separate tolls. France and Spain also had dense networks of internal customs gates, including around Paris.

England’s rulers forbade local governments from charging tolls. But this left them with no motivation or ability to improve roads. In both cases, splitting infrastructure into the wrong pieces gave operators the wrong incentives.

Parliament’s solution, after the Glorious Revolution, was the turnpike act. A group of landowners and merchants would form a non-profit corporation, adopt a road, improve it with paving, bridges, and embankments, and charge tolls to cover costs. (Though they could not make profits, better roads increased property income, often by as much as a fifth per acre.) These turnpike trusts usually took over existing roads, though they sometimes added shortcuts and bypasses on new alignments secured through compulsory purchase (eminent domain).

Turnpikes dramatically improved road quality. Muddy tracks were covered with McAdam surfacing (later macadam, and tarmac when combined with tar) or Telford paving. Smoother surfaces meant carriages could be lighter, faster, and easier to pull, needing fewer horses and less fodder.

By 1840, Britain had 20,000 miles of turnpikes, more than twice France’s density of paved road per square mile, and nearly ten times Spain’s. By 1760, average travel speeds in France were half Britain’s. By 1820, British speeds had quadrupled to eight miles per hour, dazzling foreign visitors. Karl Philipp Moritz, a German traveller in England in 1782, called the country’s roads ‘incomparable’, writing: ‘I am astonished how they have got them so firm and solid … A thousand charming spots, and beautiful landscapes, on which my eye would long have dwelt with rapture, were now rapidly passed with the speed of an arrow.’ César de Saussure, a Swiss visitor to England in the 1720s, wrote that the English high roads were ‘magnificent, being wide, smooth, and well kept’.

Road freight costs fell from around 1.2 shillings per ton-mile in 1700 to 0.7 (in 1700 prices) by 1800. Diary surveys confirm that travelers greatly preferred turnpike roads for the smoother, more comfortable journeys they afforded.

A similar model improved rivers and canals. In 1700, freight on navigable rivers like the Thames and Severn cost just 0.12 shillings per ton-mile, compared with 1.2 shillings by road. The problem was that many rivers were shallow and impassable. River improvement trusts dredged channels to open them up to freight traffic, covering their costs through tolls. The total navigable length of British rivers rose from 850 to 1,600 miles by 1750.

Canals were different: they were dug across virgin land and financed by for-profit companies. Four thousand miles of canal were built before 1840, connecting river networks across watersheds and linking industrial towns like Birmingham and Manchester, which lacked natural waterways. By 1850, England and Wales had more navigable waterways per square mile than France, Spain, and Germany.

Together, improvements in roads, rivers, and canals cut transport costs by 75 percent. This enabled a degree of market specialization unseen in the rest of Europe. Manure could now be shipped from where it was plentiful to where it was scarce, on its own raising English wheat yields by a fifth between 1700 and 1840. The Bridgewater canals made Manchester’s industry possible by cutting coal costs there by half.

Regions specialized. Cheshire became a specialist in cheese. Stoke made the nation’s pottery, Burton its beer, and Sheffield its steel. A national wheat market formed, with prices converging across the country. In the 1650s, entrepreneurs in inland Lancashire built a cottage industry, exporting cotton textiles to London and nearby villages. By 1750, and especially by 1800, industries could scale and agglomerate. By 1800, Britain had 95 percent of the world’s cotton spindles, and output had grown more than thirtyfold since the seventeenth century.

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Across the rest of Europe, internal barriers took far longer to dismantle. German river tolls were scrapped by the 1831 Convention of Mainz; other barriers fell with the Zollverein after 1834. Spanish internal customs disappeared with the Mon-Santillán reforms of 1843–45. England solved its tolling problem earlier and more thoroughly by bringing the immediate beneficiaries into government and letting them drive reform.

Gloriouser and gloriouser

One reason the Industrial Revolution happened in England and not France, the Netherlands, or Germany was that its land, infrastructure, and capital markets had already been transformed.

In 1650, it was difficult to raise capital for a factory, or to transport raw materials from mine to factory and finished goods to customers. There was not nearly enough food to sustain the workers to procure these materials at scale. If the steam engine, the gas lamp, and the spinning jenny had been conceived at this time, it would have been far harder for their inventors to manufacture and sell them.

The Glorious Revolution broke these constraints. Agricultural yields rose by roughly 45 percent, while the share of the workforce in agriculture fell from 50 percent in 1600 to 30 percent in 1800. This agricultural revolution, which came as much from efficient institutions as from new technologies, transformed England’s economy, generating surpluses that fed a growing industrial workforce.

A century after William of Orange landed at Torbay, the England of the late eighteenth century was ready for an incredible acceleration of innovation across every sector, from watches to navigation, that would make it the richest country in the world. Had England remained as institutionally sclerotic as the rest of Europe, the Industrial Revolution could not have been as transformative.

A new Glorious Revolution?

Early modern Europe’s property rights held back growth not because they were too weak but because they were too strong and too rigid. Even those who stood to benefit had no power to alter them. Elites across Europe blocked reforms that would have benefited their nations as a whole.

Similar forces are at work today. Incumbents have property and a stake in elaborate regulatory systems that exist, sometimes openly, sometimes quietly, to protect them and their rights. Zoning, historic preservation, judicial review, environmental regulation all serve, among other things, to protect the property values of existing homeowners in the area. European workers hold what amounts to a right to generous compensation in the case of dismissal, which in practice discourages the restructuring that drives innovation.

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As in premodern Europe, the costs of these tangled rights are high enough that many incumbents would actually gain from well-designed reform. In Palo Alto, every homeowner could be paid tens of millions of dollars to accept Manhattan-level density, and developers might still clear hundreds of billions in profit. Danish workers receive extremely generous state unemployment insurance, up to 90 percent of income for two years, in exchange for giving up labor protections, a tradeoff the state can afford thanks to higher growth.

The lesson from the Glorious Revolution is that reorganizing rights is much easier if reformers work with incumbents rather than attempt to override them. A legislature made up of landowners, which sought supermajority approval for change or took care to make sure nearly everyone benefited from major changes, turned out to be far better at radical reform than any absolutist monarch.

These methods still work. Take housing. Small minorities often oppose any change. But building a coalition for development is as possible today as it was for enclosure. Japan, Taiwan, and Korea each used supermajorities of landowners to replan roughly a third of their cities at higher densities with better infrastructure. A very similar scheme, Pinui Binui, delivers many of Israel’s new homes. In the UK, social housing tenants have approved dozens of proposals to demolish and upgrade their own social housing.

While many of today’s challenges are new, a surprising number have been with us for centuries. But so have their solutions.

Kara Dimitruk is Assistant Professor at Hamilton College and Research Fellow at Stellenbosch University.

Ben Southwood is an editor at Works in Progress.

The Coyote Getter, invented in the 1930s, was a hunting device that spewed cyanide into the mouth of any coyote that bit its scented wool bait. Thirty years later, researchers revisited the device. But rather than revamping it to kill more efficiently, they wanted to replace the cyanide payload with something wholly different: a coyote vaccine.

Wild animal vaccines are remarkable for many reasons, but the most remarkable might be that they exist at all. Vaccines are usually tools civilization reserves to defend the humans and domesticated animals within its bounds. The wild, by contrast, is a place from which we extract resources or defend ourselves, or where we simply leave things untouched.

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But defense doesn’t have to be adversarial. Around 60 percent of infectious diseases are zoonotic in origin, meaning they are transmitted from animals to humans, and the majority of them originate from wildlife rather than livestock or pets. Ebola came from fruit bats; HIV from chimpanzees; SARS from horseshoe bats and civets; Lyme disease lurks in deer and mice. In theory, preventing disease at its source in wild populations could protect people better than simply reacting to spillovers when they occur.

Preventing human illness is not the only reason to vaccinate wild animals. Many recent programs have been motivated by conservation, such as efforts to protect bats from white-nose syndrome or koalas from chlamydia. There is also budding recognition that these programs are valuable on welfare grounds, sparing animals from pain and suffering.

Nevertheless, wild animal vaccination first emerged as a form of defense. In the mid-twentieth century, laws mandating the vaccination of dogs pushed down the number of rabies cases in the United States, from 74 reported human deaths across the country in 1921 to single digits per year by the 1960s. The remaining cases occurred overwhelmingly through contact with wildlife: bats, foxes, skunks, and raccoons. But worryingly, the prevalence of rabies in wild animals seemed to be growing, both in the United States and in Europe. To keep rabies contained, researchers had to figure out how to immunize these animals, too.

Sick as a dog

Rabies is a terrifying disease. It is transmitted to humans through bites or scratches from an infected animal, such as a dog, bat, or coyote. The virus travels silently through the peripheral nervous system, taking a month or two to creep up into the brain and spinal cord. Once it infects the central nervous system, an array of alarming symptoms emerge. The ancient Greek physician Hippocrates is thought to have been describing rabies when he wrote of ‘persons in a frenzy [who] drink very little, are disturbed and frightened, tremble at the least noise, or are seized by convulsions’. And when these appear, death is virtually guaranteed within days.

Since rabies doesn’t spread between humans, infecting us only incidentally, it’s far more cost-effective to wipe out the disease reservoir in animals than to vaccinate humans. So developed countries have long implemented public health programs to control its spread from animals to humans: vaccinating pets and regulating their movement across borders, neutering or euthanizing strays, surveilling and investigating cases, and rapidly administering treatment after potential exposure. These early efforts worked. By the 1960s, the US had largely brought dog-mediated rabies under control, reducing the number of cases affecting humans almost twentyfold. In 2007, the canine variant of the rabies virus was officially declared eradicated from the United States, with the last recorded case occurring in 2004. Many European countries had achieved this milestone earlier. The United Kingdom had been free of canine rabies since 1922; France, 1960; and Italy, 1973. Human deaths from rabies are now almost unheard of in rich countries, though it continues to kill tens of thousands of people per year in the developing world.

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But as canine rabies subsided in the West, another problem arose: wildlife rabies. Between 1938 and 1958, the annual number of rabies cases reported in wild animals grew from 44 to 2,075. Part of the reason for this was increased detection, but there also seemed to be a genuine rise in the number of cases. Rabies was spreading in raccoons, skunks, and foxes across the Americas; in Europe, too, a growing number of rabies cases were identified in red foxes, beginning in Eastern Europe in the 1940s and expanding westward. Genetic analysis of rabies strains indicates that outbreaks on both sides of the Atlantic occurred independently of one another. In both cases, the virus is thought to have jumped from dogs into wildlife.

These infected animals endanger any person who comes into contact with them. Every year, around 100,000 Americans are injected with a precautionary course of post-exposure rabies treatment after wild animal bites or scratches. This treatment, first developed in the late-nineteenth century, is thankfully highly effective, but expensive. Post-exposure treatment also works only if administered before the onset of symptoms, and the prospect of needing it is terrifying. The better solution is to control the disease at its source, in the wild.

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By the 1960s, crude methods like culling and sterilizing rabies-carrying wild animal species had shown limited success, despite hundreds of thousands of foxes, coyotes and other animals being killed. These efforts may even have been counterproductive, as they increase contact between humans and animals, and could spread disease between animals in different areas. With elimination impracticable, prevention was the only solution. In 1962, early research into wildlife vaccination began, led by veterinarian and virologist George Baer at the CDC (at the time the Communicable Disease Center; now the Center for Disease Control).

Animal vaccines work in the same way as many human vaccines: killed or attenuated (weakened) pathogens trigger immune responses, teaching the immune system how to recognize a real infection. What’s different, and more difficult, is delivering those vaccines. Foxes don’t check themselves into clinics, and attempting to capture thousands of feral animals living over vast swaths of wilderness would be a logistical nightmare. Delivery methods would have to be designed differently.

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Throughout the 1960s, Baer and his colleagues attempted to solve the distribution problem with imaginative gadgets. The Coyote Getter, as mentioned, was modified to shoot out inactivated rabies vaccine instead of poison. But in field trials, the forceful device often injured animals’ mouths and was unreliable at producing immunity. Another early prototype was CDC veterinarian William Winkler’s Vac-Trap, a spring-loaded needle trap that injected a syringe full of vaccine when stepped on. However, it was expensive, inaccurate, and hazardous. Any animal, or unlucky hiker, could trigger the needle.

The breakthrough came when Baer’s group pivoted to oral vaccination. The rabies vaccine variant used in human post-exposure treatment, where the virus is fully inactivated, must be injected: otherwise, it would be destroyed by the digestive system. But in 1971, Baer’s team discovered that pipetting an attenuated rabies virus vaccine, where the virus has been rendered harmless without being killed, into the mouths of foxes produces immunity. The next step was to package the oral vaccine into something an animal would want to chew.

This concept – live, attenuated virus tucked into a tasty bait – was first field-trialed in Europe. Fox rabies had been advancing westwards across the continent since the 1940s, reaching Switzerland by March 1967. In response, Swiss veterinarian Franz Steck and colleagues built on Baer’s work and began testing a range of vaccine baits, from sausages to dog biscuits to eggs, in the mid-1970s.

Eggs were rejected, as foxes would often save them for later. Sausages and dog biscuits fared better, but the ultimate winner was chicken heads. On 17 October 1978, Steck’s team scattered over 4,000 vaccine-laden chicken heads along the eastern shore of Lake Geneva, creating a barrier against the advancing epizootic. The heads also contained tetracycline, an antibiotic that incorporates into bone and teeth and glows fluorescent yellow under ultraviolet light, allowing researchers to track which foxes had consumed the bait. Within a few years, fox rabies was cleared from the area.

