Radiolab - The Dirty Drug and the Ice Cream Tub

Episode Date: May 21, 2021

This episode, a tale of a wonder drug that will make you wonder about way more than just drugs.   Doctor-reporter Avir Mitra follows the epic and fantastical journey of a molecule dug out of a distant patch of dirt that would go on to make billions of dollars, prolong millions of lives, and teach us something fundamental we didn’t know about ourselves. Along the way, he meets a geriatric mouse named Ike, an immigrant dad who’s a little bit cool sometimes, a prophetic dream that prompts a thousand-mile journey, an ice cream container that may or may not be an accessory to international drug smuggling, and - most important of all - an obscure protein that’s calling the shots in every one of your cells RIGHT NOW. This episode was reported by Avir Mitra and was produced by Sarah Qari, Pat Walters, Suzie Lechtenberg, with help from Carin Leong and Rachael Cusick. Special thanks to Richard Miller, Stuart Schreiber, Joanne Van Tilburg, and Bethany Halford. Support Radiolab by becoming a member today at Radiolab.org/donate.  **This episode was taped prior to the news that David Sabatini was fired from The Howard Hughes Medical Institute and prior to his resignation from the Whitehead Institute. More information about Sabatini’s alleged misconduct and the investigation into his behavior can be found here.

Wait, you're listening to Radio Lab from WNYC. Hey I'm Lative Nasr, this is Radio, and this week our story comes from Hey Latte. Hi. A Vir Mietra, who is one of our contributing editors. A Vir after a stint as a Radio Lab intern, and then as an international rock star, became an emergency room doctor. Actually during the height of the pandemic, tensions are high today. March 26, 2020.

He brought us a gripping portrait of his ER under siege. All the ICUs are silent. Today's story is not about COVID. It's a lot less scary, a lot more fantastical. It's about dirt, dueling statues, and a secret molecule that stops time. It might even reverse it. So a lot of times I'll be working in the ER and, you know, we have just so many meds going into somebody, so many different drugs going through an IV.

And sometimes I just step back and I think like, where did these come from? Like, how did this drug end up here in my hands going into this patient? It's like a relay race, you know? And this baton has been passed forward and forward, and I'm the last guy, and I'm putting it into the patient. But I don't really even know, like, how far back did this baton go? So sometimes I go home and at night I'll look it up. And most times, honestly, it's just whatever. But recently I was looking into one of the drugs that we see pretty often in all these different contexts in the hospital and

Ever since I looked it up I've been obsessed. I think it has the craziest back story. I've ever heard for a drug All right, we are recording. Okay, so it starts with this guy name Ajay. My name is Ajay Segal and the last name you could pronounce it Segal Segal Segal So back in 1982. I remember exactly where I was. I was in Germany serving with the Canadian forces. His family was back in Montreal. And one day, it was just, it was around Christmas time, actually.

I got a telegram saying, Dad and I are moving to the United States. Stop. Your room is packed. Stop. We'll leave your stuff with Chacha. Stop. Chacha is my father's younger brother. And I go, what? Why are you moving to the United States? Well, what happened was my husband's friend deceived the notice that you will be moving to Princeton, New Jersey. This is Ajay's mom Uma Uma Segal and she says her husband Seren was working for this drug company Hears, Meccana and Harrison and out of nowhere one day they say we're shutting down our mantra alabs

Like if you want to keep your job you got to move to New Jersey So you know my parents are moving Ajay is a good son. He comes home to help them move the day We had to move was very cold cold cold freezing day my girlfriend and I were helping to help them move. The day we had to move was very cold, cold, cold, freezing day. My girlfriend and I were helping them pack and move. He's like packing things up in boxes, you know, moving dressers. And I was going to pack the freezer. And all of a sudden his dad is like, whoa, whoa, whoa. Stop right there.

He shows him these little glass jars. Like a few wiles. I think like three or four of them, sealed with plastic tape, with some white substance inside. I didn't, I didn't say anything, this is his work. But Ajay is just kind of like, um, what is this? Yep. And that's when Ajay realizes, like, oh my god, my dad is stealing this stuff from his lab. I said, that's not the to take that across the border.

And Surin just kind of shoots his son this look. Goose, just back in dry ice. So, Ajay did what he was told. I went to the grocery store, bought some dry ice, and we put this compound into an ice cream container then into another container. And you know, like, if you're Indian, you already know. Like you open any random yogurt container in the fridge.

The last thing it's gonna have is yogurt. Yes. So they took this container. And don't do not eat something like that. And it went into the freezer. And I sealed the freezer with duct tape, so United Van Lines wouldn't open it up. Nobody said anything at the border.

