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(SOUNDBITE OF MUSIC)

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

AVIR MITRA: Hey, Latif.

LATIF NASSER: Hi.

...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...

(SOUNDBITE OF MACHINE BEEPING)

UNIDENTIFIED PERSON: Why don't I go ahead and give...

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

(SOUNDBITE OF ARCHIVED RECORDING)

AVIR MITRA: Tensions are high today - March 26, 2020.

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

(SOUNDBITE OF ARCHIVED RECORDING)

AVIR MITRA: All the ICUs are slammed.

LATIF NASSER: 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 - might even reverse it.

(SOUNDBITE OF MUSIC)

AVIR MITRA: 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.

UNIDENTIFIED PERSON: Recording, then (ph).

AJAI SEHGAL: All right. We are recording.

AVIR MITRA: OK, 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 (ph), Sagal (ph).

AVIR MITRA: So back in 1982...

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

AVIR MITRA: His family was back in Montreal.

AJAI SEHGAL: And one day, it was just - it was around Christmastime, 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 (ph). 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, N.J.

AVIR MITRA: This is Ajai's mom, Uma.

UMA SEHGAL: Uma Sehgal.

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

UMA SEHGAL: It was Ayerst, McKenna & Harrison.

AVIR MITRA: And out of nowhere, one day they say, we're shutting down our Montreal labs. Like, if you want to keep your job, you got to move to New Jersey. So...

AJAI SEHGAL: You know, my parents were moving.

AVIR MITRA: Ajai, he's a good son. He comes home to help 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 MITRA: He's, like, packing things up in boxes, you know, moving dressers.

AJAI SEHGAL: And I was going to pack up the freezer.

AVIR MITRA: And all of a sudden, his dad is like, whoa, whoa, whoa, stop right there. He shows him these little glass jars.

(SOUNDBITE OF MUSIC)

UMA SEHGAL: Like, a few vials.

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

AJAI SEHGAL: Yep.

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

AJAI SEHGAL: Of just - pack in dry ice.

AVIR MITRA: 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 MITRA: 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 going to have is yogurt.

UMA SEHGAL: Yes.

AVIR MITRA: So they took this yogurt container.

UMA SEHGAL: And wrote, do not eat (laughter) - 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 MITRA: (Laughter).

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

UMA SEHGAL: The rest is history (laughter). Yeah.

AVIR MITRA: 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 NASSER: Oh, come on (laughter).

AVIR MITRA: OK, 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 going to 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 NASSER: OK, but are you going to tell me what drug it is, actually?

AVIR MITRA: I will. But not yet 'cause the story isn't just about the drug. All 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 MITRA: Suren was a biologist.

AJAI SEHGAL: A brilliant microbiologist.

AVIR MITRA: 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 MITRA: Suren's dad ran a pharmaceutical plant.

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

AVIR MITRA: 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...

(SOUNDBITE OF MUSIC)

AJAI SEHGAL: ...Everything went to hell in a handbasket, and the partition occurred.

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: As the new dominions of Pakistan and India take over their own affairs, the bloodshed goes on.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: Fleeing from their looted, blood-stained towns, a million displaced persons.

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

(SOUNDBITE OF ARCHIVED RECORDING)

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

AJAI SEHGAL: He got his Ph.D.

AVIR MITRA: 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 (ph) 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 MITRA: 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 MITRA: OK. So do me a favor, Latif. Hold this image of Suren arriving in Canada in 1976 on one side of your mind.

LATIF NASSER: OK.

AVIR MITRA: And on the other side of this split screen...

(SOUNDBITE OF WAVES)

AVIR MITRA: ...I'm going to tell you a very different migration story. This one starts in 1000 A.D.

(SOUNDBITE OF MUSIC)

AVIR MITRA: 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 NASSER: OK.

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

LATIF NASSER: Wow.

AVIR MITRA: 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.

(SOUNDBITE OF MUSIC)

AVIR MITRA: 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 flourished. 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.

(SOUNDBITE OF MUSIC)

AVIR MITRA: And so let's hop forward.