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Following this success, Switzerland scaled up its efforts dramatically. Millions of vaccine baits were distributed nationwide over the next two decades, with individual chicken heads flung onto roadsides and airdropped over the Swiss Alps by helicopter. By 1999, fox-mediated rabies was eliminated from Switzerland entirely.

In the meantime, the US was hit by multiple rabies crises. A raccoon rabies variant had emerged near Virginia in 1977, and spread across the Eastern seaboard over the following decades. To the south, two large epizootics infecting coyotes and gray foxes had spread along the Texas–Mexico border, beginning in 1988. Hundreds of canine rabies cases popped up, and, given rabies’s near-certain fatality, thousands of people faced with potential exposure needed preventive treatment at a cost of around $3,500 per person. Alarmingly, the disease was spreading north towards San Antonio and other major cities. By 1994, the animal outbreaks had become severe enough that Texas Governor Ann Richards formally declared a state health emergency.

Several affected states launched oral rabies vaccination (ORV) programs in response, though with a less grisly bait than deployed in Switzerland. Rather than chicken heads, researchers employed fishmeal blocks covered in fish oil or vanilla. Despite their manufactured, brick-like appearance, these baits proved attractive to hungry animals.

The programs were remarkably successful. The raccoon ORV program halted the westward spread of raccoon rabies, creating a barrier at the Appalachian Mountains that has held for decades. In Texas, every dollar spent on the coyote ORV program saved an estimated $4 to $13 in human treatment – not to mention reducing the risk to human life. By 2008, the state had eliminated the dog-coyote rabies variant. By 2009, the gray fox variant followed. Today, the USDA National Rabies Management Program distributes eight to ten million vaccine baits annually across the US, placed next to dumpsters or in other places raccoons and foxes are likely to frequent, or dropped over large rural areas by plane. The rabies vaccine demonstrated that wild animals could be immunized at scale.

Shielding nature

As the conservation movement grew, the technology found a second application: preserving biodiversity. Wild species have always been threatened by disease, but human activity has exacerbated this. Habitat destruction and climate change have increased crowding in animal habitats and put stress on animals’ immune systems, amping up disease transmission. Humans and livestock also spread disease directly to wildlife, a phenomenon known as spillback.

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The scale of destruction can be enormous. Chytridiomycosis, a fungal disease that infects amphibians’ skin and often fatally disrupts their vital functions, has affected at least 501 amphibian species over the past fifty years, with 90 species going extinct and another 124 declining in population by over 90 percent. In 2015, 200,000 saiga antelopes – 60 percent of the global saiga antelope population – were killed in three weeks by an outbreak of hemorrhagic septicemia, a bacterial infection that triggers sudden internal bleeding. White-nose syndrome is caused by a fungus that invades bats’ skin and disrupts their hibernation, often leading to fatal starvation and dehydration. It has killed over six million North American bats since 2007, with three bat species declining by over 90 percent. Outbreaks like these illustrate how diseases of wildlife, amplified by human activity, can push species toward extinction faster than they can recover or adapt.

Wild animal vaccines are emerging as a promising tool to fight this devastation. In September 2025, Australia approved the world’s first chlamydia vaccine for koalas. While plenty painful and embarrassing for humans, chlamydia is a far more serious threat to koalas, with infections much more likely to cause infertility and often resulting in blindness and death. Disease outbreaks account for upwards of half of all deaths in koalas and are pushing some colonies towards extinction. Alarmed by the threat posed to Australia’s iconic marsupials, Peter Timms, a microbiologist and chlamydia expert at the University of the Sunshine Coast, has spent over a decade leading development of the vaccine.

Distribution, as always, poses a challenge. Since koalas exclusively eat eucalyptus leaves, bait vaccines, like those used for rabies, don’t work. It is feasible, though, to capture koalas. Simply surround a tree with cages, and sooner or later, they will climb down and wander into the harmless traps.

After completing the largest and longest ever study conducted on wild koalas, Timms’s team found that the vaccine reduced the likelihood of developing chlamydia. With vaccines now available for wildlife hospitals, veterinary clinics, and field use, there’s new hope for preventing koala populations from vanishing.

Vaccines for other diseases are still in the pipeline, including vaccines for bats threatened by white-nose syndrome, which wakes them up repeatedly during winter hibernation, draining their stored energy and water until they die from starvation or dehydration. The fungal disease has already killed millions of North American bats, but the stakes extend even beyond their extinction. Many of these bat species are insectivores; without their voracious consumption of agricultural pests and mosquitoes, crop yields could fall and insect-borne disease transmission could rise. For reasons like these, the USGS estimates that bats contribute billions of dollars to the US agricultural economy annually.

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But their insect-based diet also makes vaccine distribution complicated. Bats, like koalas, aren’t tempted by food baits. But they won’t leisurely wander into cages either. So researchers are experimenting with novel delivery methods instead, such as a vaccine gel or paste that could be applied onto roosting bats, which they would spread as they groom themselves and other colony members. Since September 2025, epidemiologists have been actively conducting field trials at a key site in Wyoming, racing to protect bat populations before the disease wipes them out.

Human kind

From airdropped chicken heads to anti-fungal bat gel, scientists have used ingenious methods to adapt human vaccines for animal use. Some of these efforts have already brought impressive successes, protecting humans and preserving animal species. Peculiarly, in all cases, animal welfare itself is considered incidental – a positive side effect. Even with conservation-driven programs, the concern is for populations, not individuals. A species can be considered safe while millions of its members suffer painful diseases and die, as long as the population remains stable.

There’s a growing group of researchers and activists who seek to go further. Disease isn’t bad solely because it threatens a species’s survival but because it causes suffering. Every koala or raccoon that contracts a fatal illness spends days or weeks vomiting, seizing, blind, feverish, or paralyzed. None can hope for treatment. Then, alone and in pain, they die.

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Wild animal vaccines could mitigate such suffering. Vaccines like the oral rabies bait show that it’s possible to effectively improve wild animal welfare, and there are other painful diseases we could prevent, too.

In 1936, the Coyote Getter was invented to kill coyotes with cyanide. Thirty years later, it was retrofitted to administer medicine. The same ingenuity that made us effective predators could also make us effective protectors. Perhaps wild animal vaccines hint at what we’ll ultimately choose to become.

Michelle Ma is chief of staff at a startup.

Illustration by Jenna Barton.

Correction: This article previously stated that a koala chlamydia vaccine decreased mortality by around 65 percent. The cited study was found to have data handling issues that rendered the mortality reduction no longer statistically significant.

You can also watch the rest of the episode on Apple Podcasts, Spotify, and YouTube. And you can buy your copy of Issue 24 here.

European policy debates often become Americanized because of the American domination of social media. This tends to be troublesome, leading Europeans to see their policy problems through frames into which they do not really fit. But it seems to me that the housing debate in Europe, and especially in continental Europe, might actually be improved by borrowing some ideas from the Americans.

Here are some claims that many Americans agree on. They agree that their country has a housing shortage; they agree that it is caused mostly by land-use restrictions, especially zoning, which bans additional housing from being built in suburbs; and they agree that the main cause of these restrictions is suburban NIMBYism. They also think that burdening development with expensive environmental and social obligations often stops them from happening at all by making them economically unviable (they even have a catchy name for this, an ‘everything bagel’). All these claims are, in my view, broadly true.

A huge movement, known as YIMBYism (YIMBY stands for ‘Yes In My Backyard’), has developed around these ideas. It includes great scholars like Chris Elmendorf and Ed Glaeser, remarkable campaigners and thinkers like Brian Hanlon, Alex Armlovich, Nolan Gray, Sonja Trauss, Mike Kingsella, Annie Fryman, Emily Hamilton, Salim Furth and Matthew Yglesias, and a forest of organizations like California YIMBY, the Welcoming Neighbors Network, Abundant Housing Massachusetts, Open New York and YIMBY Action. I was once invited to ‘YIMBYtown’, a national conference of YIMBYs, and watched with astonishment as a huge auditorium filled with delegations representing YIMBY organizations from across the republic.

An increasing number of British people think that these claims are also true of Britain, with a few provisos to which I will return below. But I have repeatedly been struck by how rare the corresponding views are in continental Europe. Continental Europeans are aware of high housing costs, but they are much less likely to discuss a housing shortage, and even if they do, land-use rules are rarely discussed as its primary cause. There is near-total silence on the question of suburban zoning. YIMBYism is virtually nonexistent in continental Europe. When Europeans do debate housing, they tend to argue about rent controls, expropriation, public housing, and environmental regulations.

It is natural to assume that this is because Europe’s housing shortages are much less bad, and hence that Europeans can afford to focus on questions of distribution and quality instead. But this just isn’t true. In fact, European housing shortages are generally worse than America’s. You can see this in the great dataset assembled by Katharina Knoll and her collaborators, of which we have reproduced a selection above. European house prices were roughly flat in the nineteenth and early twentieth century, but they have risen steadily since the Second World War. They are now much higher than American house prices, which remained remarkably stable until recently, and which have only risen rather modestly in the last quarter of a century, though of course much more steeply in a few urban centers like San Francisco and Manhattan. Knoll found that about 80 percent of this increase is attributable to regulatory restrictions on housebuilding.

What restrictions are these, exactly? Cities can grow upwards or outwards. Historically they did both: most housing demand has generally been met through outward expansion, but cities have also densified when geographical constraints, fortifications, or transport limitations have constrained outward growth.

One possibility is that European housing shortages are caused by constraints on outward expansion, being in this respect unlike American ones, where most cities have been allowed to sprawl with little restraint. To some extent, this is certainly true. As British readers will know, England is the pre-eminent example of this. Since the 1950s England has had a system of ‘green belts’, areas around cities where building is forbidden. Many English cities are not really larger today, in terms of spatial area, than they were in 1945.

Many continental cities have constraints on outward growth too, but not to the same extent as Britain. In fact, most European cities have grown a lot since 1945. In the image above, a map of Paris from the 1930s is inset in a satellite image of the city today at the same scale. As you can see, the city’s surface area has grown severalfold. Other European capitals like Rome and Madrid have seen similar or greater expansion.

Even where constraints on outward expansion are tight, however, they cannot be the whole story behind the housing shortage. As is sometimes pointed out in Britain, if densification were allowed, then the great majority of the housing prevented by green belts would be delivered by densification instead. Housing is somewhat more costly to build at high densities than at low ones, so there is some deadweight loss in housebuilding if outward expansion is constrained while densification is permitted. But this effect is far too small to explain the increase in house prices in Europe since 1914, when, after all, most urban continental Europeans lived in flats. So although outward expansion of cities often is more constrained in Europe than it is in America, restrictions on zoning remain of decisive importance. Without densification restrictions, housing shortages will only ever be serious in cities where land is really intensely scarce, as in Hong Kong.

Now, some European countries do not really have low-density suburbia in the American manner. This is especially true of Spain, and it is somewhat true of Italy, Portugal and Greece. Density restrictions will still play a role in these places, since virtually all Mediterranean cities have strict mid-rise height limits across most of their urban areas, but they have a rather different character to those of the United States. In France, Germany, Austria, Switzerland, the Low Countries, Ireland and Scandinavia, however, extensive low-density suburbs exist, very much as they do in the USA. French or Norwegian or Irish urbanism since the 1950s has not been so wildly different in character to American, a fact which people only fail to notice because a greater share of the build stock dates from earlier times.

All of these suburbs are protected by zoning. In fact, zoning was invented in Europe, in Germany and Austria-Hungary, in the late nineteenth century. Here is the zoning scheme for Berlin in about 1905. German cities had a very sharp division at that time between rich suburbs called villa colonies, mostly along the railway lines going west from the city, and the dense and socially mixed urban core. I have marked with ‘V’s all the villa colonies on this map. You will see they all fall into the green-color zoning district, which basically prohibited anything except two-storey detached or semi-detached houses. These plans functioned from the start to protect the rich Berliners who lived in these villa colonies from disruption and loss of social exclusivity.

A hundred and twenty years later, and Berlin’s zoning plan is still doing basically the same thing. The villa colonies are now marked as ‘Wohnbaufläche mit landschaftlicher Prägung’, meaning ‘Residential areas with landscape character’. This zoning district entails much the same restrictions as the green marking did on the 1905 plan. Similar stories could be told for most other European cities.

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Are these restrictions caused by NIMBYism? Europeans are often a bit nonplussed if they are asked this. They have never heard of NIMBY resistance to suburban densification: the villains of YIMBY discourse in the USA are never mentioned in European media or politics. It seems that there is no resistance to densification in Europe, and in a sense this is true. But maybe there is no resistance to densification only because there is no political pressure for it, meaning that the issue never arises and active resistance is superfluous.

This is vividly apparent to me from the case of Britain. There is political conflict about development in Britain, but it is focused, not unnaturally, on the kinds of development that actually happen sometimes: building on fields, public housing regeneration, and urban brownfield sites. Nobody ever talks about suburban densification because it just doesn’t take place. There was a debate about suburban densification when the government briefly enabled more of it in the 2000s (‘garden grabbing’ was the buzz phrase), but after the NIMBYs decisively won, most people forgot the issue, and the NIMBYs went back to being politically inactive members of the public.

I suspect the same is often true in the rest of Europe: NIMBYism is the ultimate reason why the French and German states don’t solve their housing shortages through unbanning densification, but since the claims of the NIMBYs have been preemptively conceded by everyone, NIMBYism has basically remained latent. That doesn’t mean that NIMBYism is the source of all restrictive land-use rules in Europe – when I visited Madrid recently, I got a strong impression that the city’s outward growth is constrained less by NIMBYism than by sheer bureaucratic sclerosis – but it is probably the key factor behind restrictions on densification.