You know. We smuggled it across the US border into the United States in the freezer. That rest is history. Yeah. I mean, I don't know the numbers at all, but like this may be one of the biggest international smuggling events in medicine. Oh, come on. Okay, I actually don't know,

but that stuff in those vials on its way to New Jersey in a freezer, in a moving truck, that stuff was gonna become a billion dollar drug one day and save millions of people's lives and ultimately teach us some very fundamental lessons about our biologic nature. Okay, but are you gonna tell me what drug it is actually?

I will, but not yet, because this story isn't just about the drug. All right, it's like about this guy who was really possessed by this drug and let it through all sorts of obstacles to get it to us. My father's full name was surrender-noth-segal, but he went by surrender. Surrender was a biologist. Brilliant microbiologist. went by Seren. Seren was a biologist. Brilliant microbiologist. And the thing he really cared about was studying drugs. And where my father got it from was he essentially

followed in his father's footsteps. Seren's dad ran a pharmaceutical plant. In the 1930s, early 1940s, in the area of Kushab, which is in modern day Pakistan. And that's the environment that my father grew up in. And then when he was a teenager, everything went to Hellen and Handbasket, and the partition occurred. And all of a sudden, Seren and his family had to abandon their home and the life that

they knew. They were being from their looted bloodstained towns, a million displaced persons. With the shirts on their backs and what they could carry, Hindus and Muslims seek safety and use around it. They boarded a train and rode to New Delhi. And the family lost everything. They were very poor. But despite all this chaos, Seren manages to go to college and then grad school.

He got his PhD at 25. I remember this picture of my father. It says, Professor Segal and his class, and there's this young whipper snipper lying prone on the ground holding his head up with his arm, and a bunch of old guys behind him who were the class. And not long after that, he emigrated to Canada. He said he had 50 cents in his pocket, so that was enough to buy a meal back then. And he basically started life over in Canada.

Okay, so do me a favor, let this hold this image of Ceren arriving in Canada in 1958 on one side of your mind. Okay. And on the other side of the split screen, I'm going to tell you a very different migration story. This one starts in 1080. There's some spiritual leader on an island in the Pacific Ocean. And one day he has this vision in a dream.

In this dream he's like a bird and he flies over the ocean. And when he does that, he sees in his dream this island that has like cliffs and it has like volcanic craters. And he tells his people that, you know, a bunch of you need to go off and find this island. So what they do is they send a group of about a hundred people that are a mix of like all the different facets of society. So you've got, you know, women of childbearing age, explorers, shamans, farmers, spiritual leaders. and they basically just take two wooden canoes and put about a hundred foot platform between them. So it's kind of like a catamaran I guess. Okay. It's like this mini Noah's Ark. Wow. And they proceed to traverse these huge waves and

storms and just in the middle of nowhere for thousands of miles, at least a thousand miles they traveled, all just based on this dude having a dream. Loan behold, they find an island. It's got tons of trees, it's got cliffs, it's got volcanic craters and stones. Basically just as this guy described in his dream. So they land on this island that their descendants now call Rapa Nui. These 100 people, they flourish, like their population grows, and then, as the story goes,

their society suddenly collapses, leaving behind like lots of questions about what really happened there. And so, let's hop forward. It was a beautiful morning, December 13th, 1964. A boat with a couple dozen Canadian scientists lands on the shores of this island. It is one of the loneliest islands in the world. This is Easter Island. It sits alone more than 2,000 miles off the coast of South America.

Oh, like the Easter Island with a big head? Yeah, exactly. Some weighing 30 tons. Some 20 feet tall. These huge two-story stone heads. No one knows for sure who made them. Or how long it is as they have been staring seawid to mystify the world. heads. And so the Canadian government had sent this expedition because of like how removed the island was from the rest of the world. And so the scientists wanted

to explore everything about the island and learn about the people. Learn about the bacteria, the plants, animals, and one of the things they do is... The island was mapped into small squares. They take dozens of samples of soil from all over the island. What is this soil best suited to grow? Why would they look in the dirt? Like, it seemed so random to me. The dirt was an afterthought for them. But they kind of just wanted to see,

like, is there anything in here that we haven't seen before? So to figure that out, once they collect the soil, they pack it up and send it to a bunch of different scientists all over Canada to take a closer look. And one of them is our friend, Seren. Yes. So by this time in Seren's life in the 60s, he's got a job doing drug research.

