LATIF NASSER: Hey. I'm Latif Nasser. This is Radiolab. And this week, our story comes from ...

AVIR MITRA: Hey, Latif.

LATIF: Hi!

LATIF: ... Avir Mitra, who's one of our contributing editors. Avir, after his stint as a Radiolab intern and then as an international rock star, became ...

[ARCHIVE CLIP: Why don't I go ahead and give him a breathing test ...]

LATIF: ... an emergency room doctor. Actually, during the height of the pandemic ...

[ARCHIVE CLIP, Avir: Tensions are high today. March 26, 2020.]

LATIF: ... he brought us a gripping portrait of his ER under siege.

[ARCHIVE CLIP, Avir: All the ICUs are slammed.]

LATIF: 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—and might even reverse it.

AVIR: So, you know, 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 backstory I've ever heard for a drug.

AJAI SEHGAL: All right. We are recording.

AVIR: Okay, so it starts with this guy named Ajai.

AJAI SEHGAL: My name is Ajai Sehgal. And the last name, you can pronounce it Sehgal, Siegel, Sagal.

AVIR: So back in 1982 ...

AJAI SEHGAL: I remember exactly where I was. I was in Germany serving with the Canadian Forces.

AVIR: His family was back in Montreal.

AJAI SEHGAL: 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 Chaja. Stop." Chaja's my father's younger brother. And I go, "What? Why are you moving to the United States?"

UMA SEHGAL: Well, what happened was my husband, Suren, received a notice that he will be moving to Princeton, New Jersey.

AVIR: This is Ajai's mom, Uma.

UMA SEHGAL: Uma Sehgal.

AVIR: And she says her husband, Suren, was working for this drug company.

UMA SEHGAL: Ayerst, McKenna & Harrison.

AVIR: And out of nowhere, one day they say, "We're shutting down our Montreal lab. Like, if you want to keep your job, you gotta move to New Jersey." So ...

AJAI SEHGAL: You know, my parents were moving.

AVIR: Ajai, he's a good son. He comes home, helps them move.

UMA SEHGAL: The day we had to move was very cold, cold, cold, freezing day.

AJAI SEHGAL: My girlfriend and I were helping them pack and move.

AVIR: He's, like, packing things up in boxes, you know, moving dressers.

AJAI SEHGAL: And I was gonna pack up the freezer.

AVIR: And all of a sudden, his dad is like, "Whoa, whoa, whoa! Stop right there." He shows him these little glass jars.

UMA SEHGAL: Like, a few vials.

AVIR: I think, like, three or four of them sealed with plastic tape, with some white substance inside.

UMA SEHGAL: I didn't say anything. It's his work.

AVIR: But Ajai is just kind of like, "Um, what is this?"

AJAI SEHGAL: Yep.

AVIR: And that's when Ajai realizes, like, "Oh my God, my dad is stealing this stuff from his lab."

AJAI SEHGAL: I said, "That's not legal to take that across the border."

AVIR: And Suren just kind of shoots his son this look.

AJAI SEHGAL: Goes, "Just pack it in dry ice."

AVIR: So Ajai did what he was told.

AJAI SEHGAL: I went to the grocery store, bought some dry ice, and we put this compound into an ice-cream container, then into another container.

AVIR: 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.

UMA SEHGAL: Yes.

AVIR: So they took this container ...

UMA SEHGAL: And wrote, "Do not eat." [laughs] Or something like that.

AJAI SEHGAL: And it went into the freezer. And I sealed the freezer with duct tape so United Van Lines wouldn't open it up.

UMA SEHGAL: No, nobody said anything at the border, you know?

AVIR: [laughs]

AJAI SEHGAL: We smuggled it across the US border into the United States in the freezer.

UMA SEHGAL: The rest is history. [laughs] Yeah.

AVIR: I mean, I don't know the numbers at all but, like, this may be one of the biggest international smuggling events in medicine.

LATIF: Oh, come on! [laughs]

AVIR: 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.

LATIF: Okay, but are you gonna tell me what drug it is, actually?

AVIR: I will. But not yet, because the story isn't just about the drug, right? It's, like, about this guy who is really possessed by this drug and led it through all sorts of obstacles to get it to us.

AJAI SEHGAL: My father's full name was Surendra Nath Sehgal, but he went by Suren.

AVIR: Suren was a biologist.

AJAI SEHGAL: A brilliant microbiologist.

AVIR: And the thing he really cared about was studying drugs.