So European cities have housing shortages, and they have zoning designed to prevent more housebuilding in existing suburban areas, and NIMBYism is plausibly the ultimate motivation behind this system. The situation is not really so different to the situation in America. Why don’t Europeans talk about it?

I don’t know the answer to this, but here are a couple of ideas. One possibility is that suburbs are not so dominant in European identity, and so they tend to fly under the radar of European political discourse. This is partly because lots of socially elite Europeans still live in city centers, and partly because of the historical and cultural significance of these areas. I have been particularly struck by this in Paris. Paris has vast modern suburbs of low-density, owner-occupier, single-family houses. Some of these are very wealthy, like Le Vésinet or Vaucresson. But very little has been written about their history or urbanism (even in French), they rarely feature in French literature or film, and Parisians often seem barely aware that they exist. Suburbs are central to modern French life, but their role in modern French identity is incomparably smaller than is the case in the United States.

Another possibility is that European zoning lacks the politically inflamed origins of American zoning. Early American zoning is generally thought to have been motivated partly by racism, when suburban white Americans sought to exclude poorer non-white Americans from their neighborhoods by banning the only kinds of housing that non-white Americans could afford. This brings zoning into direct relation with the most intensely charged issue in American politics. By contrast, European zoning has generally been seen as a technical issue with little emotional valence. (In Britain, indeed, the planning system is left-coded, partly because key elements of it were introduced by the 1945-51 socialist government.)

Those are just conjectures. But whatever the cause of European indifference to zoning reform may be, it might need to change. Europe’s housing shortages are getting worse, and it is unlikely that all European cities will be able to solve them entirely through outward expansion. If Europeans want to meet their housing needs, they will probably have to revisit their zoning systems, just like Americans. If we look at Europe’s housing problems through American eyes, we see them more clearly than we do through our own. The standard critiques made of the Americanization of European policy debates are all generally true. But it seems that housing is an exception.

Samuel Hughes is an editor at Works in Progress.

We’ve been writing regular round ups for a little while now, but so much has happened recently that this month’s post feels like it contains a year’s worth of breakthroughs. So pour yourself something cool, get cosy, and enjoy!

First, everything new in cancer. In our round up last month, we shared the news of daraxonrasib, the new breakthrough drug that roughly doubles survival in late-stage pancreatic cancer, which has long been considered untreatable.

This past week, however, there were results from many more major cancer trials presented at the American Society of Clinical Oncology conference (ASCO 2026), and we wanted to share some highlights.1

One presentation showed 7 year results for lorlatinib, a precision drug for metastatic lung cancers: specifically, a type (ALK-positive) that’s common in non-smokers. You rarely see a survival curve like it. 55 percent of patients were still progression-free after 7 years, versus just 3 percent on the older drug crizotinib.

A new prostate cancer drug, talazoparib, halved the risk of progression when added to hormone therapy, compared to hormone therapy alone, for prostate cancers carrying specific DNA repair gene mutations. Talazoparib belongs to a class of drugs (PARP inhibitors) that have already advanced treatment of breast and ovarian cancers with BRCA mutations. This trial suggests the same strategy also works for prostate cancer.

There was also long-term data on a recent endometrial cancer drug, dostarlimab, an antibody that was approved in 2023. The headline result after 4 years on the RUBY trial was that 58 percent of patients whose tumours carried ‘mismatch repair deficient’ mutations still hadn’t progressed when the drug was added to chemotherapy, versus just 16 percent on chemotherapy alone. That’s a huge difference! The drug is a ‘checkpoint inhibitor’: T cells have built-in ‘checkpoints’ that hold them back from attacking cells unnecessarily, but tumours exploit these to avoid being attacked, so blocking the checkpoint frees the T cells to attack the tumour.

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An early cancer detection blood test, the NHS Galleri blood test, was tested in a large RCT in England with about 142,000 people. The results are a little confusing, so let’s start by clarifying what a ‘good result’ here would look like: detecting non-benign cancers that would’ve missed otherwise, or catching them earlier so treatment could start sooner.

On the first count, it was successful: roughly quadrupling the overall detection rate and cutting cancers caught only at emergency presentation by around a quarter. On the second, it detected some cancers earlier: with a 16 percent rise at stage I–II, and 14 percent reduction at stage IV. But the trial missed its primary goal: there was no significant drop in combined stage III and IV cancers (because stage III diagnoses rose more than expected and roughly cancelled out the stage IV reduction). One way to interpret this – since the largest jump in detection was at stage III and the combined late-stage count barely changed – is that the ‘early’ detection test was mostly catching cancers at around stage III, rather than much earlier. That may still be useful, of course.

And finally, an mRNA cancer vaccine that might actually work. In people with high-risk melanoma, who’ve already undergone surgery, it halved the risk of cancer recurrence or death, compared to Keytruda (the blockbuster cancer immunotherapy drug) alone, in a phase 2b trial over 5 years.

Many previous mRNA cancer vaccines have been doomed by how they pick their targets. They sequence a tumour’s mutations and design the vaccine against the resulting ‘neoantigens’ (newly formed mutant proteins in a cancer cell), but most of those neoantigens are never actually displayed on the cell surface so the immune system can’t recognize them anyway. Melanoma is different: its neoantigens are readily displayed and recognize, which is why drugs like Keytruda already work well against it and why a vaccine has a much better chance of working as well.

Now, let’s move over to non-ASCO2026 news.

The most effective weight loss drug so far. Retatrutide, a new weight-loss drug, led to the largest reductions seen so far: roughly 28 percent loss in body weight at the highest dose in a phase 3 trial. The effect roughly matches the effects of bariatric surgery, where surgeons reduce the size of the stomach and reroute the small intestine so patients feel full earlier.

Retatrutide is an engineered peptide that acts on three receptors at once: the GLP-1 receptor, where it mimics a gut hormone that curbs appetite and slows gastric emptying; GIP, which also dampens appetite and improves how the body handles fats and sugars; and glucagon, which increases energy expenditure. It can do this because the three hormones are evolutionarily related, with similarly shaped receptors, and scientists engineered it as a single peptide that fits into all three of them.

Over the past few years, weight loss drugs have broadened in their effects: from one receptor (semaglutide) to two (tirzepatide) to three (retatrutide). More targets probably means higher efficacy in general, but it’s probably not linearly additive, with each added receptor contributing somewhat less than the last.

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The first in vivo gene editing therapy. A single injection has permanently edited away a rare disease: hereditary angioedema, a rare condition where a genetic mutation causes sudden, potentially fatal swelling attacks. In a phase 3 trial, a single dose of gene editing therapy reduced attack rates by 87 percent relative to placebo, and 60 percent of patients remained attack-free entirely over 6 months.

It’s notable because it’s the first time gene editing has worked inside a living human body (in vivo) in a late-stage trial. Previous gene editing medicines like Casgevy, the first approved CRISPR drug, for sickle cell disease, worked outside the body, ex vivo, meaning they involved removing cells from the patient, editing them in the lab, and replacing them. But this new gene editing therapy packages CRISPR machinery inside a lipid nanoparticle, a tiny fat bubble, that travels through the bloodstream to the liver and edits DNA there directly.

Editing within the body will make the therapy far simpler in the real world than editing outside the body. It’s likely easier to scale up, and opens the door to treating diseases where you can’t easily remove and return cells. For now, the lipid nanoparticle delivery system mostly targets diseases of the liver, but researchers are working to extend it to other tissues like the lungs and eyes.

Permanent gene-editing to reduce cholesterol. Speaking of gene editing: a gene therapy has now been used to permanently edit a gene in liver cells to lower LDL cholesterol. These results come from a phase I trial, in which 35 adults with an inherited disease causing very high blood cholesterol (hypercholesterolemia) or premature coronary artery disease got the therapy.

The therapy, called VERVE-102, is carried by a GalNAc lipid nanoparticle, which delivers it to the liver, where cholesterol is produced. There, the therapy edits the PCSK9 gene. PCSK9 regulates cholesterol levels in the body, typically reducing how much cholesterol is removed from the blood and taken up by liver cells. The way it does this is by binding to the LDL receptor, which grabs cholesterol, and tagging it for destruction, meaning less cholesterol is absorbed from the blood. So, by editing the PCSK9 gene, LDL receptors aren’t broken down as much, more cholesterol is taken up by liver cells from the bloodstream, and blood cholesterol levels are reduced.

At the highest dose, the average reductions were huge: PCSK9 levels fell by 88 percent and LDL cholesterol fell by 62 percent. These changes lasted more than a year, with no observed toxicity at the higher doses. VERVE-102 is possibly a one-off treatment, which is great because around 40 percent of people taking cholesterol-lowering medicines stop taking them regularly.

The target of the gene edit, PCSK9, has actually become one of the most heavily pursued ones in cholesterol medicine. Several recent drugs act on it, including injectable antibodies like evolocumab, which mop up PCSK9 directly, and the oral pill enlicitide. There’s also inclisiran, an siRNA drug that reduces the liver’s production of the protein, which is off-the-shelf and needs an injection just once every six months. The patients who’d benefit most from a one-time gene edit instead of those alternatives are likely not the wider population, but rather people with inherited conditions causing high blood cholesterol, who have a strong lifelong need to reduce their cholesterol and would most value a permanent fix.

An incredible feat of pharmaceutical synthesis. One of the recent drugs that helps patients lower their cholesterol level by blocking PCSK9 is called enlicitide. In a recent phase 3 trial, it lowered LDL cholesterol by an additional 50–60 percent for people already on statins.

Enlicitide is chemically fascinating for two reasons. One is that it’s formulated as a daily pill: all the other PCSK9 drugs on the market, including antibodies like evolocumab, the siRNA inclisiran, and the gene editor VERVE-102, have to be injected. The second is that enlicitide is a synthetic peptide. That’s surprising, because peptides are normally broken down in the gut before they can work. So how can a peptide be taken orally?

Well, enlicitide has an unusual structure. It’s a synthetic peptide made from eight amino acids that fold into a ring. This ‘closed’ shape helps the molecule survive the stomach and get absorbed in the small intestine. But the ring also makes enlicitide hard to manufacture. Some of its amino acids are ‘unnatural’, meaning they don’t appear in nature, so the peptide can’t easily be made by engineered cells, unlike other peptide drugs like semaglutide. And it’s hard to make chemically, too: the original synthesis took 63 reactions, and resulted in very low yields. The main bottleneck is the step where the chain closes into a ring, called macrocyclization.

Now, in a new study, Merck scientists improved the yield massively: with a 14-fold increase (to 70 g/L, at over 99 percent purity) by merging traditional chemistry with enzymes. They split enlicitide into three segments, called Northern, Eastern, and Western. The Eastern and Western parts were easy to make with conventional chemistry, but the Northern bit, which contains the unnatural amino acids, was instead built using enzymes. The team used directed evolution – repeatedly mutating an enzyme and keeping the best-performing ones over successive rounds – to engineer seven enzymes which, together with three natural ones, assemble the fragments and close the final ring. It’s one of the most ambitious feats of pharmaceutical chemistry ever published. And it shows that, even the most complex peptide drugs, made today at low yields, could in principle be manufactured at industrial scale through clever enzyme engineering.

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A cure for some patients with hepatitis B. Hepatitis B is a virus that causes liver damage and liver cancer in middle- and old-age. It’s preventable with birth-dose hepatitis B vaccines, but there are still around 250–300 million people globally who have chronic infections, mostly being infected before the vaccines were introduced.

Hepatitis B infections are particularly difficult to ‘cure’ because the virus has a little mini-chromosome that goes inside the nuclei of liver cells. So even if you destroy all the RNA transcripts, the mini-chromosome lives on and the infection persists.

But new drugs could destroy them. In two phase 3 trials, about 1,800 adults with chronic hepatitis B infections were treated weekly for 24 weeks with antisense oligonucleotides (short strings of nucleotides, called ASOs) or placebo. These ASOs bind to the virus’ RNA transcripts and mark them for destruction by enzymes. Then, the ASOs are recycled by the body.

Interestingly, even though the ASOs target RNA, they also reduce viral DNA, because hepatitis B can only make new DNA by reverse transcription (turning its RNA back into DNA), so cutting off the RNA cuts off the supply of new DNA. It also stops the virus churning out viral proteins like HBsAg, a surface antigen produced in enormous quantities to misdirect our immune cells.

About 20 percent of the patients who received the drug, called bepirovirsen, had a ‘functional cure,’ versus none in the placebo group. Here, a functional cure meant no detectable hepatitis B viral DNA and a loss of HBsAg sustained for at least 24 weeks post-treatment.

Human cells can ‘swap’ DNA with each other. It’s long been assumed that each human cell’s genome is sealed up in the nucleus and evolves independently of its neighbours. A new study finds that isn’t always true. The researchers found that large, chromosome-sized pieces of DNA can move directly from one human cell into another, lodge in the next cell’s genome, and remain functional, getting transcribed into RNA and translated into protein.

How on earth are they doing it? The authors observed DNA passing through ‘nanotubes’, which are thin bridges that briefly form when cells touch. Scientists have known about these for a few decades, and that cells were shuttling things like mitochondria through them, but it wasn’t confirmed that genomic DNA could be transferred through them until now.

To measure it, the researchers grew two batches of human cells together, and tagged DNA packaging proteins in each batch with a different fluorescent colour, one green and one red. They then stressed the cells to break their chromosomes or scatter them during cell division (using mitosis-blocking drugs, radiation, and CRISPR) and filmed what happened. On the time-lapses, they watched DNA of one colour travel down a nanotube into a cell of the other colour.