He's married Uma, they've had Ajay. He's just kind of like your typical Indian dad. What does he look like, by the way? He looks like one of my uncles. Even when I'm saying his name like Seren, now I feel like I should actually be saying Seren uncle, he's just got a very Indian uncle vibe. You want to explain what an Indian uncle vibe is? What does it mean to be an Indian uncle?

All right. First of all all they're not Your actual uncle not really not definitely not related to yeah, sirin when I see pictures of him He's wearing a suit, you know, that's what the Indian uncle will wear. He's got glasses on like very like 80s glasses But then in another one. He's got like sunglasses on which like, that's also part of being the Indian uncle, is your little cool. Your little cool sometimes. He's clean-shaven, kind of, balding. When I was talking to his son,

before I could go out and play at night, I had to read any article in the Encyclopedia Britannica and then write a one-page essay on it. I feel like I already know this guy. Probably started when I was eight years old. Because science oriented family man, just trying to like establish himself in a new country. And it's in the midst of this, you know,

kind of humdrum life when this dirt, I always imagine that it as a canister of dirt. From this mysterious island in the middle of the Pacific Ocean lands on his desk. So he's just kind of like, let's see what's in this soil. And he began to try to isolate unique compounds from that soil sample. So he basically takes this soil. They examined it under the microscope. And eventually, Seren and his team, they go, that's interesting.

Seren and his team, they go, that's interesting. They isolated a compound that was not seen before and it had a very interesting molecular structure. And it's kind of this clear white crystalline type of powder looking thing. And Seren's like, I wonder what it does. And so, they tested. They put the compound on different petri dishes and they exposed it to certain bacteria, certain fungi To kind of see how they'll react to the compound And then they observe and after a few days they notice any

fungus they put it in contact with would just stop growing It's like time. just kind of frozen. Huh. Like he would have expected that like that amount of fungi would just keep like dividing and boop boop boop boop boop boop. Exactly. Yeah. By this point, it should have coded the whole plate just covered in fungi.

Just like if you leave, you know, old yogurt in the fridge, you'll just get covered in mold, you know. So that's what should have happened, but instead, it didn't happen. So he's like, ooh, maybe this could be an anti-fungal. Get a tough case of athlete's foot and your bench. Like all those creams people can use, like for yeast infections, like, you know, tough actin to actin. Maybe something like that, right? Right. So for the next few years, Seren is just like trying to stuff out on mice Basically, you know giving them fungal infections and seeing if it works

He tries it on dogs as Jay even says he tried it on a friend's wife who had a fungal infection on her arm Wait, can you even do that? Yeah, he's carrying it around like in his back pocket and he pulls it out at this family friend's house And he puts it on her arm and she tried it and completely eliminated the fungal infection. So he's totally stoked at this point. Wait, like to me, this is so strange because it's like the opposite of what you expect. Like you expect like it's like, okay, disease, we got a problem now. Let's go find a solution. But this is like, this is like the opposite. It's like, okay, we have a solution now, let's go find a solution, but this is like the opposite,

it's like, okay, we have a solution, let's go find a problem, it feels backwards. Oh, so you think scientists know what they're doing, which is funny, because they don't, we don't. That sort of backwards discovery, I think that's actually pretty common.

Think of something like aspirin, right? Like people were using this bark off of this tree before any scientist ever knew what was going on. Hmm. So anyhow, going back to Seren, he feels like he's got a hit on his hands, like a perfect fungal freezer. He said, I'm sure it's better than anything else

I've ever worked on. My dad used to call it my compound. My compound. Yeah. He also call it my compound. My compound? Yeah. He also gives it a name. Rapamysin. Rapamysin after the rapa-nui island that it came from. So he files for a patent for this drug

and he publishes his first paper in 1975. But then there's the problem. Seren is starting to see that not only does his compound freeze the problem. Seren is starting to see that not only does his compound freeze the fungus. It had very strong immunosuppressive properties. It does the exact same thing to immune cells too. Ah, so it's like Elsa from Frozen, like just anything it touches it just freezes. That's exactly his thought.

Wow, okay. Which is a bad thing because you need immune cells to basically grow really quickly when you have an infection and kind of destroy the infection. I sensed like a disappointment in him because he'd been working on this for quite some time. Like, he felt like he was just getting started with rapamycin. But, Ayers, the company that Seren was working for,

didn't give a damn for that, you know? To them, rapamyison is now useless. They ordered the lab to be destroyed. This was that moment in 1982 where Ayrst was shutting down its entire Montreal office. They were all clearing the tables, destroying so many things, so much work of everyone. What was he saying at that time? What did he say to you about his feelings? Oh, he was so disappointed. He said, I have such a good thing in my hand and they want me to destroy it. He knew that if they destroyed all the samples of it, they'd never be able to set the size of again.