AJAI SEHGAL: And where my father got it from was he essentially followed in his father's footsteps.

AVIR: Suren's dad ran a pharmaceutical plant.

AJAI SEHGAL: In the 1930s, early 1940s, in the area of Khushab.

AVIR: Which is in modern day Pakistan.

AJAI SEHGAL: And that's the environment that my father grew up in. And then when he was a teenager, everything went to hell in a handbasket and the partition occurred.

[NEWS CLIP: As the new dominions of Pakistan and India take over their own affairs, the bloodshed goes on.]

AVIR: And all of a sudden, Suren and his family had to abandon their home and the life that they knew.

[NEWS CLIP: Fleeing from their looted, blood-stained towns, a million displaced persons.]

AJAI SEHGAL: With the shirts on their backs and what they could carry ...

[NEWS CLIP: Hindus and Muslims seek safety in new surroundings.]

AJAI SEHGAL: ... they boarded a train and rode to New Delhi. And the family lost everything. They were very poor.

AVIR: But despite all this chaos, Suren manages to go to college and then grad school.

AJAI SEHGAL: He got his PhD.

AVIR: At 25.

AJAI SEHGAL: And I have—I remember this picture of my father. It says "Professor Sehgal and his class." And there's this young whippersnipper lying prone on the ground, holding his head up with his arm and a bunch of old guys behind him who are the class.

AVIR: And not long after that ...

AJAI SEHGAL: He emigrated to Canada. He said he had 50 cents in his pocket. So, you know, that was enough to buy a meal back then. And he basically started life over in Canada.

AVIR: Okay, so do me a favor, Latif. Hold this image of Suren arriving in Canada in 1958 on one side of your mind.

LATIF: Okay.

AVIR: And on the other side of this split screen, I'm gonna tell you a very different migration story. This one starts in 1000 AD. 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 a about 100-foot platform between them. So it's kind of like a catamaran, I guess.

LATIF: Mm-hmm. Okay.

AVIR: It's like this mini Noah's Ark.

LATIF: Wow!

AVIR: 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.

AVIR: Lo and 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.

[ARCHIVE CLIP: It was a beautiful morning. December 13, 1964.]

AVIR: A boat with a couple dozen Canadian scientists lands on the shores of this island.

[ARCHIVE CLIP: It is one of the loneliest islands in the world.]

AVIR: This is Easter Island.

[ARCHIVE CLIP: It sits alone more than 2,000 miles off the coast of South America.]

LATIF: Oh, like the Easter Island with the big heads?

AVIR: Yeah, exactly.

[ARCHIVE CLIP: Some weighing 30 tons. Some 20 feet tall.]

AVIR: These huge, two-story stone heads.

[ARCHIVE CLIP: No one knows for sure who made them, or how long it is they have been staring seaward to mystify the world.]

AVIR: And so the Canadian government had sent this expedition.

[ARCHIVE CLIP: A medical expedition to Easter Island.]

AVIR: Because of, like, how removed the island was from the rest of the world.

[ARCHIVE CLIP: Isolation has been their protection.]

AVIR: And so these scientists wanted to explore everything about the island, and learn about the people.

[ARCHIVE CLIP: Prepares blood samples.]

AVIR: Learn about the bacteria, the plants, animals. And one of the things they do is ...

[ARCHIVE CLIP: The island was mapped into small squares.]

AVIR: ... they take dozens of samples of soil from all over the island.

[ARCHIVE CLIP: What is this soil best suited to grow?]

LATIF: Why would they look in the dirt? Like, it seems so random to me.

AVIR: The dirt was an afterthought for them.

LATIF: Oh.

AVIR: 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 Suren.

UMA SEHGAL: Yes.

AVIR: So by this time in Suren's life in the '60s, he's got a job doing drug research. He's married Uma. They've had Ajai. He's just kind of like your typical Indian dad.

LATIF: What does he look like, by the way?

AVIR: He looks like one of my uncles. Even when I'm saying his name, like, Suren, now I feel like I should actually be saying "Suren uncle." He's just got a very Indian uncle vibe.

LATIF: You want to explain what an Indian uncle vibe is?

AVIR: What does it mean to be an Indian uncle? All right. First of all, they're not your actual uncle.

LATIF: Not related to you.

AVIR: Not—definitely not related to you.

LATIF: Yeah.

AVIR: Suren, 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.