It’s not yet clear how much this matters in the body. But the authors note it could let genomically unstable cancer cells pass on their mutations to neighbouring cells. If that’s the case, the nanotubes themselves could be a target for cancer therapies.

CRISPR’s ancestors, hiding in bacteriophages. Researchers in Jennifer Doudna’s lab at UC Berkeley, which helped pioneer CRISPR as a gene-editing tool, have found a system that predates CRISPR and described it in two new preprints. CRISPR is a defense system bacteria use to recognize and cut up invading DNA, including from viruses. A subset of its proteins are built around a core structure called a RAMP, which has stayed remarkably constant over many millions of years, even as the genes encoding it have drifted apart. So the team used AlphaFold, the protein structure prediction tool, to hunt for proteins that look like RAMPs but are encoded by unrelated sequences. They found some hidden in bacteriophages, probably as a weapon that they use against rival phages.

They named the system VIPR, and it appears to be older than CRISPR itself. Like CRISPR, it’s guided by an RNA, but it differs in a few notable ways. It doesn’t cut DNA at all; instead it clamps onto a target sequence and silences the gene by physically blocking the enzymes that read it, leaving the DNA unaltered. It also finds that target with an unusual ‘noncontiguous’ code: the guide RNA reads the DNA two bases at a time and skips every third one, wrapping around the intact double helix rather than unzipping it. And it’s tiny: Vipr proteins are only about 180 amino acids, roughly an eighth the size of Cas9, paired with an RNA under 100 nucleotides. That means the whole thing can fit very easily into an AAV vector (often used as a delivery vehicle for gene therapy), and in principle you could pack many of them into a single therapy to fix several genetic errors at once.

A preventive antiviral for Covid-19, finally. The first oral drug to prevent COVID after exposure succeeded in phase 3 trials. It’s called ensitrelvir and is taken as a 5-day course of pills. In a phase 3 trial, people who took it after a household member caught COVID were 67 percent less likely to develop symptoms themselves.

It’s taken a long time to get here. A preventive antiviral pill is scientifically more challenging to develop than an mRNA vaccine, which mostly needs the specific genetic sequence (of the virus’s spike protein) to be identified and swapped in. In contrast, an antiviral like this is a custom-designed molecule that physically blocks a viral protein. That’s exactly why the vaccines were so important: they could be developed quickly, at a time when they were needed most.

Unlike the vaccines, ensitrelvir works by blocking the virus’s protease, a cutting enzyme it uses to mature its proteins. Because the protease mutates far more slowly than the spike protein the vaccines target, the drug should stay effective across naturally circulating variants. It could still face drug resistance over time, but the escape mutations seen so far seem to come at a cost to the virus’s own fitness. It’s worth noting that it’s approved in the US for post-exposure prevention specifically, not as a general pre-exposure prophylactic, and not for treating active infection.

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The first approved PROTAC drug. The FDA approved the first-ever ‘PROTAC’ drug, vepdegestrant, to treat a common form of advanced breast cancer. While most drugs work by blocking a disease-causing protein by binding to a pocket it uses to attach to its natural target, a PROTAC instead just destroys the protein. It’s a two-sided molecule that uses one end to grab the target protein and the other end to grab an enzyme (an E3 ubiquitin ligase) that tags the protein for recycling. This physically brings the two together, so the target protein gets marked for destruction and broken down.

Here, the target is the oestrogen receptor, which drives a common form of breast cancer. The drug treats tumours in which the receptor has mutated to stay permanently switched on and grows despite hormone therapy. In its phase 3 trial, it roughly doubled the time before the cancer progressed compared to the existing drug fulvestrant.

The approach could in principle reach the many disease-causing proteins that have no good pocket to block, which have long been considered ‘undruggable.’ This is just the first approved PROTAC, and many more are likely to come through the pipeline, and change the trajectory of diseases that we consider untreatable today.

What’s behind so much progress?

Part of it is timing: many cancer papers are published to coincide with the American Society for Clinical Oncology’s annual conference. But there’s more beneath that too.

Many new breakthroughs were precision drugs, targeted towards particular genetic mutations and tumours with certain genetic markers. Although the genomic revolution began a few decades ago, some of those advances have taken a long time to make it through the pipeline.

Another part is advances in structural chemistry. Daraxonrasib (the pancreatic cancer breakthrough), enlicitide (the oral PCSK9 cholesterol drug), and retatrutide (the new weight loss drug), for example, came from better understanding of the precise structure of proteins and how they interact with each other.

Both the genomic revolution and structural chemistry have helped researchers understand drug targets better and engineer them, including producing mutant KRAS proteins to find new druggable pockets for the pancreatic cancer drugs, and adapting new platforms, like the mRNA cancer vaccines, for melanoma.

This progress seems like an odd contrast with the cuts we’re seeing to science in the US, including to the National Cancer Institute, which is spending 80 percent less this year than its typical pace. It was responsible for funding fundamental research that eventually led to some of the breakthroughs in this post, including 1980s research into KRAS, which led to new pancreatic cancer drugs, and 2010s research into cancer immunotherapy targeted towards neoantigens, which led to cancer vaccines. The National Heart, Lung, and Blood Institute is also spending around 80 percent less than usual; decades ago, it funded fundamental research on LDL-receptor biology and PCSK9 that brought about cholesterol drugs.

In other words, the breakthroughs we’re seeing today are a lagging indicator of inputs into the pipeline: they reflect choices people made in the past. We’ll only be able to see the gaps created by reduced investment in retrospect, years from now, and see that technology isn’t the only reason for progress; sometimes it’s about the funding, institutions and incentives we create.

Illustration: Bacteriophages at work.

In a corner of the prestigious Kits Point suburb in Vancouver, eleven great towers are beginning to rise from their foundations. This is Senakw (pronounced sen-AHK), a new development owned, managed and championed by the Squamish Nation, an indigenous group native to British Columbia. It will ultimately house 9,000 people, and represents seven percent of Vancouver’s entire projected housing output up to 2033.

Senakw has an unusual history. The land it is built on was home to the Squamish people until they were forced out in 1913. Almost a century later, a court case restored the land to the descendants of those who were expelled, along with almost 100 million Canadian dollars in compensation. Freed from the restrictive planning rules that hold back densification in the rest of Vancouver, the Squamish decided in 2019 to use the land to build apartment blocks that, as well as housing Squamish people, are expected to generate around C$10 billion in income, equivalent to more than two million per person.

This is a story of a dispossessed group that is making the most of a rare and remarkable set of circumstances to generate wealth through upzoning. But it is also a story with relevance all over the world. Senakw shows that when local residents stand to benefit from development, obstacles to housebuilding can be overcome, to the benefit of a much broader group of people.

The village that was lost

The Squamish are one of the Coast Salish peoples, the precolonial inhabitants of British Columbia. Today there are about 4,000 Squamish, and historically, the population inhabited a considerable territory, including the land on which the city of Vancouver was built.

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Wilson Williams, council chairperson of the Squamish Nation, explains that in the precolonial period, the False Creek inlet served as a seasonal gathering place: ‘Senakw was a place of abundance ... It was the mainstay for spring and summer for our people. It was a welcome place for our families during those warm seasons because of the abundance of food’. Salmon, oysters, and berries, key ingredients in Coast Salish cuisine, thrived there. By the 1860s, records suggest it had evolved into a permanent village, featuring traditional Squamish longhouses.

Between 1869 and 1877, eighty acres were allocated by the Canadian government as False Creek Indian Reserve No. 6, more commonly known as the Kitsilano Indian Reserve. Like all reserves, the land was owned by the federal government and held in trust for its indigenous residents, a legal arrangement that would prove crucial more than a century later.

European settlers quickly drove out the existing villagers. The city of Vancouver was incorporated in 1886 and expanded rapidly. Conflict between settlers and natives over space began to worsen. A 1911 amendment to the Indian Act enabled the forced removal of indigenous people from urban areas. Vancouver did not wait: in 1913, the residents of the Kitsilano Indian Reserve village were summoned to meet British Columbia officials under attorney general William John Bowser. They were told they either had to accept a small cash offer for the land or receive nothing. They had no federal representatives to support them, which was unlawful even at the time, and many did not even speak English. Believing they had no choice but to accept, the residents disinterred the remains of their ancestors. Most sailed north to relatives in Howe Sound, and the village was burned.

Contemporary newspaper articles imply that the motive for removal was not primarily financial. At the time, the land was not nearly as valuable as it is now: it sits on the opposite side of the False Creek inlet from the city, and the Burrard Street Bridge that links it today would not be constructed for another twenty years. Instead, newspapers focused on concerns about noise from traditional ceremonies, and alleged immorality and public disorder.

City officials originally intended to designate the land for either courthouses or a public park, but had no fixed plans. The land seizure itself was the primary goal.

After the Squamish residents were evicted, the site was neglected for decades. It ended up being occupied by squatters, who made a living fishing and pulling in logs that floated down the creek. Throughout the 1920s and 1930s, newspapers complained of worsening disorder and mess, as well as the city’s repeated failed attempts to evict the squatters. Ironically, the removal of the original residents in the interest of public order had failed even on its own terms.

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Throughout the twentieth century, the land was parceled up and passed between various public bodies, including the harbor authority, as well as private companies like sawmills and breweries. From the 1940s, it was used by the Royal Canadian Airforce as a storage depot. In 1967, it was eventually turned into Vanier Park and became a museum complex.

The long fight back

The 1911 Indian Act amendment made it easier to expropriate land from indigenous people. Unfamiliar with legal processes and sometimes lacking a working command of the English language, they found the deck stacked against them. But even in 1913, the province’s actions in the Kitsilano Indian Reserve village were not lawful: the land was federally owned, and the province could not acquire it without federal consent. The Crown immediately began efforts to reclaim the land.

The Squamish people also began organizing. Between 1913 and 1923, sixteen local families amalgamated into the Squamish Nation band. But for the first few decades, they were legally prohibited from pursuing their claim to the land.

Wilson Williams’s great-grandfather, Andy Paull, was a young man when the village burned. Selected at a community meeting to learn English and represent the nation’s interests, Paull studied in a Catholic residential school in North Vancouver and was educated as a lawyer. Williams recalls his grandfather telling him that the seizure of the village was the catalyst for the nation’s focus on strengthening their legal capabilities. But indigenous people were legally prohibited from joining the bar unless they gave up their indigenous status, which Paull was unwilling to do. ‘He became an off-the-record lawyer’, Williams explains, helping not just the Squamish Nation but other indigenous people across Canada.

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The Indian Act heavily restricted the ability of indigenous people to seek legal redress over land. Throughout his career, Paull focused instead on advocacy, using his legal skills indirectly to push for the right to launch land claims, a right that was eventually won in 1973.

The eventual breakthrough for the Squamish came from an unexpected direction: academic research. In 1971, anthropologists Dorothy Kennedy and Randy Bouchard began what at first seemed an uncontroversial project: recording historical place names to preserve indigenous peoples’ languages and history. Working with Squamish chief Louie Miranda, they had no idea they were assembling evidence for a legal case that wouldn’t be heard for decades.

Chief Miranda, who had himself been a resident of the Kitsilano reserve, was the Squamish Keeper of the Names, responsible for memorizing ancestral names and history going back generations. Without him, there would have been little to work with.

Following Catholic missionary efforts from the 1840s, almost all Squamish people had converted to Catholicism by 1913. Accordingly, their births, deaths and marriages were usually recorded by the Church. However, Kennedy recalls that ‘the church was reluctant to hand over information’. They did eventually gain access, and not only did they accurately reflect Chief Miranda’s memory, the records also enabled them to ‘bring back hundreds and hundreds of names’, something of great cultural significance in Squamish tradition.

By cross-referencing Miranda’s extraordinary memory against Catholic church records, government surveys, and early anthropological notes, Kennedy and Bouchard could reconstruct not just genealogies but precise information on who lived where. ‘We transcribed all the Catholic records for the Squamish back to 1860’, Kennedy explains. Thanks to the connection between anglicized names in the church record and traditional Squamish names, ‘We could reconstruct where the houses were, who lived there, and their descendants... All of the success was thanks to Chief Miranda’. This painstaking work would prove invaluable in the court battles that began in late 1977, led by Chief Joe Mathias. It took several decades of legal dispute, but the case that turned the tide was decided in 2001: Mathias vs Canada. The case centered on the fiduciary duty of the federal government towards Indian Bands. Several other indigenous groups also made competing claims over the same land.

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One focus was proving that the 1869 residents, when the land was originally set aside as a reserve, were Squamish. The court accepted the anthropological evidence as overwhelming proof, largely because of Kennedy, Bouchard, and Miranda’s meticulous work decades earlier.

Most of the other claims were dismissed by the court, partly due to the statute of limitations expiring. But in order to close the decades of continued legal battles, the federal government came to an out-of-court settlement with the Squamish Nation: it paid C$92.5 million (USD $66.9m) in compensation, which, under the terms of the settlement, would be held in a trust fund for band members. The settlement also included something that received much less media attention at the time, but which has since proven far more significant: 11.7 acres of the original 80 acres of land.

In a ceremony in 2002, the Squamish Nation sailed 28 canoes to the beach in Kitsilano, a symbolic homecoming for the Squamish people. The site did not seem especially valuable: a thin patch of land, approximately half of which lies directly beneath the Burrard Street Bridge in an unusual tri-point shape. With the neighborhood zoned largely for single-family housing, observers did not initially notice its development potential.