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: It was a beautiful morning - December 13, 1964.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: It is one of the loneliest islands in the world.

AVIR MITRA: This is Easter Island.

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: It sits alone more than 2,000 miles off the coast of South America.

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

AVIR MITRA: Yeah, exactly.

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: Some weighing 30 tons, some 20 feet tall.

AVIR MITRA: These huge, two-story stone heads.

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: No one knows for sure who made them or how long it is they have been staring seaward to mystify the world.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: A medical expedition to Easter Island.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: Isolation has been their protection.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: Prepares blood samples.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: The island was mapped into small squares.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: What is this soil best suited to grow?

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

AVIR MITRA: The dirt was an afterthought for them.

LATIF NASSER: Oh.

AVIR MITRA: 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.

UNIDENTIFIED PERSON: Yes.

AVIR MITRA: 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 NASSER: What does he look like, by the way?

AVIR MITRA: 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 NASSER: You want to explain what an Indian uncle vibe is?

AVIR MITRA: What does it mean to be an Indian uncle? All right.

(SOUNDBITE OF MUSIC)

AVIR MITRA: First of all, they're not your actual uncle.

LATIF NASSER: Not related to you.

AVIR MITRA: Not - definitely not related to you.

LATIF NASSER: Yeah.

AVIR MITRA: 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 NASSER: (Laughter).

AVIR MITRA: 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 know? You're a little cool sometimes.

LATIF NASSER: (Laughter).

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

AJAI SEHGAL: Probably started when I was 8 years old.

LATIF NASSER: (Laughter).

AVIR MITRA: 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 MITRA: ...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 MITRA: So he basically takes the soil.

AJAI SEHGAL: They examined it under the microscope.

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

AJAI SEHGAL: I wonder what it does.

AVIR MITRA: And so...

AJAI SEHGAL: They test it.

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

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

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

AJAI SEHGAL: And then they observe.

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

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

AVIR MITRA: Would just stop growing.

(SOUNDBITE OF MUSIC)

AVIR MITRA: It's like time had just kind of frozen.

LATIF NASSER: Huh. Like, he would have expected that, like, that amount of fungi would just keep, like, dividing and - boop (ph), boop, boop, boop, boop, boop, boop.

AVIR MITRA: 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. So he's like, ooh, maybe this could be an antifungal.

(SOUNDBITE OF ARCHIVED RECORDING)

JOHN MADDEN: Get a tough case of athlete's foot, and you're benched.

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

(SOUNDBITE OF ARCHIVED RECORDING)

JOHN MADDEN: Boom - tough-acting Tinactin.

AVIR MITRA: Maybe something like that, right?

LATIF NASSER: Right.

AVIR MITRA: 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 rapamycin 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.

Wait. Can you even do that?

AJAI SEHGAL: Yeah.

(LAUGHTER)

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

LATIF NASSER: 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, OK, disease - we've got a problem; now let's go find a solution. But this is like the opposite. It's like, OK, we have a solution; let's go find a problem.

AVIR MITRA: (Laughter).

LATIF NASSER: Like, it feels backwards.

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

LATIF NASSER: (Laughter).

AVIR MITRA: ...Which is funny 'cause 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. 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 MITRA: My compound.

AJAI SEHGAL: Yeah (laughter).

AVIR MITRA: He also gives it a name.

AJAI SEHGAL: Rapamycin.

AVIR MITRA: Rapamycin 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.

AJAI SEHGAL: But then there's the problem.

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

AJAI SEHGAL: It had very strong immunosuppressant properties.

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

LATIF NASSER: So it's like Elsa from "Frozen." Like, just anything it touches, it just freezes.

AVIR MITRA: That's exactly his thought.

LATIF NASSER: Wow. OK.

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

UMA SEHGAL: But...

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

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

AVIR MITRA: To them, rapamycin is now useless.

UMA SEHGAL: They ordered the lab to be destroyed.

AVIR MITRA: 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 MITRA: 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.