LATIF: [laughs]

AVIR: But then in another one, he's got, like, sunglasses on, which is like, that's also part of being the Indian uncle is you're a little cool. You're a little cool sometimes.

LATIF: [laughs]

AVIR: He's clean-shaven, kind of balding. When I was talking to his son ...

AJAI SEHGAL: 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.

AVIR: ... I feel like I already know this guy.

AJAI SEHGAL: Probably started when I was eight years old.

LATIF: [laughs]

AVIR: Like a 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 ...

AJAI SEHGAL: I always imagined it as a canister of dirt.

AVIR: ... 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."

AJAI SEHGAL: And he began to try to isolate unique compounds from that soil sample.

AVIR: So he basically takes the soil.

AJAI SEHGAL: They examined it under the microscope.

AVIR: And eventually, Suren and his team ...

AJAI SEHGAL: They go, "Oh, that's interesting." They isolated a compound that was not seen before, and it had a very interesting molecular structure.

AVIR: And it's kind of this clear, white, crystalline-type of powder-looking thing. And Suren's like ...

AJAI SEHGAL: Hmm, I wonder what it does.

AVIR: And so ...

AJAI SEHGAL: They test it.

AVIR: ... they put the compound on different petri dishes, and ...

AJAI SEHGAL: They exposed it to certain bacteria, certain fungi.

AVIR: To kind of see how they'll react to the compound.

AJAI SEHGAL: And then they observe.

AVIR: And after a few days, they notice ...

AJAI SEHGAL: Any fungus they put it in contact with ...

AVIR: Would just stop growing. It's like time had just kind of frozen.

LATIF: Huh! Like, he would have expected that, like, that amount of fungi would just keep, like, dividing and boop boop boop boop boop boop boop.

AVIR: Exactly. Yeah. By this point, it should have coated the whole plate, just covered in fungi, just like if you leave, you know, old yogurt in the fridge, it'll just get covered in mold, you know? So that's what should have happened, but instead, it didn't happen.

LATIF: Hmm!

AVIR: So he's like, "Ooh, maybe this could be an antifungal."

[ARCHIVE CLIP, John Madden: Get a tough case of athlete's foot, and you're benched.]

AVIR: Like all those creams people can use, like, for yeast infections, like, you know ...

[ARCHIVE CLIP, John Madden: Boom! Tough-acting Tinactin.]

AVIR: Maybe something like that, right?

LATIF: Right.

AVIR: So for the next few years, Suren is just, like, trying this stuff out on mice, basically, you know, giving them fungal infections and then seeing if it works. He tries it on dogs. Ajai even says he tried it on a friend's wife who had a fungal infection on her arm.

LATIF: Wait. Can you even do that?

AJAI SEHGAL: Yeah. [laughs]

AVIR: 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.

AJAI SEHGAL: And she tried it, and it completely eliminated the fungal infection.

AVIR: So he's totally stoked at this point.

LATIF: Wait. Like, to me, this is so strange because it, like—it's, like, the opposite of what you expect. Like, you expect, like, it's like, okay, disease. We've got a problem, 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.

AVIR: [laughs]

LATIF: Like, it feels backwards.

AVIR: Oh. So you think scientists know what they're doing?

LATIF: [laughs]

AVIR: Which is funny, because they don't. We don't. Like, 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 scientists ever knew what was going on.

LATIF: Hmm!

AVIR: So anyhow, going back to Suren, he feels like he's got a hit on his hands, like, a perfect fungal freezer.

UMA SEHGAL: He said, "I'm sure it's better than anything else I've ever worked on."

AJAI SEHGAL: My dad used to call it "My compound."

AVIR: My compound.

AJAI SEHGAL: Yeah. [laughs]

AVIR: He also gives it a name.

AJAI SEHGAL: Rapamycin.

AVIR: Rapamycin after the Rapa Nui island that it came from.

LATIF: Huh!

AVIR: So he files for a patent for this drug, and he publishes his first paper in 1975.

AJAI SEHGAL: But then there's the problem.

AVIR: Suren is starting to see that not only does this compound freeze the fungus ...

AJAI SEHGAL: It had very strong immunosuppressant properties.

AVIR: It does the exact same thing to immune cells, too.

LATIF: Ah, so it's like Elsa from Frozen. Like, just anything it touches, it just freezes.

AVIR: That's exactly his thought.

LATIF: Wow. Okay.

AVIR: 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.

AJAI SEHGAL: I sensed, like, a disappointment in him because he'd been working on this for quite some time.