The grand bargain

Vancouver is one of the most expensive housing markets in Canada. An average detached house there now costs over C$2 million (USD $1.5 million). Data scientist Jens von Bergmann and UBC associate professor Nathan Lauster estimate that the metro area has 130,000 to 200,000 suppressed households: people doubling up with family or roommates who would live independently if they could afford to. That backlog alone represents six to ten years of recent construction. In 1981, two thirds of 25- to 29-year-olds in Vancouver lived in their own households; by 2021, only a third did. Rental vacancy rates often hover below one percent; vacancy rates in more affordable housing markets, such as Austin, Texas, hover around ten.

This pressure comes in part from Vancouver’s success. Vancouver is Canada’s third-largest metropolitan economy. With its stunning backdrop of mountains and ocean and its mild winters, it repeatedly ranks among the world’s most liveable cities. Accordingly, the metro area adds over 40,000 new residents each year, each needing somewhere to live.

Despite this massive demand for housing, and its dense urban core, most of the city looks as it did decades ago. Vancouver pioneered single-family zoning in Canada: the municipality of Point Grey became the first in the country to adopt such rules in 1922. When Point Grey amalgamated with Vancouver in 1929, the principle spread citywide, although initially in a relatively permissive fashion. In the 1960s, the city briefly experimented with allowing apartment towers in residential areas, but a political backlash voted in a council in 1972 that was more resistant to development. From that point onwards, Vancouver systematically downzoned, restricting building heights and locking most of its land into low-density use. Today, 52 percent of Vancouver’s residential land supports just 15 percent of its homes.

Vancouver never managed to comprehensively reverse the downzoning of the early 1970s, despite the huge pressure on housing affordability since. But it did find a way to permit intensive development in narrow strips, typically along transport corridors, while leaving the suburban expanses largely untouched. The city is dependent on such developments: property taxes are low, so almost half of its C$3.5 billion capital budget comes from developer payments. Through a mixture of fixed development fees and Community Amenity Contributions, which are negotiated during spot rezoning on a case-by-case basis, planners extract funding for parks, childcare centers, and affordable housing units in exchange for permission to build. They aim to capture 75–80 percent of the land value uplift. Because each negotiation process can be lengthy, the city prefers to allocate a small number of highly valuable permits, creating an incentive structure that favors concentrated towers, rather than gentle density across the city.

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The downside is that the negotiation process is slow, expensive, and unpredictable. Von Bergmann notes that planners ‘typically get it wrong – they either charge too much or too little’. Getting it right requires predicting market conditions years in advance. Charge too much and the project is rendered unviable and dies, potentially taking the developer and many jobs down with it. Charge too little and the city misses out on valuable capital spending opportunities. Frances Bula, a journalist who has covered Vancouver planning for decades, describes the practical reality: ‘Big developers just cough up when planners demand.’ Smaller builders, including homeowners wishing to add small extensions to their own houses, lack the resources to play the game.

This system is what is known as Vancouver’s grand bargain, and what leads to the largely untouched suburbs occasionally punctuated with tall, thin towers. The grand bargain generates some income for public spending, while minimizing property taxes and development across most of the city. But the price is paid through worsened housing affordability and the economic costs of suppressed construction.

The mandate to build

After the land at Kits Point was returned to the Squamish Nation, they initially made plans to develop it at low density: two residential towers and some mid-rise offices, barely distinguishable in scale from the commercial buildings that already exist nearby. However, these plans stalled after the 2008 financial crisis, and it took some time for the Nation to return to its development ambitions.

In 2018, the Nation established a development arm, Nch’ḵay Development Corporation, bringing in much-needed expertise in construction. Moving quickly, in April 2019, they formally requested the Minister to order a referendum on the designation of the site, which Squamish people were eligible to vote in. In two votes, they approved the land designation for a mixed-use development, passing with 87 percent approval, and business terms with the development partner Westbank, one of Canada’s largest developers, passing with 81 percent approval. The Nation agreed to a 50-50 partnership with Westbank, though Westbank later sold its shares to OPTrust, which manages one of Canada’s largest pension funds. Despite a low turnout of 27 percent, the votes were considered to give a decisive mandate to the development plans.

But why did designating the land for development require a referendum? The site at Kits Point was returned to the Squamish Nation as reserve land. The Indian Act requires that reserve land be ‘designated’ by the federal government before it can be leased, a process that is considered ‘tedious, expensive and time consuming… with no guarantee of the outcome’, and which makes development difficult. Senakw’s swift progression is a testament to both political will and the Squamish Nation’s effective navigation of the system.

While reserve land can be leased with federal permission, it cannot be alienated from the band, meaning freehold ownership cannot be transferred in any way. This means it cannot be parceled up and sold off. It also means that the land cannot be borrowed against, because securing a loan on land is only possible if the land’s ownership can be alienated in the case of default. Traditional development finance uses loans as residential mortgages. Apartments cannot be sold as condominiums (where each unit is privately owned, like a house, and each owner also has a share of the overall building), but must instead use leasehold, where residents purchase a right to live in a property for a set period of time rather than owning their home outright.

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These restrictions might have made the project impossible without support from the federal government, which agreed to a C$1.4 billion loan through the Canadian Mortgage and Housing Corporation, the largest in the corporation’s history. To work within leasehold constraints, the residential units were earmarked for 100 percent rental.

Yet reserve land also offered a crucial advantage: because it is reserve land, it is exempt from zoning rules which apply to the rest of Vancouver. The Squamish Nation made the decision to ‘maximize economic benefits for the Squamish community’, which, in Vancouver’s housing-starved market, meant maximizing density: 6,000 rental homes plus commercial space. It also meant opting not to impose many of the costly mandates that cities typically require. They maintained the same safety and building standards that other Vancouver developments adhere to, but stripped away height limits, inclusionary zoning, zero-emissions requirements, parking minimums, design panels, and the years of public consultation that other projects must stick to.

Although Senakw is not subject to the normal city zoning rules, it nonetheless required standard public amenities like sewerage connection and transport access, including installing roads through public land. The City of Vancouver could have blocked or severely delayed the project simply by refusing these services, and might have been tempted to, given that the development sidesteps the city’s own planning rules.

Yet the city proved amenable. Kennedy Stewart, Vancouver’s mayor from 2018 to 2022, strongly supported the development and oversaw the signing of a services agreement in 2022. The Squamish Nation agreed to fund the sewerage upgrades, as well as the installation of cycle paths and seawall repairs to reduce flood risk to the neighborhood, paying roughly what they would have for site infrastructure under the standard planning process. They were not, however, required to pay the far larger sums that Vancouver normally extracts from developers to fund other municipal priorities.

Mayor Stewart emphasized to me that Canada’s intensifying political discourse around ‘reconciliation’ was critical. Many dismissed this discourse as performative symbolism, but at Senakw it had practical consequences: ‘Promises about reconciliation forced governments’ hands when it came to enabling indigenous-led developments’. The Squamish Nation’s referendums gave the project a democratic legitimacy that Vancouver’s usual stakeholder consultations rarely achieve. A city government that had spent years resisting modest density increases facilitated a far more ambitious project when backed by a clear community mandate and a compelling moral case.

The financial rewards to the Squamish Nation are substantial. A minority of the homes are earmarked as below market rate housing that will be let out to members of the Squamish Nation. The rest will be let out at market rates. With their 50 percent stake expected to generate up to C$10 billion in rental income over the entire lifespan of the buildings, and around 4,000 members, the project could be worth around C$2.5 million per person. How it will be distributed or spent is as yet undecided.

Beyond Senakw

On just one site, Senakw will provide a year’s worth of housing normally built in the city of Vancouver. It functions as a sort of policy laboratory, showing that cities like Vancouver can build many more homes if the decision-makers allow it.

Senakw also offers two lessons for those of us in other cities who want to get more homes built. The first is about incentives. When the Squamish Nation’s members voted on development, they were voting on their own land, and for the economic development of their own community. They chose to maximize density and limit the costly requirements that cities like Vancouver typically impose on new developments because they would bear the costs of these requirements directly. Yet in terms of quality and safety, Senakw is just as good or better than other new developments built just across the river. But residents voting on their own projects make very different assessments of the value of some of these mandates and vote accordingly. Similar dynamics have appeared in other resident-led ballots such as estate regeneration programs in England, and Israel’s Pinui Binui program.

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The second lesson concerns democratic legitimacy. It is partly a myth that Senakw slipped through a loophole in normal land-use restrictions. The City of Vancouver could have obstructed Senakw by refusing infrastructure connections and services. The federal government could have obstructed it by refusing the land designation or not offering the financing agreement. That both chose not to do so reflects the power of a clear democratic mandate. Governments that spend years resisting modest density increases may nonetheless facilitate ambitious projects when backed by direct community approval and a compelling moral case.

It’s an open question how replicable Senakw’s model is in the rest of Canada. Most reserve land in Canada is not urban; the Indian Act ensured that most such sites were seized long ago. However, ongoing legal battles make the future unpredictable. Indigenous groups may apply to the federal government to convert land they own to reserve status, and at the moment the federal government is amenable to doing so.

Nations may also build on land they own outside of reserves using standard zoning processes. Not far away from Senakw sit the Jericho Lands, a 90-acre site being developed in a joint partnership of the federal government and the Musqueam, Squamish and Tsleil-Waututh Nations. This site is owned on a freehold basis. The overall development plan has been approved through the standard city planning process, although it will require further approvals of rezonings on individual parcels. It is expected to take 25–30 years to deliver around 13,000 new homes, an annual rate much slower than Senakw.

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Whatever lessons cities do or do not draw from Senakw, for the Squamish Nation, the significance extends beyond housing policy. For Wilson Williams, it represents something important: ‘We’re no longer out of sight and out of mind in our own village.’ More than a century after his ancestors were forced to sail away from the burning ruins of their homes, a new generation of Squamish people will return to live where their ancestors once fished for salmon in the abundance of False Creek.

Anya Martin is policy lead at YIMBY Alliance.

Artwork by Nina Bunjevac.

The author would like to thank for their generously given time and expertise: Squamish Nation, Abundant Housing Vancouver, Revery Architecture, Jens von Bergmann, Randy Bouchard, Frances Bula, Dorothy Kennedy, Nathan Lauster, Vanna Orecchio, Kennedy Stewart, Sam Sullivan and Lynn Zanatta.

Each autumn in early modern India, certain men drifted out of the central provinces to take up their craft. Known as ‘Thuggees’, these men were said to be inspired by a bloodthirsty goddess and would attach themselves to a caravan on the road, posing as a merchant glad of the company or a cook looking for work. Days passed, sometimes weeks. The Thuggee played his part and earned the trust of the men he travelled with, and he waited. Then one night, with the camp asleep, he rose from his blanket, strangled his companions with a scarf, knifed each one in the stomach to be sure, and vanished with the caravan’s money. The perfect crime.

The modern vexillology movement works the same way. Give or take the strangling. In 2006 a pamphlet went out to the members of the North American Vexillological Association, enthusiasts who study flags. It was called Good Flag, Bad Flag, by Ted Kaye, and it laid down five principles of good design. Keep it simple, simple enough that a child could draw it from memory. Use meaningful symbolism. Hold to two or three colors that contrast and come from a standard set. No lettering, no seals. And be distinctive, or be deliberately related to flags you share something with. Like most pamphlets from fringe outfits, it sold nothing and lay dormant.

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Then in 2015 the radio host Roman Mars built a TED talk on it, ‘Why city flags may be the worst-designed thing you’ve never noticed’. Millions watched. It remains one of the most watched TED talks ever produced. American flags were wrong, Mars said. Seals on plain fields, that isn’t what a flag is for. Others were too busy. Age was no defense. A flag could have flown for a century and still stand condemned as badly designed.

His favorite target, and Kaye’s, was Milwaukee. Milwaukee’s flag, adopted in 1954, is an utterly mad chaos of city skyline, a ship, a stalk of barley, and various texts and numbers. In the middle, big as a sun, sits a gear. Tucked inside it is a Native American in a war bonnet, lifted more or less from the Milwaukee Braves logo of the day. But if that wasn’t enough, your eye continues to roam across the flag and finds a church, the county stadium, a factory, a lamp, a few houses, a flock of gulls. And just when you thought you had been overstimulated enough, you squint and realize there is a picture of another flag on it. Milwaukee put a flag on its flag.

The flag obsessives began their campaign in Milwaukee, and the city began to trust the thugs in disguise. In 2016 the city government ran a design contest, a thousand-odd entries, and crowned a winner: ‘Sunrise Over the Lake’, by a local designer named Robert Lenz. A golden sun comes up over a blue field, the blue for the lake and the rivers, three thin lines for the city's three founders. It ticks every single one of Kaye’s boxes. But hang on, could it not also be Tulsa’s flag? No, it could be Reno’s. In fact it is so similar to Reno’s that both cities believe the other stole their design.

And the city never adopted it. The council picked the fight up in 2018, dropped it, raised it again in 2024, and kept finding reasons to wait, among them that the original contest hadn’t been inclusive enough. The 1954 design is still the official flag of Milwaukee. Meanwhile the sunrise spread across the city on its own, on t-shirts and stickers and bike frames and beer cans, with no legal standing at all. So upset were the thugs that they have insisted unilaterally that their design, while not official, is the ‘Milwaukee People’s Flag’.

That is the pattern wherever the redesigners get their way. NAVA grade flags like schoolwork, F to A+, and they now sort municipal flag changes into before 2015 and after, a vexillological BC and AD. Pull up the twenty cities they rate highest and they are the same flag. Navy, near enough every one, carrying white and a single hit of gold. A sun or a star. Often a wavy line where a lake or a river should be, now and then a triangle standing in for a mountain. Tulsa, Reno, Topeka, St George. Twenty different American towns, indistinguishable. One flag drawn twenty ways.