I think there was something about Rapa Misen that was still calling to Seren. Like, the fact that it was freezing the fungus and the immune system, it just didn't make sense. So when his boss said, throw it out. He couldn't do it. He couldn't let go. So in this act of like thug passion, I guess, he walks over to the trash. He picked up from the trash.

He pulled it right out of the trash. Uh-huh. Right out of trash. He said, we have to save this. I have a feeling about this drug. He brought it home and said, Uma put this in the freezer. And smuggled it all the way to New Jersey,

just because he had this feeling, it was gonna be big. Ah-ha! I don't want to stop, but we have to go to break. Okay. Do you want to tell people why they should stick around even after the break? Um, you should stick around even after the break? You should stick around because after the break Seren's feeling turns out To be right All right, we'll be right back

Hi, this is Diagre from the Long Beach Peninsula, Washington Radio Lab is supported in part by the Alfred P. Sloan Foundation Enhancing public understanding of science and technology in the modern world. More information about Sloan at www.Sloan.org. Science reporting on Radio Lab is supported in part by Science Sandbox, a Simon's Foundation initiative dedicated to engaging everyone with the process of science. Lutthep. Radio lab.

Okay, so before the break, we met this drug researcher, Seren, who ended up with this substance called Rapamysin from Rapunee, or Easter Island, that mysteriously freezes everything it touches, which looked like it could be a great thing for people with fungal problems, but then not quite because it actually freezes your immune system too, which you need, so now what? Right, exactly. So his bosses are over it. They're like throw it out. He steals it, brings it back to New Jersey, fast forward five years, stuff is sitting in his freezer, and he ends up with some new bosses. Our next major story is from our medical beat. And by now, that feeling he'd always had, that this drug would be big, had become an idea. Successful kidney transplantation was confined to the tiny world of identical twins.

So, this is the late 80s, and organ transplantation, which is this field that until recently was basically science fiction, was just starting to go mainstream. But as the year ran on, the big hurdle doctors were facing was the immune system. Patients died, sometimes a rejection. They hadn't really perfected how to stop people's immune systems from attacking their new organs. Sometimes because the powerful drugs given to overcome rejection laid them open to infections. There were not a lot of effective immunosuppressive drugs and the ones that were out there were.

More than exactly that great. They had a lot of side effects. So Seren thought maybe Rapamyson could be used for this. So he pitches it to his new bosses. And they're like, okay, this sounds good. They actually said that, well, this is not possible because all the samples are destroyed. And he says, well, about that. Maybe not. He came home and he took it out of the freezer and this right next to the Ben and Jerry's.

They didn't know whether the compound was good enough after five years in the freezer, but to his surprise, it was just as active as it was five years ago. I know that. I was very excited about it. And that became the seed. So now it's like game on for CERN. This is his world. So he's in the lab every day trying to figure out how does this drug work? Like why in the world would this drug be freezing

everything it touches? And at the same time, he's sending it around to all these other scientists, trying to get them to help figure out what's going on. Like try this. This is like the DIY like indie band way of developing a drug. Because he really just has no idea how this stuff works.

Yeah, that's right. But that's about to change. Thanks to this guy. Sure, my name is David Sabatini. I'm a biologist. I got an institute called a Whited Institute, which, but back in 1992, when Sir and sending the sample all over the place,

Sabatini was just a student. It was about a year and a half into medical school, whatever that would put you in. He's an MD-PhD student, which means he's like, not just a high achiever enough to become a doctor. He wants to become like a doctor and a scientist at the same time, but he's been struggling. He can't figure out what to do his dissertation on.

So he's walking around the lab one day, trying to figure out, like, what am I gonna do with my dissertation on? So he's walking around the lab one day, trying to figure out, like, what am I gonna do my dissertation on? And then what I found was this notebook that said, rapamycin' and bibliography. In fact, I still have it somewhere here. And it comes with some vials of rapamycin' too. And then I had a note, like, a little post-it note.

Good luck. So Ren. And so Sabatini's like, I'm gonna be the one to figure out how this drug works. Like, that's gonna be my PhD project. And Sabatini knew that, in order for a drug to work, it basically has to attach to something in the body.

And the real question was what that something else was. And so I developed a way of looking for that something else. Picky, are you pondering what I'm pondering? I think so, Brain, but there's still a bug stuck in here from last time. So literally what you do is you sacrifice a rat. Remove its brain. Put it into a blender.