AVIR: Like, he felt like he was just getting started with rapamycin.

UMA SEHGAL: But ...

AVIR: Ayerst, the company that Suren was working for ...

UMA SEHGAL: Didn't give a damn for that, you know?

AVIR: To them, rapamycin is now useless.

UMA SEHGAL: They ordered the lab to be destroyed.

AVIR: This was that moment in 1982 where Ayerst was shutting down its entire Montreal office.

UMA SEHGAL: They were all clearing the tables, destroying so many things, so much work of everyone.

AVIR: What was he saying at that time? What did he say to you about his feelings on that?

UMA SEHGAL: Oh, he was so disappointed. He said, "I have such a good thing in my head, and they want me to destroy it."

AJAI SEHGAL: He knew that if they destroyed all the samples, that they'd never be able to synthesize it again.

AVIR: I think there was something about rapamycin that was still calling to Suren. Like, the fact that it was freezing the fungus and the immune system, it just didn't make sense. So when his bosses said, "Throw it out" ...

UMA SEHGAL: He couldn't do it.

AVIR: He couldn't let go.

UMA SEHGAL: So ...

AVIR: In this act of, like, thug passion, I guess ...

LATIF: [laughs]

AVIR: ... he walks over to the trash.

UMA SEHGAL: He picked it from the trash.

LATIF: He pulled it right out of the trash?

UMA SEHGAL: Uh-huh. Right out of trash.

AVIR: [laughs] Oh!

AJAI SEHGAL: He said, "We have to save this. I have a feeling about this drug."

UMA SEHGAL: He brought it home and said, "Uma, put this in the freezer."

AVIR: And smuggled it all the way to New Jersey just because he had this feeling it was gonna be big.

LATIF: Ah! I don't want to stop, but we have to go to break.

AVIR: Okay.

LATIF: Do you want to—do you want to tell people why they should stick around even after the break?

AVIR: You should stick around because after the break, Suren's feeling turns out to be right.

LATIF: All right. We'll be right back.

[LISTENER: Hi, this is Deirdre from the Long Beach Peninsula, Washington. Radiolab 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.]

[JAD ABUMRAD: Science reporting on Radiolab is supported in part by Science Sandbox, a Simons Foundation initiative dedicated to engaging everyone with the process of science.]

LATIF: Latif.

AVIR: Avir.

LATIF: Radiolab. Okay, so before the break, we met this drug researcher, Suren, who ended up with a substance called rapamycin from Rapa Nui, 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?

AVIR: 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. This stuff is sitting in his freezer, and he ends up with some new bosses.

[NEWS CLIP: Our next major story is from our medical beat.]

AVIR: And by now, that feeling he had always had that this drug would be big had become an idea.

[NEWS CLIP: Successful kidney transplantation was confined to the tiny world of identical twins.]

AVIR: 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.

[NEWS CLIP: But as the year ran on ...]

AVIR: But the big hurdle doctors were facing was the immune system.

[NEWS CLIP: Patients died, sometimes of rejection.]

AVIR: They hadn't really perfected how to stop people's immune systems from attacking their new organs.

[NEWS CLIP: Sometimes because the powerful drugs given to overcome rejection leave them open to infections.]

AJAI SEHGAL: There were not a lot of effective immunosuppressive drugs. And the ones that were out there were ...

AVIR: Weren't exactly that great.

UMA SEHGAL: They had lot of side effects.

AVIR: So Suren thought maybe rapamycin could be used for this. So he pitches it to his new bosses. And they're like, "Okay, this sounds good."

AJAI SEHGAL: But they actually said, "Well, there's—this is not possible because all the samples are destroyed." And he says, "Well ..."

AVIR: About that.

AJAI SEHGAL: "Maybe not." [laughs]

UMA SEHGAL: He came home.

AJAI SEHGAL: And he took it out of the freezer. And they ...

AVIR: Right next to the Ben & Jerry's.

UMA SEHGAL: They didn't know that 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 he was very excited about it.

AJAI SEHGAL: And that became the seed.

AVIR: So now it's, like, game on for Suren. 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.

LATIF: Because he really just has no idea how this stuff works.

AVIR: Yeah, that's right. But that's about to change, thanks to this guy.

DAVID SABATINI: Sure. My name is David Sabatini. I'm a biologist at an institute called the Whitehead Institute, which is ...

AVIR: But back in 1992, when Suren's sending the sample all over the place, Sabatini was just a student.