Which is the joke. Kaye’s fifth principle, the one the movement hurries past on the way to the part about the child, says ‘be distinctive’. Do not duplicate other flags. By the rubric these people carry into council chambers, their own redesigns fail. They have built a continent of flags so well behaved you cannot tell them apart, and they call it a job well done.

The twenty flags they rate worst are ugly. They are also, every one of them, unique. Belle Glade, Florida, painted an entire landscape into an oval. Nitro, West Virginia, kept a small red figure and a name left over from the explosives plant that built the town. Hideous, the lot of them, and not one you could mistake for anywhere else.

The movement’s base is r/vexillology, half a million of them looking in each week, a fresh municipality in the crosshairs every time. A man watches the talk one evening and by midnight has drawn a new flag for some town of three thousand in Iowa he has never set foot in. The forum encourages him. The design gets refined.

And then they move like the Thuggee. Not marching on anything, just drifting in. A flag nerd turns up at a council meeting wearing the face of a concerned citizen, and somewhere between the sanitation budget and the painting of the municipal fences, asks to speak on the matter of the flag. Nobody else has come. Nobody ever does. He runs through Kaye’s pamphlet from memory, explains in patient detail why the town’s flag is wrong, and the council, who have a budget to pass, defer to the helpful expert and wave through a consultation and a contest. What harm could it do? The town of three thousand never knew what hit it. Milwaukee, which is not a town of three thousand, is where the thing became a decade of trench warfare but in most of these places, the old flag is strangled in the night before anyone can realise.

A fair point cuts the other way, and it should be made before someone makes it for me. Plenty of the old flags were not like Milwaukee. But most did commit the flag obsessive’s greatest held sins, a ‘seal on a bedsheet’ (SOB), illegible from afar and identical to four hundred other city seals on four hundred other navy bedsheets. The flag thugs are right about them in theory: an SOB is never full of character but neither is the minimalist sunrise.

Paul Skallas, who writes as the Lindy Man, calls the instinct ‘refinement culture’. He claims that our civilization has lost its nerve for making new things and instead sands the character off old ones, then calls the sawdust left on the floor progress. Once you are told about refinement culture, it is hard to miss. The car badges that all went flat and wordless within about three years of each other. Every new film in the cinema being an already exhausted intellectual property. And of course the old fashion houses that swapped their idiosyncratic and romantic logos for the same anonymous sans font.

James Scott wrote the book on it, more or less. Seeing Like a State is about taking a tangled reality and making it clean and legible from above, then finding the clean version holds none of what made the thing worth having.

Which brings us back to the Thuggee sneaking through the camp at night, because there is something about them I left out. The strangling cult, the goddess, the scripture that blessed the killings, much of it may never have existed as imperial Britain described it. The more recent histories tell us that the thuggee was a colonial construction, to cover up good old fashioned banditry scattered across central India. Tidied up by an administration into a single category with a scary backstory so it could be cataloged and stamped out. The British did to highway robbery exactly what the refiners do to flags. They took something various and local and difficult, and made it simple enough to draw from memory. Twenty cities, one flag. Stand a man from Tulsa in front of the winning twenty and he could not find his own.

Ned Donovan is a policeman. You can follow him on Twitter.

This piece will not appear in Issue 24 of Works in Progress which arrives with subscribers next week. Subscribe in the next few weeks to receive it, and a further issue, every two months. Want- to subscribe for your business or institution? Check out our recently launched corporate subscriptions.

Multiple myeloma is among the most painful of all cancers. The disease originates in the bone marrow, where a single abnormal plasma cell, one of the blood cells that normally fights against infection, begins to proliferate uncontrollably, crowding out healthy blood-forming cells. In doing so, multiple myeloma destroys the bone from within.

Healthy bone is maintained by a perpetual exchange between osteoclasts, which dismantle old bone, and osteoblasts, which rebuild it. Myeloma disrupts this equilibrium, accelerating the action of osteoclasts and silencing that of osteoblasts – more bone is dismantled and less is rebuilt. The spine is especially exposed: its vertebrae bear the body’s weight and harbor the marrow in which myeloma thrives. As they are eroded from within, the result is a persistent ache, unrelieved by rest and often worse at night. As the disease advances, weakened vertebrae may collapse under the simple burden of standing upright, adding acute fracture pain to a chronic background ebb.

During the twentieth century, cancer treatment rested on three pillars: surgery, radiotherapy, and chemotherapy. Surgery has been used against tumors since antiquity and radiotherapy since the discovery of X-rays in the 1890s. Chemotherapy, the newest of the three, was developed in the 1940s and 1950s, its origins tracing back to observations about mustard gas during the Second World War.

These therapies were developed before anyone understood cancer at a molecular level. Blunt and often brutal tools, they work by exploiting the fact that cancer cells tend to divide faster than normal ones, and then doing something destructive enough to kill dividing cells preferentially. And while these treatments can cure some cancers discovered at an early stage, they offer little hope of a real cure for more advanced or relapsed cases.

Then, in the mid-2010s, a new class of genuinely transformative drugs arrived: immunotherapies. These treatments recruit the body’s own immune system to recognize and destroy malignant cells. The results, particularly in metastatic and relapsed disease, have been extraordinary. Multiple myeloma is one of the cancers that illustrates this most vividly, with the immunotherapy Carvytki, which was first approved by the FDA in 2022 for patients who had returning disease after four or more lines of therapy. Carvykti marks a turning point in the treatment of multiple myeloma for two reasons. First, unlike the conventional approach, in which patients endure continuous cycles of treatment, remission, and relapse for the rest of their lives, it is administered as a single, one-time infusion. Second, it is producing something that has never before been seen in this disease: durable, long-term remissions in patients which had been refractory to several other treatments, raising the possibility of a cure.

But Carvykti matters beyond multiple myeloma. In retrospect, its development story, which began in 2016, was an early signal of a transformation that is only now, a decade later, making headlines: the United States is beginning to lose its dominance in drug discovery to China. The foundational science behind Carvykti was largely American, but the therapy that changed the field came from a Chinese company that moved quickly from idea to patient. If the US does not address the regulatory and clinical-trial bottlenecks that slow the generation of early in-human data, more breakthroughs like Carvykti will be developed elsewhere, weakening the ecosystem on which American biopharma depends.

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The brutality of myeloma treatment

The treatment regimen for multiple myeloma is particularly brutal, even compared to other cancers. Under the newest standard approach, it often begins with months of induction therapy built around four drugs: daratumumab, an antibody that marks myeloma cells for immune attack; bortezomib, a proteasome inhibitor injected under the skin; lenalidomide, an immunomodulatory drug taken as a pill; and dexamethasone, a steroid powerful enough to restructure the rhythm of every week.

Patients come in and out of the clinic for injections, take pills at home and undergo repeated blood tests, living according to a calendar organized around treatment days and recovery days. They also have to contend with the side effects of the medications. Dexamethasone can produce a sleepless agitation followed by a physical and emotional crash. Bortezomib often damages peripheral nerves, causing tingling and a burning pain in the hands. Daratumumab often leads to immune suppression, leaving patients more vulnerable to infections.

For patients fit enough to withstand it, this induction regimen is followed by a stem cell transplant. This begins with high-dose chemotherapy that destroys the bone marrow entirely, followed by weeks of isolation with no functioning immune system and a recovery that continues for months after discharge. This stage is accompanied by repeated infections, extreme fatigue and mucositis, a painful inflammation of the digestive tract lining from mouth to gut. Patients are also profoundly vulnerable to even ordinarily minor pathogens that would pose no risk in a healthy person. After the transplant, the patient still has to do lenalidomide maintenance.

What is worse is that even after this brutal treatment most patients relapse, meaning their cancer returns. For these patients, what follows is further cycles of treatment. Doctors start patients on new combinations of drugs, including proteasome inhibitors and more chemotherapy. While these combinations can lead to remission, the myeloma almost always relapses again, leaving patients with progressively fewer options. Each treatment cycle means a lower possibility of survival.

Then there is quality of life. Many of the therapies for relapsed multiple myeloma are administered with intravenous injections or infusions and are given frequently, even weekly. For most patients, a one-time shot would represent a major improvement for their quality of life, even if efficacy were the same. What if the one-time shot also prolonged survival by years and appeared to cure relapsed cancers completely in a proportion of patients? This is what CAR-T therapies like Carvykti can offer.

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My other car is a T cell

CAR-T therapies make clever use of a patient’s own immune system. T cells, a type of immune cell that can attack tumours, are first extracted from a patient’s blood. Then, they are shipped to a manufacturing facility where they are genetically re-engineered to carry a new receptor on their surface. This is a chimeric antigen receptor, abbreviated as CAR, which is designed to recognize and bind to a specific protein on cancer cells.

The modified cells are then cultured until there are hundreds of millions of them, before they are frozen and shipped back. After a short course of chemotherapy to clear space in the immune system, they are infused back into the patient. From that point, the CAR-T cells are free to seek out cells carrying their target protein and destroy them. Because they are living cells rather than inert drugs, they can persist, proliferate, and continue hunting for months or years.

Multiple myeloma is perfectly suited to this approach for two reasons. First, because multiple myeloma is a blood cancer. Unlike solid tumors which form dense, poorly vascularized masses that T cells struggle to penetrate, myeloma cells circulate through the bone marrow and bloodstream. They are, in the language of immunotherapy, accessible. The same feature that makes blood cancers so difficult to surgically remove makes them unusually vulnerable to a therapy that travels through the blood to find its target.

The second reason comes from a protein called B cell maturation antigen, or BCMA. The fundamental challenge of any targeted cancer therapy is selectivity: the ability to kill tumor cells without destroying healthy ones. Most oncology targets are imperfect in this regard, expressed on tumor cells at elevated levels but present in healthy tissue too, which limits how aggressively they can be pursued. BCMA was first identified in 1992 by a French research group led by Yves Laabi. Laabi’s group were trying to find genes preferentially expressed in mature B cells, but had no idea what use to put their discovery to.

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For most of the decade following its discovery, BCMA sat in relative scientific obscurity: an interesting receptor without an obvious clinical application. But researchers gradually began to understand that BCMA was expressed at high levels on malignant plasma cells in multiple myeloma and that it was largely absent from most other tissues in the body.

In 2013, preclinical data from the lab of James Kochenfelder at the National Cancer Institute showed that BCMA-targeted CAR-T cells were effective against myeloma cells in the laboratory. But what followed illustrates the enormous and often underappreciated gap between a promising laboratory finding and a treatment that reaches patients.

The importance of being llama

Today, there are two CAR-T cell therapies for multiple myeloma in the US market: Abecma, approved in 2021, and Carvykti, approved in 2022. Both target BCMA on the surface of myeloma cells. Yet they arrived by strikingly different routes: Abecma from American research institutions and corporate laboratories in the early 2010s; Carvykti from an early-stage biotechnology company and a clinical trial first conducted in China in 2016. Only later was it licensed to a Western company and eventually brought to global approval.

Of the two, Carvykti is the clear winner. Its story speaks to the outsized role that China’s 2015 regulatory reforms have played in accelerating the country’s path from laboratory to clinic, and to producing medicines that work. Being first to market or doing the fundamental science counts for far less than being the nimblest in getting to the clinic. Carvykti also carries another important lesson for the industry: never underestimate the llama.

The technology developed in Kochenfelder lab was licensed to the biotech start-up Bluebird Bio, which developed it in partnership with the large biopharmaceutical company Bristol Myers Squibb into what would eventually become Abecma, the first CAR-T therapy approved for multiple myeloma. Over 80 percent of patients saw their cancers shrink in the National Cancer Institute’s first-in-human trial, published in 2016. This validated the premise of BCMA targeting and set the field moving.

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Meanwhile, a parallel story was unfolding on the other side of the world. In 2014, a team of Chinese scientists began investigating cell therapies for cancer, initially working in what the company describes as a room the size of a freight elevator. After focusing their research solely on BCMA-targeting CAR-T cells in 2015, Legend Biotech began conducting its first clinical trials in 2016.

Central to their approach was a significant departure from convention. Traditional CAR-T constructs relied on using existing antibody fragments, derived from humans, to seek out and bind to their target protein; in this case, BCMA. Legend took a different path, turning to an unlikely source: the llama. Human antibody fragments almost always bind to at least two targets, meaning that if doctors give a patient too much of the drug, they risk causing side effects associated with the second protein the drug binds to.

Camelid animals, including llamas and alpacas, produce a unique class of antibodies known as nanobodies, which can be engineered to do the work of their much larger human counterparts. Their compact size and remarkable stability allow CAR-T cells armed with them to target tumors more efficiently. CAR-T cells using nanobodies also seem to stay active longer and kill tumors more effectively.

The Chinese researchers enrolled their first patient in a clinical trial in 2016, the same year the American team published their initial results. But they moved fast. By 2017, just a year later, they were presenting stunning data at one of the biggest conferences in the field. The decision to learn from the llamas seemed to have massively paid off.

Xi loves you (yeah, yeah, yeah)

It can take years for enough people in a cancer trial to die to clarify that one treatment is prolonging survival over another, so researchers rely on proxies instead. In the American trial, 80 percent of patients responded to treatment, meaning their tumors shrank to some measurable degree, a result already considered impressive given how much these patients had already been treated, to no avail. The Chinese trial did better: every single patient responded. What’s more, 74 percent of patients in the Chinese trial saw their cancer completely wiped out, compared to 56 percent in the American equivalent.