Mix this up, make a smoothie. It looks like a milkshake at that point. I'm gonna put rapper Mison in the smoothie. Let's see what this thing attaches to. And the way he does that is he creates this experiment. He basically puts a little radioactive label onto Rappamycin, so it will light up. And he mixes that in with the brain smoothie.

Then he just dumps out the brain and looks at it and sees if anything lights up. Because if it does, you know that the rapamycin is there. It attaches to something in the brain. And there's some part of this brain sticking to the rapamycin. So the rapamycin is doing something. It's sticking to something. Yeah, I certainly remember that first time that I ran my ass a and I could tell that it had clearly bound to something. How did you feel? Oh, it was amazing, right? That's why nightbiz, he stopped sleeping. Because he still didn't know what that thing was,

that the rapid-mice was sticking to. That was gonna take a lot more work and a lot more rat brains. I ended up doing experiments where, I would sometimes have 300 rats that have to use 300 rat brains. I mean, I did those multiple times to get enough material eventually

to identify what that protein was and it turned out to be a very big protein. And when he tries to look it up in a database, it's not there. Uh-huh. This is a completely unknown, huge protein nobody had ever seen it before. And scientists ended up settling on the name M-TOR, which stood for Mechanistic Target of Rappamycin. And it turns out, Surinid sent this sample, you know, to other people too. So a couple other labs are just at the same time

making the same discovery. And they find out that this thing that it's attaching to doesn't just exist in rat brains. It exists in every cell of the rat. And in fact, it exists in every cell of yeast, of worms, and basically of every single living multicellular species. Oh wow. So it lives in all of our cells too?

Yeah. But somehow we had never seen it before, and nobody knew what it was doing. I didn't know what Emtore did. Couldn't figure out anything. And it took me a long time, like almost a decade. I remember I once gave a talk to my lab at a lab retreat, and I think I called it the Dark Ages. Obviously, this requires hundreds of experiments, but M-Tore, what is it doing? Okay, no, of course. So, you know, from the

earliest days, before we knew about M-Tore, we had a rapmyson. And the beauty of rapmyson was that in many ways it gave us a window into what M-Tore was doing before we even knew M-Tore existed. And what he realizes is M-Tore, it's a sensor. It senses nutrients. And then it tells the cell grow or don't grow. And what he realizes is, MTOR, it's a sensor. The sensor's nutrients? And then it tells the cell grow or don't grow. It basically receives signals from the outside of the cell, right? And the signals it's sensing is like, how much good stuff is there that I have access to?

Is there glucose, protein, fat, oxygen, a lack of stress? We have all that stuff. M-tore turns up and tells the cell then to grow. Sure. If the good stuff isn't there, M-tore turns down and the cell stops growing as much. It doesn't get as big. And so the way I like to think about it is that M-tore

is basically at a construction project. And in a construction project, you have all these different trades, the plumbers, the carpenters, the electricians, the concrete porters, the bricklayers. So MTOR is the organizer of that and in the construction trade you'd call this a general contractor. So MTOR is taking the signals for example, what the owners of the building want, whether there's money or not, whether the concrete supplier can't bring concrete tomorrow, is taking all those inputs and then controlling all those processes.

And if the inputs look bad for building, like say there's not enough pipes, the general contractor is not going to let the plumber install the pipes. If you know, if the general contractor knows there aren't enough pipes to install right now. So it's going to say, stop. An MTOR is making the decision as to which of those two states you're in

by measuring the presence or absence of nutrients. What Rapamysin does is it tricks cells in your body to thinking there's low nutrients when nutrients are there. So if you think about MTOR as a general contractor, Rapamysin is like a blindfold. It's covering the general contractor's eyes so it can't see the plumbing or the concrete or whatever. And so the general contractor just shuts down the project,

even though all the things it needs are there. Does that make sense? Yeah, I think so. And so the effect of it basically is that Rapplemysen just slows down growth. Yeah, exactly. More or less it freezes it. Whether it's fungus cells or immune cells, it just can't grow.

So when it turns out, while Sabatini was figuring out all this stuff with M-Tour, Seren had been sending out rapamycin to all these transplant doctors. And it was working. It was working so well in fact that rapamycin would end up getting FDA approval for immune suppression in 1999. And not only that, other doctors are starting to realize like maybe I can use this as an immune to suppressant too for like other things. Like doctors had recently come up with this new technology to save people who are having a heart attack, called a stent.

And what it is is, it's basically a little tube that you slip into someone's artery in their heart to keep it open. The only problem is that when you put a tube into someone's body, their body is like, why is this tube inside of me? Like, I don't want it. Get it away from me.