DAVID SABATINI: I was about a year and a half into medical school, whatever that would put you in.

AVIR: 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 my dissertation on?

DAVID SABATINI: And then what I found was this notebook that said, "Rapamycin bibliography." And in fact, I still have it somewhere here.

AVIR: And it comes with some vials of rapamycin, too.

DAVID SABATINI: And then it had a note.

AVIR: Like, a little Post-it note.

DAVID SABATINI: Good luck. Suren.

AVIR: 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.

DAVID SABATINI: And the real question was what that something else was. And so I developed a way of looking for that something else.

[ARCHIVE CLIP, Pinky and the Brain: Pinky, are you pondering what I'm pondering?]

[ARCHIVE CLIP, Pinky and the Brain: I think so, Brain. But there's still a bug stuck in here from last time.]

DAVID SABATINI: So literally what you do is you sacrifice a rat.

AVIR: Remove its brain.

DAVID SABATINI: Put it into a blender.

AVIR: Mix this up, make a smoothie.

DAVID SABATINI: It looks like a milkshake at that point.

AVIR: I'm gonna put rapamycin 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 rapamycin so it will light up.

LATIF: Okay.

AVIR: 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, he knows that the rapamycin is there, it attached to something in the brain.

LATIF: Huh!

AVIR: And there's some part of this brain sticking to the rapamycin. So the rapamycin is doing something. It's sticking to something.

DAVID SABATINI: Yeah, I certainly remember that first time that I ran my assay, and I could tell that it had clearly bound to something.

AVIR: How did you feel?

DAVID SABATINI: Oh, it was amazing, right? And that's when I basically stopped sleeping.

AVIR: Because he still didn't know what that thing was that the rapamycin was sticking to. That was gonna take a lot more work—and a lot more rat brains.

DAVID SABATINI: I ended up doing experiments where, you know, I would sometimes have 300 rats that I'd have to use, 300 rat brains. I mean, and 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.

AVIR: And when he tries to look it up in a database, it's not there.

LATIF: Uh-huh?
AVIR: This is a completely unknown, huge protein. Nobody had ever seen it before. And scientists ended up settling on the name mTOR, which stood for "mechanistic target of rapamycin." And it turns out Suren had 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.

LATIF: Oh, wow! So it lives in all of our cells, too?

AVIR: Yeah. But somehow, we had never seen it before, and nobody knew what it was doing.

DAVID SABATINI: I didn't know what mTOR did. Couldn't figure out anything. And it took me a long time.

AVIR: Like, almost a decade.

DAVID SABATINI: I remember I once gave a talk to my lab at a lab retreat, and I think I called it the Dark Ages.

AVIR: Obviously, this requires hundreds of experiments, but mTOR, what is it doing?

DAVID SABATINI: Okay. Now of course—so, you know, from the earliest days before we knew about mTOR, we had rapamycin. And the beauty of rapamycin was that in many ways, it gave us a window into what mTOR was doing before we even knew mTOR existed.

AVIR: And what he realizes is mTOR, it's a sensor.

DAVID SABATINI: That senses nutrients, and then it tells the cell grow or don't grow.

AVIR: It basically receives signals from the outside of the cell, right? And it's—the signals it's sensing is, like, how much good stuff is there that I have access to? Is there glucose, you know, protein, fat, oxygen, a lack of stress? If we have all that stuff, mTOR turns up and tells the cell then to grow.

LATIF: Sure.

AVIR: If the good stuff isn't there, mTOR turns down and the cell stops growing as much. It doesn't get as big.

DAVID SABATINI: And so the way I like to think about it is that mTOR is basically at a construction project. And, you know, in a construction project, you have all these different trades, right—the plumbers, the carpenters, the electricians, the concrete pourers, 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, of what the owners of the building want, whether there's money or not, whether the concrete supplier can't bring concrete tomorrow. It's taking all those inputs and then controlling all those processes.

AVIR: And if the inputs look bad for building, like, say, there's not enough pipes, the general contractor is not gonna 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 gonna say stop.

DAVID SABATINI: 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 rapamycin does is it tricks cells in your body to thinking there's low nutrients when nutrients are there.

AVIR: So if you think about mTOR as a general contractor, rapamycin 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?

LATIF: Yeah, I think so. And so the effect of it, basically, is that rapamycin just slows down growth.