Such results did not go unnoticed. Within months of the 2017 presentation, Janssen Pharmaceuticals, the pharmaceutical subsidiary of the large American company Johnson & Johnson, was in negotiations with Legend Biotech. In December 2017, the two companies announced a global licensing and codevelopment agreement: Legend got $350 million upfront plus half of any revenue generated in the US, while also contributing to half of the development costs.

After years of clinical development, later-stage trial results confirmed what earlier data had suggested: Carvykti was the superior treatment. In later stage trials, oncologists and regulators switch from looking at how many patients respond at all to looking at progression-free survival, or the length of time a patient lives without their disease worsening or claiming their life. The gold standard is overall survival, but it is also the hardest to measure, requiring trials long enough to capture the full arc of a patient’s outcome. For that reason, regulators often grant approval on the basis of progression-free survival data, with overall survival figures following later as evidence accumulates.

On both measures, Carvykti pulled clearly ahead. In the CARTITUDE-1 trial, its 12-month progression-free survival rate was 76 percent. In the KarMMa trial for Abecma, by contrast, this figure was 55 percent. But what happened afterwards is perhaps even more striking: in the Abecma progression free survival curve, the line falls continuously. By contrast, in Carvykti, the line starts to plateau. Extended follow-up at five years confirmed that 33 percent of Carvykti patients remained disease-free. The significance of this result cannot be overstated. These were patients for whom, on average, four prior lines of therapy had already failed and whose immune systems were heavily challenged.

The CARTITUDE-1 trial results led to Carvytki’s approval in 2022 for patients with myeloma who have failed four other lines of treatment. In 2024 the FDA approved Carvytki in patients who have relapsed after just one prior treatment, on the basis of results from the CARTITUDE-4 trial. Here, Carvykti shows even greater benefits over standard care. The best hypothesis as to why has to do with the fitness level of the patients’ T cells. CAR-T therapies are made from the patient’s own T cells, but those cells wear down over years of fighting cancer and enduring multiple rounds of chemotherapy. Used earlier, after just one prior treatment, the harvested T cells are in far better shape, and the therapy built from them is more effective at fighting disease.

Carvykti is currently being evaluated in clinical trials as a first-line treatment, which means that it would be given to newly diagnosed myeloma patients before any other therapy has been tried. If the trial results are positive, this would be a historic game-changer in how patients are treated, with a one-time injection becoming the standard over the arduous procedure of induction regimen, bone marrow transplant and lenalidomide maintenance.

Kochenderfer's lab at the National Cancer Institute first validated BCMA as a target and ran the first-in-human trial. Most of the intellectual groundwork was largely laid in Bethesda, Maryland, in the US. But the therapy that ultimately reached patients and that is now rewriting the prognosis for multiple myeloma did not emerge from that lineage. This was an early sign that China would become an important force in biotechnology.

Made in China

Just last week, in late May 2026, the New York Times ran an article reporting on a clear shift at ASCO, oncology’s most prestigious annual conference. The stage was increasingly dominated by novel therapeutics developed in China. Global pharmaceutical companies are racing to license Chinese-developed drugs, drawn by a combination of lower costs, faster development timelines and a streamlined regulatory environment. The end result of this is a realignment of where the world’s medicines are being discovered. Roughly half of all major drug licensing deals struck so far this year involve drugs originating from China. What is striking is that this share was nearly zero just a decade ago.

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The Carvykti case should have been an early warning. Already by 2016, the same year Legend began the clinical trial that would first reveal Carvykti’s potential, China had overtaken the United States in the number of cell-therapy clinical trials. The gap has been growing since.

China’s ongoing biotechnology transformation is the product of deliberate industrial policy. The Made in China 2025 initiative explicitly identified biotechnology and advanced medical technologies as strategic national priorities, and a series of targeted policies followed. Among them was the Thousand Talents Plan, designed to draw overseas Chinese scientists back from Western institutions. BeiGene, Innovent, and Junshi, which are now three of China’s leading oncology biotechs, were all founded or are now led by researchers who had trained in the United States before returning home.

Yet perhaps the most consequential advantage China has built lies in its clinical trial ecosystem. Chinese hospitals make extensive use of investigator-initiated trials. These are early-stage studies that allow oncologists to quickly assess whether a drug shows genuine promise. In China, such a trial can be up and running within roughly six months of a patient consultation with an academic oncologist. In the United States, the same process can take eighteen months or more, bogged down by regulatory preparation that includes a lengthy Investigational New Drug application. This is a document that can run to thousands of pages and is laden with a host of requirements which are unnecessary at such an early stage of development.

The most valuable thing early-stage trials enable is iteration. They allow tight feedback between the clinic and the lab. There are countless ways to engineer a better CAR-T cell, and many cannot be evaluated in the laboratory alone. No cell culture or animal model fully replicates the complexity of a human tumor, and AI is unlikely to close that gap anytime soon. We simply lack the training data to capture what tumors are actually like in vivo: their geometry, vascularization and biomechanical properties.

China’s ability to run these trials quickly and at scale gave it a structural advantage in that learning process, whereas the US is currently undermining itself through burdensome manufacturing requirements and regulatory bureaucracy that make early experimentation slower and more costly than it needs to be. The policy world has, belatedly, taken notice of this. A proposal in the President’s 2027 FDA budget would streamline early-stage trials. This a welcome recognition that regulatory friction on early experimentation is a competitive liability. But a budget proposal is not a policy and will remain aspirational unless Congress acts.

For now, American and European pharmaceutical companies largely retain the upper hand in the later stages of clinical development, as shown by the fact that Legend ultimately licensed Carvytki to a large American biopharmaceutical company to get it approved. But the pipeline that feeds those late-stage trials is increasingly Chinese. Such early-stage dominance turned into vertical integration of the entire chain in solar panels, batteries and electric vehicles, and LCD panels. The question is how long Western companies can sustain their advantage at the later stages, when the discoveries that make those stages possible are increasingly being made elsewhere.

Ruxandra Teslo is an editor at Works in Progress. Amol Punjabi is chief product officer at OpenEvidence.

You can also watch the rest of the episode on Apple Podcasts, Spotify, and YouTube.

Cities are often centers of agglomeration, places where people gather to collaborate with one another. But this is not the only reason they exist. Sometimes, cities are chiefly centers of consumption, where elites gather to devour resources extracted from the rest of the country. And occasionally, they are something like prisons, where troublesome social groups are concentrated so that the authorities can keep an eye on them. Many premodern cities, like Versailles, Naples, or Imperial Rome, were a little like this. But perhaps the greatest example was Tokugawa Edo.

Between 1600 and 1868, Japan was dominated by the Tokugawa family. The Tokugawas had prevailed over their rivals after a series of civil wars, establishing a sort of dictatorship known as the Shogunate. They developed a remarkable social system, crafted to preserve their power, and with it, the peace and social stability of Japan. At the apex of this system was the city of Edo (today’s Tokyo), at times the largest city in the world, and one of the strangest urban structures in history.

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The Tokugawa social system

In early modern Europe, most people were tenant farmers, who paid rent to landowners. The state sometimes taxed landowners, sometimes tenants, and sometimes both through consumption taxes. In peacetime, however, the early modern state did not do very much, so taxes generally ran at just a few percent of national income.

The picture in Japan was profoundly different. The peasantry was directly taxed by the government, at rates varying from 15 to 70 percent of the harvest, with 40 percent as a rough norm. The authorities distributed most of their tax receipts to the samurai, a hereditary, quasi-noble class making up about six percent of the population. In both cases, the agricultural surplus ended up in the hands of a leisure class, but the Japanese system was structured very differently, with the surplus reaching the leisure class only through the funnel of public taxation.

Measured by agricultural output, about 15 percent of Japan fell under the direct control of the Shogunate. These were areas that had always belonged to the Tokugawa, or that had been conquered by them during the civil wars. About a tenth of samurai were Tokugawa retainers, who received their stipends directly from the Shogunate.

In about three quarters of Japan, the tax authorities were a different group, the daimyo. The daimyo had originally been the territorial nobility, and in the pre-Tokugawa era, the breakdown of central authority had left them as the effective rulers of their domains. After 1600 the surviving daimyo submitted to the Tokugawa and were rewarded with a role somewhat akin to that of regional governors. There were about 260 daimyo, and about nine tenths of samurai were their retainers.

Urban design as a panopticon for the nobility

The city of Edo played a crucial role in this system. The daimyo were required to maintain mansions in Edo, in which their families were obliged to live permanently. Any act of disloyalty by a daimyo would thus place his family in the gravest peril. Most women of the daimyo class passed their lives as effective hostages of the state, never visiting the domains that their husbands, fathers, and sons governed. The daimyo themselves were also required to spend alternate years or half-years in Edo, bringing with them great crowds of samurai retainers. Edo thus had a dual nature: on the one hand, it was the apex of Japanese society, in which the country’s agricultural surplus was consumed; on the other, it was a kind of prison, in which Japan’s potentially dangerous elites were contained and monitored.

This gave Edo a peculiar demographic and economic character. For one thing, it was enormous. Japanese rice agriculture was extremely productive by premodern standards and generated a huge surplus for the capital’s benefit. Edo’s population seems to have been over a million by 1700, which would make it the largest city in the world at the time: London reached a population of a million only around 1800, while New York did not reach it until 1880.

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It was also extremely top-heavy socially. Unlike the knights of the European feudal system, Tokugawa-era samurai were usually required to live in cities. The Shogun’s own samurai were permanently concentrated in Edo, while each daimyo brought hundreds or thousands of his samurai with him during his years of residence in the capital. This meant that almost half of Edo’s population at any given time were samurai.

The samurai were theoretically a warrior class, but since Tokugawa Japan was at peace, there was little real soldiering to do. Most non-military work was seen as degrading, with the exception of gentlemanly occupations like civil administration and tutoring in calligraphy. Most samurai thus lived as pensioners of the state, deriving the bulk of their income from hereditary government stipends assigned to their families at the start of the Tokugawa era.

Stipends were generous for high-ranking samurai but very modest for the majority: in 1876 the Japanese state calculated that only 5.1 percent of samurai had stipends worth more than 100 yen, equivalent to a little over $4,000 today. The result was that most samurai lived in dignified but extreme poverty. It is a testament to the primacy of status among human ends that, although some samurai surreptitiously took on side jobs to supplement their tiny incomes, very few abjured their rank to take up more gainful occupations openly. Interclass marriages were forbidden, and there was theoretically no process for ennoblement, though some wealthy commoners worked around this by arranging to be adopted into impecunious samurai families.

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The High City

Edo was zoned according to social class, probably the largest-scale use of zoning before modern times. Samurai neighborhoods made up a large minority of the total surface area, concentrated in western areas that came to be known as the High City. Higher-ranking samurai had substantial homes, but most lived in extremely austere conditions: the median family lived in a tiny, two-room rowhouse with no garden and communal latrines.

The samurai shared the High City with the daimyo. Each daimyo was expected to maintain several estates in Edo, including a more compact estate near the Shogun’s castle and a more spacious garden estate further out. These were made up of single-storey buildings connected by covered walkways, set amid exquisitely landscaped gardens. Each estate was surrounded by a perimeter wall broken by just one or two richly ornamented gates. The great expense of all this was, from the Shogunate’s perspective, part of its appeal: the more resources daimyo expended on maintaining mansions and circulating between them, the less remained for fomenting trouble.

These samurai and daimyo neighborhoods made up a substantial majority of Edo’s surface area. In some ways, they foreshadowed affluent American suburbs, though they would have felt quite different at street level. Physically, the closest modern parallel might be elite neighborhoods in countries like South Africa or Brazil, where fear of crime has driven the wealthy behind high walls and electric fences.

In fact, however, Edo seems to have been an unusually safe city, a fact that often struck early Western visitors. Most people had no locks on their front doors. The English writer Isabella Bird wrote that a solitary foreign woman could travel in Japan in ‘perfect safety’ and that she had never encountered ‘a single instance of incivility’, though at home she would often have been ‘exposed to rudeness, insult, and extortion, if not to actual danger’. The walls and gates of the High City may thus tell us more about elite culture and status display than they do about any distinctive security needs.

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The Low City

Much of the rest of Edo’s surface area was taken up with religious complexes and institutional buildings belonging to the Shogunate. The commoners were crowded into the remainder, mostly in riverside areas known as the Low City. Though most commoners were very poor, some were richer than most samurai, and even richer than minor daimyo. Some of the greatest artistic legacies of Tokugawa Japan, like ukiyo-e prints and the kabuki theater, arose from the patronage of this class. However wealthy they might become, however, commoners’ status was axiomatically lower than that of the samurai.

Edo’s commoners worked mostly in providing goods and services to the city’s elite. The city as a whole produced little, consuming resources from the rest of Japan and providing little in return save the arguable gift of government. No international trade took place in Edo: the government was intensely wary of destabilizing foreign influences, and by the late-eighteenth century it allowed only two Dutch and ten Chinese ships to visit Japan each year, all through the carefully controlled port at Nagasaki. (For comparison, about fifteen thousand ships arrived in British harbors from foreign ports annually in the same period.) In this as in other respects, the Shogunate’s political needs had a decidedly fitful relationship to the country’s economic growth: although the political stability that the regime provided certainly did foster prosperity, the steps it took to ensure that stability often stifled it.

The physical form of the Low City was even more remarkable than that of the daimyo neighborhoods. Commoner Edo was divided into some 1,500-2,000 fenced and gated blocks called chō. These were then subdivided into roji, alleys lined with small houses, often also gated. The Low City was thus divided up by many thousands of internal checkpoints, all of which closed at night. Edo was not under threat of attack in the Tokugawa period and the city as a whole was not fortified. The purpose of this immense labyrinth of walls and gates was to control and monitor the movement of the population.