So your immune system starts sort of rejecting it. Until one day, a doctor who had read one of CERN's papers thinks, let me try coating the stent in rapamycin and boom, like that, all of a sudden, stents last thing. Wow. He was so excited that the heart stents are coated with his drug. And one day, Cern has this moment where he really sees up close the kind of impact that Rapamysen is having. Oh, Pittsburgh. He and Umar and Pittsburgh, and one of the doctors who'd been using Rapamysen

invites them to tour the Children's Ward at this hospital. There were kidney transplantation survivors who were on my father's drug as part of this clinical trial. And as CERNs being led around this Children's Transplet Ward, the doctor giving the tour said, this is the guy that invented rapamycin. That guy who discovered the drug you are taking. And because of rapamycin, a lot of them were responding to their transplants

really well. Really, really well. You have to understand that in these clinical trials, the patients that they select are the ones that are not being helped by any other immunosuppressive. So this was sort of last resort for these kids. The word starts spreading around the hospital. Oh, he met so many patients. All the patients wanted to see him. The parents of these kids were like, can I shake his hand? They all wanted to shake his hand. They just wanted to thank him, constantly, thank him for keeping their kids alive. He was so happy that it was working.

Especially because at that moment, he was stage 4 and we didn't have much longer with him. Wait, what? My father had been diagnosed with colon cancer. It was pretty serious. His doctor said he only had six months to live. But Uma says when Surn got this news, he said to the oncologist, I'll be here for five years, you'll see.

He was very determined I have to get better. I have to get better. He tells his wife, he wanted to be around for his grandkids, but it wasn't just that. He said, it's lot has to go on with my work also. He has so much work that he still wants to do on Rapa Micell. Including his most daring experiment yet. Taking Rapa Micell. Taking Rapa Micell to see if it would treat his own cancer. So like his doctor prescribed him Rapa Micell?

No, no, he was getting it from the lab. He just decided to take it on his own in pill form. I believe in this drug and I think it just might be able to save me. But why would Rapa Micein help for cancer? Well, think about it, right? Like, what does Rapa Micein do? It stops cells from growing. So why not cancer cells? You know, and no human had ever tried this. It's definitely a long shot. But he said, let me try that.

And then the six month mark comes and goes. The tumor action stopped. Another six months go by, he's still alive. Yes, yes. In fact, he's thriving. We were traveling all over the world. He's flying to conferences for work. We went to Japan, we went to China, we went to Thailand, we went to Europe many times. Another six months, he's publishing papers. He was very busy.

And another, he's going to his grandkids, birthdays, and another. And then he just kept living, right? Oh my God, wow. So, like, what actually is happening? So, like, the rap amicin is like slowing, it's like freezing the cancer? Well, maybe that's happening. But maybe something even crazier is happening

that even CERN had no idea about. Huh. What scientists are now just starting to wrap their head around is that when you turn down M-Tore because you don't have enough of the good stuff, it doesn't just say stop. In fact, it deploys a whole nother program. Some people call that the starvation protocol. All right, so let's go back to this general contractor guy, right, M-Tore. What this general contractor actually says is like,

we've fallen on hard times everybody. There's no new materials coming in. Don't just sit there and wait for something good to happen. Instead, start fixing yourself up. Take all this junk laying around, recycle it. For example, if there are no pipes, hey, plumbers, like, why don't you go around this house and pick up all this junk that's sitting there

and fix it up and see if you can make some pipes? Oh, God. So that's what's going on inside the cell. Like, it's like, it's doing that thing. It's like taking up the garbage and like, making it useful. Yeah, exactly. Some people call that autophagy, meaning eating yourself, auto-fagy, eating yourself.

But what is the garbage actually though in the cell? It's crazy because even in med school we had histology and we would look at cells and we would be trying to identify all the little pieces of the cell and I would always see, like you could see on one side there's this huge brown gunk just sitting there and I would be like, what is that? And I came to later learn that that's just junk. It's just deposit sitting there. Huh, and it's like clogging up the function of the cell? Is that what's going on?

Yeah, that buildup of junk inside ourselves over time makes us less efficient. It makes us sick. I talk to a bunch of scientists who study this, one of them, this guy, Matt, Kabilin. I am a professor of laboratory medicine and pathology at the University of Washington. Study the effects of rapamycin on how long mice live.

And we had this one mouse that kept going and going and going. They named him Ike. Ike, if we translated that linear lady human years, was about 125 years old. 130 years, yeah. Hi. Wow. But is this just like one super old mouse who you just made super older? No, no, that's the thing.