AVIR: Yeah, exactly. More or less, it freezes it. Whether it's fungus cells or immune cells, it just can't grow. So—and it turns out while Sabatini was figuring out all this stuff with mTOR ...

[NEWS CLIP: Transplants are becoming so much easier to perform.]

AVIR: ... Suren ...

[NEWS CLIP: Improved immunosuppressant drugs.]

AVIR: ... had been sending out rapamycin to all these transplant doctors. And it was working.

[NEWS CLIP: Recent medical advances ...]

AVIR: 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 immunosuppressant 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 Suren's papers thinks, let me try coating the stent in rapamycin. And boom! Like that, all of a sudden, stents lasting.

LATIF: Wow!

UMA SEHGAL: He was so excited that the heart stents are coated with his drug.

AVIR: And one day, Suren has this moment where he really sees up close the kind of impact that rapamycin is having.

UMA SEHGAL: Oh, Pittsburgh.

AVIR: He and Uma are in Pittsburgh, and one of the doctors who'd been using rapamycin invites them to tour the children's ward at this hospital.

AJAI SEHGAL: There were kidney transplantation survivors who were on my father's drug as part of this clinical trial.

AVIR: And as Suren's being led around this children's transplant ward, the doctor giving the tour said ...

AJAI SEHGAL: This is the guy that invented rapamycin.

UMA SEHGAL: That guy who discovered the drug you are taking.

AVIR: And because of rapamycin, a lot of them were responding to their transplants really well.

AJAI SEHGAL: 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 immunosuppressant. So this was sort of last resort for these kids.

AVIR: The word starts spreading around the hospital.

UMA SEHGAL: Oh, he met so many patients. All the patients wanted to see him.

AVIR: The parents of these kids were like ...

UMA SEHGAL: "Can I shake his hand?" They all wanted to shake his hand. They just wanted to thank him, constantly thank him.

AJAI SEHGAL: For keeping their kids alive.

UMA SEHGAL: He was so happy that it was working.

AVIR: Especially because, at that moment ...

AJAI SEHGAL: He was stage four, and we didn't have much longer with him.

AVIR: Wait. What?

AJAI SEHGAL: My father had been diagnosed with colon cancer.

UMA SEHGAL: It was pretty serious.

AVIR: His doctor said he only had six months to live. But Uma says when Suren got this news ...

UMA SEHGAL: 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."

AVIR: He tells his wife he wanted to be around for his grandkids. But it wasn't just that.

UMA SEHGAL: He said a lot has to go on with my work also.

AVIR: He has so much work that he still wants to do on rapamycin, including his most daring experiment yet.

AJAI SEHGAL: Taking rapamycin.

AVIR: Taking rapamycin to see if it would treat his own cancer.

LATIF: So like, his doctor prescribed him rapamycin?

AJAI SEHGAL: No. No, he was getting it from the lab.

AVIR: He just decided to take it.

AJAI SEHGAL: On his own in pill form.

AVIR: "I believe in this drug, and I think it just might be able to save me."

LATIF: Wait, but why? Like, why would—why would rapamycin help for cancer?

AVIR: Well, think about it, right? Like, what does rapamycin do? It stops cells from growing. So why not cancer cells?

LATIF: Hmm.

AVIR: You know? And no human had ever tried this. It was definitely a long shot. But ...

UMA SEHGAL: He said, "Let me try that."

AVIR: And then the six-month mark comes and goes.

AJAI SEHGAL: The tumor action stopped.

AVIR: Another six months go by, he's still alive.

UMA SEHGAL: Yes, yes.

AVIR: In fact, he's thriving.

UMA SEHGAL: We were traveling all over the world.

AVIR: He's flying to conferences for work.

UMA SEHGAL: We went to Japan. We went to China. We went to Thailand. We went to Europe many times.

AVIR: Another six months, he's publishing papers.

UMA SEHGAL: He was very busy.

AVIR: And another. He's going to his grandkids' birthdays. And another.

AJAI SEHGAL: And then he just kept living, right?

LATIF: Oh, my God. Wow! So, like, what actually is happening? So, like, the rapamycin is, like, slowing—it's, like, freezing the cancer?

AVIR: Well, maybe that's happening, but maybe something even crazier is happening that even Suren had no idea about.

LATIF: Huh!

AVIR: What scientists are now just starting to wrap their head around is that when you turn down mTOR because you don't have enough of the good stuff, it doesn't just say stop. In fact, it deploys a whole 'nother program. And some people call that the starvation protocol. All right, so let's go back to this general contractor guy, right? MTOR.