(SOUNDBITE OF MUSIC)

AVIR MITRA: 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 MITRA: ...He couldn't let go.

UMA SEHGAL: So...

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

LATIF NASSER: (Laughter).

AVIR MITRA: ...He walks over to the trash.

UMA SEHGAL: He picked up from the trash.

AVIR MITRA: He pulled it right out of the trash?

UMA SEHGAL: Mmm hmm. Right out of trash.

AVIR MITRA: (Laughter).

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 MITRA: And smuggled it all the way to New Jersey just 'cause he had this feeling it was going to be big.

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

AVIR MITRA: OK.

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

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

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

Latif.

AVIR MITRA: Avir.

LATIF NASSER: RADIOLAB. OK, so before the break, we met this drug researcher Suren who ended up with a substance called rapamycin from Rapanui, 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 MITRA: 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.

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED REPORTER: Our next major story is from our medical beat.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED REPORTER: Successful kidney transplantation was confined to the tiny world of identical twins.

AVIR MITRA: 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.

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED REPORTER: But as the year ran on...

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED REPORTER: Patients died, sometimes of rejection.

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

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED REPORTER: 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 MITRA: Weren't exactly that great.

UMA SEHGAL: They had lot of side effects.

AVIR MITRA: So Suren thought maybe rapamycin could be used for this. So he pitches it to his new bosses. And they're like, OK, 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 MITRA: About that.

AJAI SEHGAL: Maybe not.

UMA SEHGAL: He came home.

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

AVIR MITRA: 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 MITRA: 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 NASSER: 'Cause he really just has no idea how this stuff works.

AVIR MITRA: 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 MITRA: 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 MITRA: He's an M.D. Ph.D. 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 going to 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 MITRA: And it comes with some vials of rapamycin, too.

DAVID SABATINI: And then I had a note.

AVIR MITRA: Like, a little Post-it note.

DAVID SABATINI: Good luck, Suren.

AVIR MITRA: And so Sabatini's like, I'm going to be the one to figure out how this drug works. Like, that's going to be my Ph.D. 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.

(SOUNDBITE OF TV SHOW, "PINKY AND THE BRAIN")

MAURICE LEMARCHE: (As The Brain) Pinky, are you pondering what I'm pondering?

ROB PAULSEN: (As Pinky) 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 MITRA: Remove its brain.

DAVID SABATINI: Put it into a blender.

AVIR MITRA: Mix this up, make a smoothie.

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

AVIR MITRA: I'm going to 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 NASSER: OK.

AVIR MITRA: 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 attached 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.

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 MITRA: How did you feel?

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

AVIR MITRA: Because he still didn't know what that thing was that the rapamycin was sticking to. That was going to 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, 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 MITRA: And when he tries to look it up in a database, it's not there. 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 NASSER: Oh, wow. So it lives in all of our cells, too?

AVIR MITRA: 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 MITRA: Like, almost a decade.

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

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

DAVID SABATINI: OK. No, 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 MITRA: 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 MITRA: 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? We have all that stuff. mTOR turns up and tells the cell then to grow.

LATIF NASSER: Sure.

AVIR MITRA: 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, 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 MITRA: 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.

(SOUNDBITE OF WHISTLE BLOWING)

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

AVIR MITRA: 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...

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: Transplants are becoming so much easier to perform.

AVIR MITRA: ...Suren...

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: Improved immunosuppressant drugs.

AVIR MITRA: ...Had been sending out rapamycin to all these transplant doctors, and it was working

(SOUNDBITE OF ARCHIVED RECORDING)

UNIDENTIFIED PERSON: Recent medical advances...

AVIR MITRA: 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 NASSER: Wow.

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

AVIR MITRA: 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 MITRA: 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 MITRA: And as Suren's being led around this children's transplant ward, the doctor giving the tour said, this is the guy that invented rapamycin.

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

AVIR MITRA: 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 MITRA: The word starts spreading around the hospital.

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

AVIR MITRA: 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 MITRA: Especially because, at that moment...