Like there's a government study that did this with a bunch of mice, these mice look and act younger. And it's not just mice. Like scientists have seen these kind of results in every species they try it on. So it's yeast, worms, flies. They're even doing a study to try it in pet dogs. Wow. And so all of this is just because like,

rapamycin is just like, clearing out all the junk. Yeah, because all that junk basically causes aging. And over time, we'll kill us. Like Kabilin says, take something like Alzheimer's disease. Right. What is that? That's tangles of proteins and junk that's sitting around in your brain cells.

That's getting in the way of like you having a thought. And there's tons of data in mice that rapamycin can improve cognitive aging in mice. Starting rapamycin before the decline starts, prevents the decline, and starting rapamycin after the decline starts partially reverses the decline. So we are saying that rapamycin reverses Alzheimer's and mice.

That's right. Wow. And it's not just Alzheimer's. It's like every marker of aging. It's other diseases too. Like heart attacks, strokes, and cancer, which kind of brings us back to CERN. He was given six months in 1998. And now it's 2002.

Oh wow. So like almost the five year mark. Yeah. Five years when he was supposed to have been dead. He's still taking rap amicin and he's still alive. And so yeah, maybe some of that anti-aging stuff is happening in Seren's body. Actually, there was no cancer in his colon anymore

or the stomach or the liver. I mean, but like, how do you know? Like, is there any way of measuring that that's the thing that's prolonging his life? At this point mean, but like, how do you know? Like, is there any way of measuring that that's the thing that's prolonging his life? At this point, it's hard to tell, you know? Like, at one point, he also did chemo for his cancer. So, is it the chemo? Is it the traditional meds?

Is it the rapamycin? Certain has no idea. That's a mystery in his mind that's actually kind of eating away at him. And one day he goes and he tells my mom, he says, How do I know? I feel good. But how do I know if it's working or not? My drug is working or not?

Is this working or am I just a fluke? Is it just so happening that I'm living longer than I was expected? But he's always going to stay the scientist, right? So he's like, there's only one way I'm going to figure out if rapamising is keeping me alive. Uma, the only way I'm going to know if my drug works is if I stop taking it. He was experimenting on himself. And that's what he does.

So he stopped taking the drug and, you know, six months later. It came with vengeance. The cancer. It was, it came into the lungs. It was in his lungs and he was not going to last very much longer. And so Umat tells him like you made your point. I said to him, I begged him to take it. Just start taking the wrap of my sin again.

Yeah. He said no. Just it's so, it's okay. Let nature take its course. That's all. So it's okay, let nature take its course, that's all. He worked until the day he died. The day before he died, he was still writing a paper. In bed, with the oxygen on his face, writing a paper, advocating the anti-tumor properties

of rapamycin. Yeah. Seren died on January 21st, 2003. So Seren is gone, but this drug is still alive. It's still here. It's still being used. Yeah, really it's just coming to life. It had been approved for a immune suppression and stents during his lifetime. And then in the years after he died, these slight variations on it started getting approved for all these rare cancers, like dominoes, really approved for this one, approved for that one, approved for another one.

Wow. And today, this drug is just a part of my world. 86 year old male, he's last, that's that's place at NYU three years ago. Like just the other day. All right, sir. I know a lot's going on right now. Everyone's running all over the place.

We're concerned because we think you may be having a heart attack. Guy came in with a heart attack. 50 years ago, he probably would have died, but we gave him a stent, coated with a variation of rapamycin, and he's doing just fine. So that's all I can plan to you? And on top of that, there's like dozens of studies going on to see if rapamycin can maybe one day prevent or reverse aging in humans. Oh wow. And I mean, who knows?

You know, it's not some miracle drug. Like it doesn't work for every cancer. It has side effects. But what makes the story interesting to me personally, all right, is not rapamycin, per se. It's what rapamycin taught us about ourselves. And what is that? So to me, it's like, emtour.

That general contractor protein, that rapamycin showed us that we have. It tells ourselves when to grow and when to recycle the trash that's piled up inside them. If I was to design a cell, if I was to design myself, I would say, I should be in a state where I can grow, and I should also be able to clean up at the same time. Totally. But that turns out, the way our bodies do do it and the way every single living species does it is not that way.

We have two states. And the more you do one, the less you can do the other. So you can be in a state where you are getting nutrients, you're getting the things you need. And when you're in that state, you're like building, you're growing. And only when you don't have those things, in other words, only the times where you run out of food, those are the times where your body doubles back and decides, okay, now is when I'm going to fix myself up. So what I think is profound is that there's just, you can be one or the other, but you can't really be both. Yeah.