LATIF: Yeah.

AVIR: 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?"

LATIF: Oh, got it. 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.

AVIR: Yeah, exactly. Some people call that "autophagy," meaning eating yourself, auto-phagy, eating yourself.

LATIF: But what—like, what is the—what is the garbage actually, though, in the cell?

AVIR: 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'd be like, "What is that?" And I came to later learn that that's just junk. It's just deposit sitting there.

LATIF: Huh! And it's, like, clogging up the function of the cell? Is that what's going on?

AVIR: Yeah. That buildup of junk inside our cells over time makes us less efficient. It makes us sick. I talked to a bunch of scientists who study this. One of them, this guy, Matt Kaeberlein ...

MATT KAEBERLEIN: I am a professor of laboratory medicine and pathology at the University of Washington.

AVIR: ... studied the effects of rapamycin on how long mice live.

MATT KAEBERLEIN: And we had this one mouse that kept going and going and going.

AVIR: They named him Ike.

MATT KAEBERLEIN: Ike, if we translated that linearly to human years, was about 125 years old. 130 years, yeah.

AVIR: Ike! Wow!

MATT KAEBERLEIN: [laughs] Right?

LATIF: But is this just, like, one super old mouse who you just made super older?

AVIR: 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.

LATIF: Wow! And so all of this is just because, like, rapamycin is just, like, clearing out all the junk?

AVIR: Yeah. Because all that junk basically causes aging, and over time, will kill us. Like Kaeberlein 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.

MATT KAEBERLEIN: 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.

AVIR: So you're saying that rapamycin reverses Alzheimer's in mice?

MATT KAEBERLEIN: That's right.

LATIF: Wow!

AVIR: 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 Suren. Like, he was given six months in 1998, and now it's 2002.

LATIF: Oh, wow. So, like, almost the—almost the five-year mark.

AVIR: Yeah.

AJAI SEHGAL: Five years when he was supposed to have been dead.

AVIR: He's still taking rapamycin, and he's still alive. And so yeah, maybe some of that anti-aging stuff is happening in Suren's body.

UMA SEHGAL: Actually, there was no cancer in his colon anymore, or the stomach or the liver.

LATIF: I mean, but, like, how do you—how do you know? Like, is there any way of measuring that that's the thing that's prolonging his life?

AVIR: 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? Suren has no idea. That's a mystery in his mind that's actually kind of eating away at him.

AJAI SEHGAL: And one day he goes, and he tells my mom, he says ...

UMA SEHGAL: How do I know? I feel good, but how do I know if it's working or not, my drug is working or not?

AVIR: 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 gonna stay the scientist, right? So he's like, there's only one way I'm going to figure out if rapamycin is keeping me alive."

AJAI SEHGAL: "Uma, the only way I'm gonna know if my drug works is if I stop taking it."

UMA SEHGAL: He was experimenting on himself.

AVIR: And that's what he does.

AJAI SEHGAL: So he stopped taking the drug. And, you know, six months later ...

UMA SEHGAL: It came with vengeance.

AVIR: The cancer ...

UMA SEHGAL: It was—it came into the lungs.

AJAI SEHGAL: It was in his lungs, and he was not gonna last very much longer.

AVIR: And so Uma tells him, like, you made your point.

UMA SEHGAL: I said to him—I begged him to take it.

AVIR: Just start taking the rapamycin again.

LATIF: Yeah.

UMA SEHGAL: He said, No, just—it's okay. Let nature take its course. That's all.

AJAI SEHGAL: He worked until the day he died. He—the day before he died, he was still writing a paper, in bed.

UMA SEHGAL: Without oxygen on his face.

AJAI SEHGAL: Writing a paper on advocating the anti-tumor properties of rapamycin.

UMA SEHGAL: Yeah.

AVIR: Suren died on January 21, 2003.

LATIF: So Suren is gone, but this drug is still alive. It's still here. It's still being used.

AVIR: Yeah. Really, it's just coming to life. It had been approved for 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.

LATIF: Wow!

AVIR: And today, this drug is just a part of my world.

[ARCHIVE CLIP, emergency room: An 86-year-old male, he last had stents placed at NYU three years ago.]

AVIR: Like just the other day ...

[ARCHIVE CLIP, Avir: 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.]

AVIR: A guy came in with a heart attack. Fifty 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.

[ARCHIVE CLIP, Avir: Does that sound like a plan to you?]