AJAI SEHGAL: He was stage 4, and we didn't have much longer with him.

LATIF NASSER: Wait. What?

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

UMA SEHGAL: It was pretty serious.

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

AJAI SEHGAL: Taking rapamycin.

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

LATIF NASSER: So like, his doctor prescribed him rapamycin?

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

AVIR MITRA: He just decided to take it.

AJAI SEHGAL: On his own in pill form.

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

LATIF NASSER: But why? Like, why would - why would rapamycin help for cancer?

AVIR MITRA: Well, think about it. Right? Like, what does rapamycin do? It stops cells from growing. So why not cancer cells? 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 MITRA: And then, the six-month mark comes and goes.

AJAI SEHGAL: The tumor action stopped.

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

UMA SEHGAL: Yes, yes.

AVIR MITRA: In fact, he's thriving.

UMA SEHGAL: We were traveling all over the world.

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

UMA SEHGAL: He was very busy.

AVIR MITRA: And another, he's going to his grandkids' birthdays - and another.

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

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

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

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

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

AVIR MITRA: It's crazy 'cause 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 NASSER: And it's like clogging up the function of the cell? Is that what's going on?

AVIR MITRA: 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 MITRA: ...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 MITRA: They named him Ike.

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

AVIR MITRA: Ike, wow.

MATT KAEBERLEIN: (Laughter) Right.

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

AVIR MITRA: 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 NASSER: Wow. And so all of this is just 'cause, like, rapamycin is just, like, clearing out all the junk?

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

MATT KAEBERLEIN: That's right.

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

LATIF NASSER: Oh, wow, so, like, almost the five-year mark.

AVIR MITRA: Yeah.

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

AVIR MITRA: 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 NASSER: 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?

AVIR MITRA: 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 MITRA: 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 rapamycin is keeping me alive.

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

UMA SEHGAL: He was experimenting on himself.

AVIR MITRA: 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 MITRA: The cancer...

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

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

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

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

AVIR MITRA: Just start taking the rapamycin again.

LATIF NASSER: Yeah.

UMA SEHGAL: He said, no, just - it's OK. 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 antitumor properties of rapamycin.

UMA SEHGAL: Yeah.

AVIR MITRA: Suren died on January 21, 2003.

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

AVIR MITRA: 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 dominos, really - approved for this one, approved for that one, approved for another one.

LATIF NASSER: Wow.

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

UNIDENTIFIED PERSON: An 86-year-old male, he last had stents placed at NYU three years ago.

AVIR MITRA: 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.

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.

Does that sound like a 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.

LATIF NASSER: Oh, wow.

AVIR MITRA: But what makes this 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, mTOR, 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.

LATIF NASSER: Totally.

AVIR MITRA: But it turns out the way our bodies 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, OK, 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 NASSER: Yeah.

AVIR MITRA: And why would nature do that? Well, I think, you know, 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.

LATIF NASSER: (Laughter).

AVIR MITRA: It's actually bad for us.

LATIF NASSER: (Laughter).

AVIR MITRA: And we see that everywhere, obviously, right? - diabetes, hypertension, obesity.

LATIF NASSER: Right.

AVIR MITRA: 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 going to be painful, but it's good for you. I think that's the true lesson that came from the dirt of Easter Island.

LATIF NASSER: 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 MITRA: 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 NASSER: Huh. What do you mean?

AVIR MITRA: OK, 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. 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 MITRA: 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 MITRA: 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 MITRA: 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 MITRA: 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 MITRA: 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 going to say this is a failed island.

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

AVIR MITRA: 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 MITRA: 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.

(SOUNDBITE OF MUSIC)

LATIF NASSER: 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 MITRA: (Laughter).

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

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

LATIF NASSER: None. None. None.

AVIR MITRA: Right. Exactly. Yeah.

(SOUNDBITE OF MUSIC)

LATIF NASSER: 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.

KIRA: Hi. This is Kira (ph) from Philadelphia, Pa. 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.

(SOUNDBITE OF FLEVANS' "FLICKER")

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