And why would nature do that? Well, I think life is a mix of both of those states. We're never going to be always fed. We're never going to be always hungry. We're going to be in some mix. So why don't we delegate certain activities to happen during certain times of life? I think that's the meaning to me.

So if you look at us today, look at the world we've created. You know, we don't like discomfort. We don't like pain. Because we're evolved to seek the good things. And that makes sense. But we are not evolved to actually have ever achieved a state where we get all the good things all the time. It's actually bad for us.

And we see that everywhere, obviously, right? Diabetes, hypertension, obesity. We see that on that level. But to me, this is the cell saying to us, the cell is saying, I was actually designed, and you were designed to have a mix of times where you have everything you want, and a mix of times, and sometimes where you don't have everything you want.

And it's gonna be painful, but it's good for you. I think that's the true lesson that came from the dirt of Easter Island. So it's like the thing that we pulled out of Easter Island, it responded to a thing in us that we didn't even know was there, which is like a tiny switch on each of our cells that on one side says grow,

and on the other side it says like fix, basically. Right, exactly. And one of the coolest things I learned while reporting this story is that in a way that lesson that rapper Micein is teaching us about ourselves, that lesson has been present in a place that rapper Micein came from for a really long time. Huh, what do you mean? Okay, so when you think about rapper Nui, like Easter Island, present in the place that Rapid Mice and came from for a really long time. Huh.

What do you mean? Okay, so when you think about Rapid Nui, like Easter Island, you picture these huge Moai statues. They're basically like big stone old men with big, well-fed bellies. Those statues were built when the culture was thriving. There was food, livestock, maybe 15 to 20,000 people were living there. They were feasting.

But what most people don't know is that there's this other kind of statue on the island. Here, I'll pull one out here. A very different kind of statue. My uncle carved this a long time ago, and I sort of inherited it. This is Sergio Matau-Rapu. He grew up on the island, and he's

the one who told me about these statues. Yeah, these statues are about a foot high or like two feet high, made out of wood, pretty fragile wood. And they represent these like very starving, skinny naked, almost frightened figures. Instead of hands wrapped around a big fat belly, it's these protruding ribs. His spine is sticking out, his face is sunken, his eyes are just looking at you. Sergio says these statues came from a very different time on the island's history. At one point, we lost our massive trees and resources started diminishing. Without trees, it became hard to make boats to go fishing,

and it also became hard to grow crops. People really started to struggle, and they started to starve. And around the same time, Europeans started coming to the island, and they brought disease, they enslaved people, and a lot of people in Rapa Nui died. My ancestors is massive, powerful community. They build these giant statues, like diminishes down to about 111 people. And that, Sergio says,

is when they started making these little statues, the Moai Kava Kava. And I mean, when you read the history books about this island, Rappinui, right? The history books are gonna say this is a failed island. That the Moai construction is like the pinnacle of my community. But Sergio says that's not how he sees it. To me, like the fact that people were able to adapt to difficult situations is what allows you to survive. It was important for them to understand,

like, how to really do a lot with a little bit. And he says that even though most of the tourists come to see those big giant statues, for the people on the island, they treasure those small skinny statues just as much. I think the story of Rapa Nui is a metaphor for what Ropinui is and does in your body.

The way that I understand it, the way that Ropinui is and tricks your body into thinking that you're starving, it being a positive thing, I think often times, we on Ropinui also realize that having close to nothing is also positive in some ways. It reminds you of what you have. I think my big takeaway from this story is like I need to go to my parents' house

and look through every yogurt container in that fridge. Uh, cause there are a lot of them. And who knows? Uh, look at you. Well, how many of them have yogurt in them? None. None. Right. Exactly.

Yeah. Right. Exactly. Yeah. Contributing editor of your Mitra. This episode was produced by Sara Cari, Pat Wal Walters and Susie Lektemberg with production help from Karine Lyong and Rachel Kusik. Fact checking by Diane Kelly, special thanks to Richard Miller, Stuart Schreiber, Joanne

Van Tilberg, Bethany Halford, and Ike The Mouse. Thank you very much for listening. Hi, this is Kira from Philadelphia, Pennsylvania. and Ike the Mouse. Thank you very much for listening. of sound design. Our staff includes Simon Adler, Jeremy Bloom, Becca Brestler, Rachel Cusick, David Gabel, Matt Tilti, Annie McEwan, Alex Niesen, Sara Kauri, Arian Wack, Pat Walters, and Molly Webster. With help from Shima Oliayi, Sarah Sandbach, and Karen Leong, our fact checkers are Diane Kelly and Emily Greiger. Sarah Sandbach and Karen Leong. Our fact checkers are Diane Kelly and Emily Greiger.