[ARCHIVE CLIP, patient: Mm-hmm.]

[ARCHIVE CLIP, Avir: All right.]

AVIR: 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.

LATIF: Oh, wow!

AVIR: 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 this story interesting to me personally, all right, is not rapamycin, per se.

LATIF: Hmm.

AVIR: It's what rapamycin taught us about ourselves. And what is that? So to me, it's like, mTOR, that general contractor protein that rapamycin showed us that we have. It tells our cells 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.

LATIF: Totally.

AVIR: But it turns out the way our bodies do it, and the way every single living species does it is not that way.

LATIF: Hmm!

AVIR: 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.

LATIF: Yeah.

AVIR: And why would nature do that? Well, I think, you know, life is a mix of both of those states. We're never gonna be always fed; we're never gonna be always hungry. We're gonna 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.

LATIF: Mm-hmm.

AVIR: 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.

LATIF: [laughs]

AVIR: It's actually bad for us.

LATIF: [laughs]

AVIR: And we see that everywhere, obviously. Right? Diabetes, hypertension, obesity.

LATIF: Right.

AVIR: 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.

LATIF: 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.

AVIR: Right, exactly. And one of the coolest things I learned while reporting this story is that in a way, that lesson that rapamycin is teaching us about ourselves, that lesson has been present in a place that rapamycin came from for a really long time.

LATIF: Huh. What do you mean?

AVIR: Okay, so when you think about Rapa Nui, Easter Island, you picture these huge mo'ai 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.

LATIF: Hmm.

AVIR: They were feasting. But what most people don't know is that there's this other kind of statue on the island.

SERGIO MATA'U RAPU: Here I'll pull one out here.

AVIR: A very different kind of statue.

SERGIO MATA'U RAPU: My uncle carved this a long time ago, and I sort of inherited it.

AVIR: This is Sergio Mata'u Rapu. He grew up on the island, and he's the one who told me about these statues.

SERGIO MATA'U RAPU: 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.

AVIR: 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 in the island's history.

SERGIO MATA'U RAPU: At one point, we lost our massive trees, and resources started diminishing.

AVIR: 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.

SERGIO MATA'U RAPU: My ancestors, this massive, powerful community who build these giant statues, like, diminishes down to about 111 people.

AVIR: And that, Sergio says, is when they started making these little statues, the mo'ai kavakava. And I mean, when you read the history books about this island, Rapa Nui, right? The history books are gonna say this is a failed island.

SERGIO MATA'U RAPU: That the mo'ai construction is like the pinnacle of my community.

AVIR: But Sergio says that's not how he sees it.

SERGIO MATA'U RAPU: 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.

AVIR: And he says that, you know, 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.

SERGIO MATA'U RAPU: I think the story of Rapa Nui is a metaphor for what rapamycin does in your body. The way that I understand it, the way that rapamycin tricks your body into thinking that you're starving, it being a positive thing, I think oftentimes we on Rapa Nui also realize that having close to nothing is also positive in some ways. It reminds you of what you have.

LATIF: I think my big takeaway from this story is I—like, I need to go to my parents' house and look through every yogurt container in the fridge.

AVIR: [laughs]

LATIF: Because there are a lot of them. And who knows what could be discovered?

AVIR: Well, how many of them have yogurt in them?

LATIF: None. None. None.

AVIR: Right. Exactly. Yeah.

LATIF: Contributing editor Avir Mitra. This episode was produced by Sarah Qari, Pat Walters and Suzie Lechtenberg, with production help from Carin Leong and Rachael Cusick. Fact-checking by Diane Kelly. Special thanks to Richard Miller, Stuart Schreiber, Joanne Van Tilburg, Bethany Halford and Ike the mouse. Thank you very much for listening.

[LISTENER: Hi, this is Kira from Philadelphia, Pennsylvania. Radiolab was created by Jad Abumrad and is edited by Soren Wheeler. Lulu Miller and Latif Nasser are our co-hosts. Suzie Lechtenberg is our executive producer. Dylan Keefe is our director of sound design. Our staff includes: Simon Adler, Jeremy Bloom, Becca Bressler, Rachael Cusick, David Gebel, Matt Kielty, Annie McEwen, Alex Neason, Sarah Qari, Arianne Wack, Pat Walters and Molly Webster, with help from Shima Oliaee, Sarah Sandbach and Carin Leong. Our fact-checkers are Diane Kelly and Emily Krieger.]

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