Wealthy merchants lived in substantial houses called machiya, featuring a series of small garden courtyards around which living spaces were ingeniously laid out. In plan, machiya recall the domus house type of the urban middle and upper classes in the Roman Empire. Many machiya must have been rather agreeable houses, and some Japanese people still live in modernized machiya today. Most commoners, however, lived in nagaya, tiny terraced houses frequently built back-to-back. A standard specification for nagaya was 2.7 meters wide and 3.6 meters deep, yielding a total floorspace of only 13.2 square meters.

An enormous number of people were crammed into commoner neighborhoods. The most crowded had 58,000 inhabitants per square kilometer, about twice the population density of Manhattan today. Remarkably enough, however, their dwellings were largely single-storey. This seems to have been required by regulation, in turn motivated by fire risk or by dislike of commoner buildings towering over the mansions of the nobility. Japanese builders were perfectly capable of erecting taller structures, so the fact that these intensely crowded neighborhoods forewent the floorspace that additional storeys could have provided is not least among the paradoxes that Tokugawa Edo presents to history.

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In a way, the Tokugawa system was a success. Japan experienced near-total peace between 1600 and the late nineteenth century, a remarkable achievement for a premodern society and a dramatic contrast to Europe or China, where tens of millions of people died in wars. The Tokugawa succeeded in bribing, blackmailing, and intimidating Japan’s armed elites into a quarter of a millennium of passivity, enabling steady economic growth and a remarkable artistic flowering. One might thus argue that Edo’s apparent parasitism was an illusion. Edo was indeed a gilded prison, but prisons can be useful things.

Still, it would have been nice if Japan had not needed a vast prison capital in the first place. Tokugawa Edo stands as a monument to the power of rent-seekers, producing little and demanding immense resources as a condition of civil peace. It shows how the physical form of cities may be reshaped by these demands, as governments apportion space and limit movement in line with their political needs. These forces yielded a city with tight restrictions on built density and land use, an acute housing shortage, and a huge share of privileged state stipendiaries. Edo is a particularly striking example of these phenomena. But it is far from alone.

Samuel Hughes is an editor at Works in Progress. Follow him on Twitter.

Thanks to Fabian Drixler for generous help.

In the TV miniseries Lessons in Chemistry, chemist Elizabeth Zott presents her research on de novo nucleotide synthesis to a panel of suited and bespectacled colleagues. ‘Unlike the amino study group’, says Zott, ‘we are starting with the basic assumption that DNA, not protein, is the basic foundation of life’. The panel scoffs at this apparently ridiculous claim. The head of her department dismisses DNA as a ‘dead end’ and Zott’s method for making it from scratch as ‘nothing more than a party trick’. Zott’s proposal is rejected.

Zott was a fictional character, but the scientific debate was real. The fact that DNA encodes genetic information is now taught in biology classrooms worldwide, but until the late 1940s it was a fringe idea. Most scientists instead believed genes were made of protein. James Watson and Francis Crick are now household names for discovering DNA’s double helix structure, but the importance of that discovery rested on earlier work establishing that DNA, not protein, carries genetic information. The scientists who made this more fundamental discovery have often been overlooked.

The organisms that enabled this discovery were similarly unexpected: bacteria. At the time, few scientists, even microbiologists, thought that bacteria could offer anything of value to genetics. Many doubted they even had genes! Those primitive blobs swimming under microscope lenses were thought to be nothing more than tiny bags of enzymes – a totally different kind of life. So it came as a surprise when the pivotal discovery of modern genetics emerged not from a geneticist but a microbiologist.

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What parents pass on

Evolution by natural selection requires that organisms inherit characteristics from their parents. Heredity wasn’t a new idea when Darwin published On the Origin of Species in 1859. Farmers had exploited it for centuries, selectively breeding livestock and crops for desirable traits. But neither Darwin nor anybody else at the time could explain how traits were passed down from parents to offspring.

Inheritance was full of mysterious patterns: skin color tended to be a blend of the parents’, eye color could differ from either, and sex only matched one. How could such variation be explained? There were plenty of theories – including Darwin’s own provisional hypothesis of ‘pangenesis’, in which every cell in the body shed tiny particles called ‘gemmules’ that traveled to the reproductive organs and were passed to offspring – but nobody had persuasive evidence to support one over another.

Nobody, that is, except a little-known Austrian monk named Gregor Mendel. Mendel’s experiments with pea plants showed that inheritance depended on discrete factors transmitted from parents to offspring. Some traits, such as peas being wrinkled rather than smooth, could disappear and then pop up again in later generations – an impossibility if traits were a simple blend of both parents. Mendel’s work went unnoticed in his lifetime, but in 1900 three botanists independently rediscovered and confirmed his findings. By 1909 these factors had been given a name: genes. But the original meaning differed significantly from today’s. Wilhelm Johansen, who coined the term, explicitly rejected the idea that genes were physical particles, instead conceptualizing them as a chemical or physiological process.

The geneticist Thomas Hunt Morgan hypothesized that genes might either be a ‘chemical molecule’ or a ‘fluctuating amount of something’, but concluded: ‘I see at present no way of deciding’. By 1933, the confusion hadn’t resolved. Morgan wrote in his Nobel Prize lecture: ‘There is no consensus of opinion amongst geneticists as to what the genes are – whether they are real or purely fictitious’.

A common thread was the assumption that genetic information must be encoded in protein, not DNA. Proteins are made from long chains of simpler molecules called amino acids, joined in sequence like beads on a string. With 20 different amino acids for each position, like letters in an alphabet, even short protein sequences can produce an astronomical number of combinations. Meanwhile, the alphabet of DNA has only four ‘letters’, made from the four simpler molecules called nucleotides that join in sequence to make strands of DNA. Today, a four-letter alphabet may seem luxurious compared to the binary language of computers (1 and 0), but while information theory would eventually come to influence biologists’ thinking, this would not take hold for a few decades more.

Further, the best evidence suggested that the four letters of DNA were present in equal proportion in every organism, and arranged in repeated blocks. Such a monotonous molecule could be structural, but surely not informational. The physicist-turned-biologist Max Delbrück spoke for many at the time when he derided DNA as ‘so stupid a substance’.

For decades, geneticists remained stuck. To establish causality, they needed to show that a chemical induced predictable and hereditary changes in cells. The dream experiment would be to isolate and purify either DNA or protein from one organism, introduce it into another, and observe a heritable change. But living things could not take up genetic material from their environment – or so they thought. That assumption would be overturned by experiments with bacteria.

An unlikely answer

For much of the early twentieth century the study of bacterial variation and heredity was hopelessly confused. As late as 1942, the biologist Julian Huxley excluded bacteria from his theory uniting Mendelian genetics with Darwinian natural selection on the grounds that ‘they have no genes’. It seemed unlikely that bacteria had anything to offer genetics.

Then, in 1928, the British bacteriologist Frederick Griffith published a paper that shocked researchers around the world. Griffith was studying pneumococci, the bacteria responsible for pneumonia, and a promising new treatment called ‘serum therapy’ in which antibody-rich serum from patients who survived an infection could be used to treat others. But subtle differences between pneumococci rendered serum from one infection ineffective against others, so scientists categorized pneumococci into ‘serotypes’ (I, II, III, and IV). A pneumococcus’s type was fixed and inherited: it was genetic. The bacteria also differed in their colony shapes. Some produced smooth (‘S’) dome-shaped colonies, while others were rough (‘R’) and irregular. The S form was virulent and deadly, thanks to a slippery coat that protected it against our immune cells. But the R form, lacking this coat, rarely caused disease.

In his experiment, Griffith combined two bacterial strains that should have been harmless when mixed: live type I bacteria of the rough form, which didn’t cause disease, and heat-killed type II bacteria of the smooth form, which had once been virulent but were now inert. Injected into mice separately, neither was harmful. But together, the mixture proved unexpectedly deadly. Even more surprising, when Griffith isolated bacteria from the dead mice, he recovered live type II smooth pneumococci. Somehow, by coming into contact with the remains of the virulent dead bacteria, the harmless live bacteria had been ‘transformed’ to match the dead ones. And this change was not temporary: the transformed bacteria continued to produce descendants of the same type as they multiplied. It was heritable.

Immunologists were initially skeptical of Griffith’s work. Perhaps some small fraction of the virulent pneumococci hadn’t really been killed? But soon the experiment was confirmed independently by labs around the world.

Among those struck by Griffith’s experiment was Oswald Avery at The Rockefeller Institute. For 20 years, Avery had studied the immunology of pneumococci. After reading Griffith’s paper, he assigned trainees to investigate transformation. One was JL Alloway, who showed that transformation could also be brought about in vitro with chemical extracts from the killed smooth cells. By dissolving living cells and filtering out cellular fragments, Alloway extracted the ‘thick syrupy precipitate’ that contained whatever it was that was causing bacteria to change serotype. This mixture became known as the ‘transforming principle’.

Solving the puzzle

Avery had shown that the transforming principle caused hereditary changes. That meant it contained genes. If he could isolate the component responsible for transformation and determine its chemical composition, he’d finally have an answer to the long-sought question of what genes were made of.

But on the precipice of a major scientific breakthrough, progress suddenly stopped. Avery was diagnosed with Graves’ disease, a thyroid condition that exhausted him and gave him a tremor that made it difficult to perform experiments. After having his thyroid surgically removed he spent months recovering; when he finally returned to work, he shifted his research focus to newly discovered antibiotics.

When Avery came back to the question of the transforming principle eight years later, the field was largely unchanged. Why no other group swooped in during his absence remains a mystery. Perhaps geneticists were uninterested in working with bacteria, or bacteriologists had prioritized practical research into vaccines and antibiotics.

Whatever the reason, Avery began by refining the method to extract the transforming material with the help of scientists Colin MacLeod and Maclyn MacCarty. Their new process required vast quantities of bacterial culture: 75 liters of broth teeming with bacteria to obtain just 10 to 25 milligrams of transforming principle. They adapted a steam-driven kitchen cream separator to separate bacterial cells from the broth. Obviously, the device was not intended for handling pathogenic bacteria. Tiny gaps in the seals meant that its use filled the room with an invisible mist of potentially lethal pneumococci. Avery’s team had to construct a vessel that could contain and sterilize the machine before opening. The cake of bacteria it collected had to be handled with towels soaked in germicide, and the recovering Avery left the lab whenever it was being used.

Through this effort, the team purified a substance that had rich transforming activity. It contained a mixture of polysaccharides, proteins, RNA, and DNA. Next, they needed to work out which of these was responsible for transformation. Adding enzymes that inactivated proteins or polysaccharides did not stop the bacteria from transforming. But when they added an enzyme that destroyed DNA, transformation no longer occurred. That meant the transforming principle, and therefore the gene, was DNA.

The mood in the lab was electric. But Avery knew it would be an uphill battle to convince others that DNA, not protein, was the genetic material. Opponents would argue that minute traces of protein remained and these were what accounted for the transforming activity. Since it was impossible to prove a negative (that the samples were protein-free), Avery aimed to gather as much evidence as he could: chemical composition, enzyme inactivation, centrifugation, electrophoresis, and ultraviolet absorption. Every result converged on DNA.

In a letter Avery wrote to his brother, he overflowed with excitement about the implications of his discovery. ‘It touches genetics, enzyme chemistry, cell metabolism and carbohydrate synthesis, etc.’ But in his public addresses, he was cautious to a fault. ‘It’s lots of fun to blow bubbles – but it’s wiser to prick them yourself before someone else tries to’.

Avery, MacLeod, and McCarty’s paper was published in 1944. Reflecting Avery’s caution, the word ‘gene’ does not appear in the title, summary, or conclusion, and the paper ends by acknowledging that minute amounts of contaminants nevertheless could be the true source of the transforming activity. But the conclusion was unmistakeable: genes were made of DNA. The response to the paper was mixed: many praised Avery’s work, while some critics argued that contamination by protein could explain the results. But the burden of proof now rested on them to identify such a protein, and nobody was able to do so.

The molecule that changed everything

Avery’s experiment not only settled the question of the physical nature of genes, but also made it possible to ask a hundred more. How does DNA encode genetic information? Do other living organisms also use DNA, or just pneumococci? What is DNA’s molecular structure, and how does it replicate itself?

Hundreds of papers would be published on the nature of DNA over the following decades. Their authors are among the most celebrated scientists of the twentieth century, including the Nobel laureates Joshua Lederberg, who studied how bacteria can exchange DNA; Alfred Hershey and Martha Chase, who demonstrated that DNA, not protein, is transferred from bacteriophages to bacteria during viral infection; and of course Watson and Crick, who discovered the double helix structure of DNA.

Avery however never received a Nobel Prize, despite having been nominated 38 times. The Nobel committee, unaccustomed to Avery’s ‘restraint and self-criticism bordering on the neurotic’, as described by his protégé René Dubos, perhaps decided it best to wait for further confirmation. But Avery was already 65 when he published his DNA work, and died 11 years later; Nobels are not awarded posthumously. Avery’s work has received less notice than that of other geneticists, in large part because he never received science’s top prize. Nevertheless, it is the foundation upon which the last 75 years of genetic and biomedical research has been built.

DNA now dominates all facets of biomedical research. But perhaps the most important consequence of Avery’s investigations has been the recognition that all living things on Earth – from deep-sea algae to high-flying birds, sharks to iridescent beetles, disease-causing bacteria to humans – store their genes in the same way: in the twisting strands of DNA.

Kevin Blake is scientific editor at Washington University in St Louis.

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